Nephronophthisis

Genetic MONDO:0019005 Pathograph 35 Show in embeddings browser Tubulointerstitial Kidney Disease Ciliopathy

Nephronophthisis is a ciliopathy caused by mutations in more than 20 causative genes, with NPHP1 being the most common. Gene products predominantly localize to the ciliary transition zone and basal body, where they regulate ciliary structure and signaling. That generalization has real exceptions, and this entry models them as separate mechanisms rather than folding them into the ciliary node: GLIS2 (NPHP7) is a transcription factor acting on the fibrogenic program, XPNPEP3 (NPHP-like 1) is a mitochondrial aminopeptidase, and MAPKBP1 (NPHP20) is a JNK scaffolding protein that is absent from the cilium and whose patient fibroblasts show no ciliogenesis defect at all. Defective ciliary signaling deranges Wnt, Hedgehog, EGFR, and Hippo/YAP pathways and impairs renal tubular function, driving tubular dysfunction, interstitial fibrosis, and corticomedullary cyst formation. Histopathologically, the disease is characterized by corticomedullary cysts, tubular atrophy, interstitial fibrosis, and cystic dilatation of distal tubules, with kidneys appearing normal early but gradually shrinking with progression. Progressive loss of renal function culminates in end-stage kidney disease, and extrarenal manifestations (retinal degeneration, liver fibrosis, neurologic involvement) occur when ciliary dysfunction affects other organs, defining nephronophthisis-related ciliopathies (NPH-RC).

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Classifications

Harrison's Part

Mechanistic Nosology

👪

Inheritance

Autosomal Recessive

Show evidence (2 references)

PMID:29717526 SUPPORT

"Nephronophthisis is an autosomal recessive cystic kidney disease and one of the most common genetic disorders causing end-stage renal disease in children."

The literature clearly states that nephronophthisis follows an autosomal recessive inheritance pattern.

PMID:31810733 SUPPORT

"There is increasing appreciation of nephronophthisis (NPHP) as an autosomal recessive cause of kidney failure and earlier stages of chronic kidney disease among adults."

The literature confirms that nephronophthisis is inherited in an autosomal recessive manner, even in cases diagnosed in adults.

Tubulointerstitial Fibrosis

Progressive fibrosis of the kidney's tubulointerstitial region.

Show evidence (2 references)

PMID:35533128 SUPPORT

"Nephronophthisis is an autosomal recessive cystic kidney disease... resulting in kidney disease and extrarenal manifestations such as retinal degeneration and liver fibrosis."

The literature indicates that nephronophthisis involves chronic tubulointerstitial changes compatible with fibrosis.

PMID:27169608 SUPPORT

"Chronic tubulointerstitial nephritis (CTN) is characterized by interstitial scarring, fibrosis and tubule atrophy, resulting in progressive chronic kidney disease."

While the article discusses tubulointerstitial nephritis in general, it supports the idea that fibrosis occurs in this region, although it does not specifically discuss nephronophthisis.

◆

Subtypes

Infantile Nephronophthisis MONDO:0011190

INVS hgnc:17870

Early onset in infancy characterized by rapid progression to end-stage renal disease.

Show evidence (1 reference)

PMID:16966065 SUPPORT

"Infantile nephronophtisis is a recessive autosomic tubulo-interstitial nephritis with cortical microcysts which progress to end stage renal failure before age 5."

The source indicates that infantile nephronophthisis is characterized by early onset and rapid progression to end-stage renal disease, supporting the statement.

Juvenile Nephronophthisis

Most common form with onset in childhood and progressive renal failure by adolescence.

Show evidence (2 references)

PMID:16966065 SUPPORT

"Juvenile nephronophtisis, the most frequent, progress to end stage renal failure before age 15."

The provided excerpt states that juvenile nephronophthisis is the most frequent subtype and typically progresses to end-stage renal failure by adolescence.

PMID:35570616 SUPPORT

"Nephronophthisis is the most common genetic cause of kidney failure in childhood... outcomes of kidney transplant recipients with primary diagnosis of juvenile nephronophthisis..."

The excerpt indicates that juvenile nephronophthisis is a common pediatric kidney failure cause, aligning with 'most common form with onset in childhood'.

Adolescent Nephronophthisis

Later onset in teenage years with slower progression to renal failure.

Show evidence (2 references)

PMID:16966065 SUPPORT

"Adolescent nephronophtisis is a less frequent form of nephronophtisis."

The term 'adolescent nephronophthisis' is noted, and it is described as a less frequent form of nephronophthisis which is consistent with later onset.

PMID:16966065 SUPPORT

"Medullary cystic disease is transmitted as an autosomic dominant trait. Clinical and histological signs are similar to nephronophthisis, but the disease progress later to terminal renal failure and is not accompanied by extra-renal symptoms."

Medullary cystic disease presents similar signs but progresses later, implying a slower progression to renal failure, corroborating the adolescent nephronophthisis description.

Late-Onset Nephronophthisis MONDO:0019742

Presentation after adolescence in young adulthood or later, with variable disease progression.

Show evidence (1 reference)

PMID:42400345 SUPPORT

"The clinical spectrum of NPH is broad and can be classified according to the age at onset into infantile, juvenile, adolescent, and late-onset forms."

Recent comprehensive review identifies late-onset nephronophthisis as a distinct clinical form of the disease spectrum.

Nephronophthisis 3 (NPHP3) MONDO:0011456

NPHP3 hgnc:7907

The adolescent-onset molecular form, caused by biallelic NPHP3 variants. Nephrocystin-3 interacts with nephrocystin-1, and the reported families span isolated nephronophthisis, nephronophthisis with hepatic fibrosis, and nephronophthisis with tapeto-retinal degeneration.

Show evidence (3 references)

PMID:12872122 SUPPORT Human Clinical

"We describe mutations in NPHP3 in families with isolated NPHP and in families with NPHP with associated hepatic fibrosis or tapeto-retinal degeneration."

The gene-delineation result for NPHP3 and the source of this row's clinical range.

PMID:12872122 SUPPORT In Vitro

"Here we report the identification of NPHP3, encoding a novel 1,330-amino acid protein that interacts with nephrocystin."

The nephrocystin interaction this row describes, and the basis for wiring NPHP3 alongside the other nephrocystin-module genes.

CGGV:assertion_47c3a0f1-9c14-4c92-83f2-e1105d528097-2021-07-24T160000.000Z SUPPORT Other

ClinGen classifies the gene-disease relationship as Definitive, but curates it against the umbrella class MONDO:0019005 rather than against the numbered class MONDO:0011456 this row binds.

Nephronophthisis 16 (ANKS6) MONDO:0014158

ANKS6 hgnc:26724

Caused by biallelic ANKS6 variants, reported in six families with nephronophthisis that included severe cardiovascular abnormalities, liver fibrosis and situs inversus. ANKS6 sits at the centre of the module that connects NEK8, INVS and NPHP3, which is why those four genes produce overlapping disease.

Show evidence (3 references)

CGGV:assertion_62df8a40-0b65-46a4-89c8-51f26424c523-2021-08-25T160000.000Z SUPPORT Other

ClinGen curates this relationship against MONDO:0014158 itself, the class this row binds, and classifies it Definitive.

PMID:23793029 SUPPORT Human Clinical

"We also identify six families with ANKS6 mutations affected by nephronophthisis, including severe cardiovascular abnormalities, liver fibrosis and situs inversus."

The human genetic evidence and the clinical description this row gives.

PMID:23793029 SUPPORT In Vitro

"Network analyses uncovered additional putative NPHP proteins and placed ANKS6 at the center of this NPHP module, explaining the overlapping disease manifestation caused by mutation in ANKS6, NEK8, INVS or NPHP3."

The module membership this row asserts and the basis for the inversin-compartment pathophysiology node.

Nephronophthisis 20 (MAPKBP1) MONDO:0014997

MAPKBP1 hgnc:29536

Juvenile or late-onset nephronophthisis with massive renal fibrosis, caused by biallelic MAPKBP1 variants. This is the one form in the series that is explicitly cilia-independent: MAPKBP1 is a JNK scaffolding protein absent from the primary cilium, and patient fibroblasts show no ciliogenesis defect. It reaches the shared phenotype through increased DNA damage response signaling instead.

Show evidence (3 references)

CGGV:assertion_b8542450-d48b-45ba-bd5f-4e55d210aa6b-2024-06-10T160000.000Z SUPPORT Other

ClinGen curates this relationship against MONDO:0014997 itself, the class this row binds, and classifies it Definitive.

PMID:28089251 SUPPORT Human Clinical

"In conclusion, we identified mutations in MAPKBP1 as a genetic cause of juvenile or late-onset and cilia-independent NPH."

The gene-delineation conclusion and the source of this row's onset and cilia-independence statements.

PMID:28089251 SUPPORT In Vitro

"Immunofluorescence analyses showed that MAPKBP1 is not present at the primary cilium and that fibroblasts from affected individuals did not display ciliogenesis defects"

The measured absence of a ciliary defect, which is why this gene is not wired to the ciliary nodes of this entry.

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Pathophysiology

Ciliary Dysfunction

Mutations in NPHP genes disrupt the structure and function of primary cilia, which are essential for cell signaling and homeostasis. NPHP gene products predominantly localize to the ciliary transition zone and basal body, where they regulate ciliary structure and signaling.

Renal Tubular Epithelial Cell CL:1000494

NPHP1 hgnc:7905 NPHP3 hgnc:7907 NPHP4 hgnc:19104 INVS hgnc:17870 NEK8 hgnc:13387 CEP164 hgnc:29182 TMEM67 hgnc:28396 DCDC2 hgnc:18141

Primary Cilium GO:0005929 Ciliary Transition Zone GO:0035869 Ciliary Basal Body GO:0036064

Downstream

Impaired Cell Signaling

Show evidence (8 references)

PMID:18199800 SUPPORT In Vitro

"All mutant forms of Nek8 showed defects in ciliary localization to varying degrees; the H431Y mutant (human H425Y) was completely absent from cilia and the amount localized to centrosomes was decreased."

Direct support for this node's claim that NPHP gene products act at the cilium and basal body, and that disease variants disturb that localisation. Measured on transfected NEK8 constructs in IMCD-3 cells.

PMID:19118152 SUPPORT

"Nephronophthisis (NPHP), a recessive cystic kidney disease... Mutations in NPHP genes cause defects in signaling mechanisms that involve the noncanonical Wnt signaling pathway and the sonic hedgehog signaling pathway, resulting in defects of planar cell polarity and tissue maintenance."

The provided snippet indicates that mutations in NPHP genes affect mechanisms that disrupt cellular functions related to cilia, supporting the statement that these mutations lead to impaired cilia.

PMID:42400345 SUPPORT

"More than 20 causative genes have been identified, with NPHP1 being the most common. These genes encode proteins that localize predominantly to the ciliary transition zone and basal body, where they regulate ciliary structure and signaling."

This comprehensive review identifies the ciliary transition zone and basal body as the primary subcellular localization sites of NPHP gene products, establishing the structural basis for their ciliary dysfunction mechanism.

+ 5 more references

Inversin Compartment Module Disruption

INVS (NPHP2), NPHP3, NEK8 (NPHP9) and ANKS6 (NPHP16) form one physical module rather than four independent lesions, with ANKS6 at its centre connecting NEK8 to INVS and NPHP3. Loss of any one member disturbs the same assembly, which is the stated explanation for why variants in the four genes produce overlapping disease.

INVS hgnc:17870 NPHP3 hgnc:7907 NEK8 hgnc:13387 ANKS6 hgnc:26724

proximal cilium GO:0005929

Downstream

Ciliary Dysfunction Disruption of the module removes proteins that act at the cilium, feeding the shared ciliary-dysfunction state of this entry.

Show evidence (3 references)

PMID:23793029 SUPPORT In Vitro

"Here we identify ANKS6 as a new NPHP family member that connects NEK8 (NPHP9) to INVS (NPHP2) and NPHP3."

The module membership of all four genes on this node.

PMID:23793029 SUPPORT In Vitro

"We show that ANKS6 localizes to the proximal cilium and confirm its role in renal development through knockdown experiments in zebrafish and Xenopus laevis."

The ciliary localisation this node's cellular-component binding asserts.

PMID:23793029 SUPPORT In Vitro

The source of this node's claim that the four genes are one lesion rather than four.

Retrograde Intraflagellar Transport Defect

TTC21B (IFT139, NPHP12) and WDR19 (IFT144, NPHP13) are both subunits of intraflagellar transport complex A, which drives retrograde transport back down the ciliary axoneme. Loss of either subunit impairs that transport step rather than the transition-zone gate, which is why they are modeled apart from the transition-zone genes.

TTC21B hgnc:25660 WDR19 hgnc:18340

retrograde intraflagellar transport GO:0035721 ↓ DECREASED

intraflagellar transport complex A GO:0030991

Downstream

Ciliary Dysfunction Failure of retrograde transport perturbs ciliary abundance and morphology, feeding the shared ciliary-dysfunction state of this entry.

Show evidence (3 references)

PMID:22019273 SUPPORT In Vitro

"WDR19 encodes IFT144, a member of the intraflagellar transport (IFT) complex A that drives retrograde ciliary transport."

The complex membership and the retrograde-transport process this node binds.

PMID:22019273 SUPPORT In Vitro

"We show that IFT144 is absent from the cilia of fibroblasts from one of the Sensenbrenner patients and that ciliary abundance and morphology is perturbed, demonstrating the ciliary pathogenesis."

The measured ciliary consequence behind this node's downstream edge.

PMID:21258341 SUPPORT Human Clinical

"Here we show that mutations in TTC21B, which encodes the retrograde intraflagellar transport protein IFT139, cause both isolated nephronophthisis and syndromic Jeune asphyxiating thoracic dystrophy."

Places TTC21B on this node as the second complex A subunit.

Distal Appendage Docking Failure

CEP83 (NPHP18) and CEP164 (NPHP15) are distal appendage proteins of the mother centriole. The distal appendages dock and anchor the mother centriole to the cell membrane at the start of ciliogenesis, and cells from affected individuals show altered appendage composition together with ciliary defects, so this lesion sits upstream of cilium assembly rather than in the assembled cilium.

CEP83 hgnc:17966 CEP164 hgnc:29182

ciliogenesis GO:0060271 ↓ DECREASED

Downstream

Ciliary Dysfunction Failure to dock the mother centriole prevents normal cilium assembly, feeding the shared ciliary-dysfunction state of this entry.

Show evidence (3 references)

PMID:24882706 SUPPORT In Vitro

"The distal appendages (DAPs) of centrioles are involved in the docking and anchoring of the mother centriole to the cellular membrane during ciliogenesis."

The ciliogenesis process this node binds and the function of the structure it is named for.

PMID:24882706 SUPPORT In Vitro

"Fibroblasts and tubular renal cells from affected individuals showed an altered DAP composition and ciliary defects."

The measured appendage and ciliary defect in patient cells, in the tissue this disease affects.

PMID:24882706 SUPPORT BACKGROUND Human Clinical

"mutations in two genes encoding DAPs components (CEP164/NPHP15, SCLT1) have been associated with human ciliopathies, namely nephronophthisis and orofaciodigital syndrome"

Places CEP164 on this node as the other distal appendage gene. Quoted from this paper's framing of prior work rather than from its own CEP83 result.

Mitochondrial Aminopeptidase Deficiency

XPNPEP3 is the one protein in this entry that does not act at the cilium-centrosome complex: it is an X-prolyl aminopeptidase of the mitochondrion. Its connection to the rest of the pathograph is indirect, through ciliary cystogenic proteins that are its substrates and that lose function when N-terminal proline cleavage is blocked.

XPNPEP3 hgnc:28052

X-prolyl aminopeptidase activity GO:0004177 ↓ DECREASED

mitochondrion GO:0005739

Downstream

Ciliary Dysfunction Loss of cleavage of ciliary cystogenic substrates attenuates their function, which is the route by which a mitochondrial enzyme reaches the ciliary state this entry converges on.

Show evidence (3 references)

PMID:20179356 SUPPORT In Vitro

"In contrast to all known NPHP proteins, XPNPEP3 localizes to mitochondria of renal cells."

The mitochondrial localisation this node binds.

PMID:20179356 SUPPORT Human Clinical

"In 2 families with an NPHP-like phenotype, we detected homozygous frameshift and splice-site mutations, respectively, in the X-prolyl aminopeptidase 3 (XPNPEP3) gene."

Names the enzyme class this node's molecular-function binding asserts, and records that the reported alleles are loss-of-function.

PMID:20179356 SUPPORT In Vitro

"Consistent with a role for XPNPEP3 in ciliary function, several ciliary cystogenic proteins were found to be XPNPEP3 substrates, for which resistance to N-terminal proline cleavage resulted in attenuated protein function in vivo in zebrafish."

The substrate relationship behind this node's indirect downstream edge.

Fibrogenic Transcriptional Derepression

GLIS2 (NPHP7) is a transcription factor rather than a ciliary structural protein. In its absence the mouse kidney upregulates genes promoting epithelial-to-mesenchymal transition and fibrosis and develops severe renal atrophy and fibrosis, so this form reaches the fibrotic endpoint of the entry directly rather than through the ciliary nodes.

GLIS2 hgnc:29450

epithelial to mesenchymal transition GO:0001837 ↑ INCREASED

Downstream

Interstitial Fibrosis Derepression of the fibrogenic transcriptional program drives the interstitial fibrosis that is the shared histological endpoint of this entry, without an intervening ciliary lesion.

Show evidence (3 references)

PMID:17618285 SUPPORT Model Organism

"Differential gene expression studies on Glis2 mutant kidneys demonstrate that genes promoting epithelial-to-mesenchymal transition and fibrosis are upregulated in the absence of Glis2."

The transcriptional change this node binds, measured in mouse kidney.

PMID:17618285 SUPPORT Model Organism

"Kidneys of Glis2 mutant mice show severe renal atrophy and fibrosis starting at 8 weeks of age."

The fibrotic outcome this node's downstream edge asserts, in the mouse model.

PMID:17618285 SUPPORT Model Organism

"Thus, we identify Glis2 as a transcription factor mutated in NPHP and demonstrate its essential role for the maintenance of renal tissue architecture through prevention of apoptosis and fibrosis."

The transcription-factor identity this node is named for.

Impaired Cell Signaling

Defective primary cilia lead to disrupted signaling pathways including Wnt, Hedgehog, EGFR, and Hippo/YAP pathways, affecting cell differentiation, proliferation, and polarity. Inversin, the NPHP2 gene product, is the worked case: it acts as a switch between the canonical and non-canonical Wnt cascades, restraining canonical Wnt signaling by targeting cytoplasmic dishevelled for degradation, and its level in ciliated tubular epithelium responds to fluid flow.

INVS hgnc:17870 NEK8 hgnc:13387 DCDC2 hgnc:18141

Downstream

Abnormal Cell Proliferation

DNA Damage and Senescence

Show evidence (9 references)

PMID:15852005 SUPPORT In Vitro

"Here we report that inversin acts as a molecular switch between different Wnt signaling cascades. Inversin inhibits the canonical Wnt pathway by targeting cytoplasmic dishevelled (Dsh or Dvl1) for degradation"

Supplies the mechanism behind the Wnt half of this node and behind the INVS gene binding, naming dishevelled degradation as the step.

PMID:25557784 SUPPORT In Vitro

"We show that DCDC2 interacts with DVL and DCDC2 overexpression inhibits β-catenin-dependent Wnt signaling in an effect additive to Wnt inhibitors."

Places DCDC2 on the Wnt half of this node. It converges on the same dishevelled step as inversin, which is why the two genes sit together here rather than on separate signaling nodes.

PMID:25557784 SUPPORT In Vitro

"A Wnt inhibitor likewise restores ciliogenesis in 3D IMCD3 cultures, emphasizing the importance of Wnt signaling for renal tubulogenesis."

The pharmacological rescue tying the Wnt defect to renal tubulogenesis, which is what this node's downstream edges assert.

+ 6 more references

Renal Tubular Dysfunction

Ciliary dysfunction in renal tubular epithelial cells impairs fluid and electrolyte balance, leading to polyuria and polydipsia.

Renal Tubule UBERON:0009773

Downstream

Polyuria

Polydipsia

Electrolyte Imbalance

Interstitial Fibrosis

Show evidence (4 references)

PMID:21071979 SUPPORT

"Nephronophthisis is a recessive disorder of the kidney that is the leading cause of end-stage renal failure in children. Through positional cloning, many of the causative mutations have been mapped to genes involved in centrosome and cilia function."

The literature supports that nephronophthisis is related to ciliary dysfunction, but it does not explicitly mention polyuria and polydipsia as part of its pathophysiology.

PMID:16186680 SUPPORT

"Renal tubular disorders may affect multiple (e.g., Fanconi syndrome) or specific (e.g., nephrogenic diabetes insipidus, renal glucosuria) tubular functions. Most conditions are primary and monogenic but occasionally are secondary to other disorders."

The reference discusses renal tubular disorders, which can result in polyuria and electrolyte imbalance, but it does not explicitly link these to ciliary dysfunction in nephronophthisis.

PMID:9790573 SUPPORT

"Cysts originate within the glomeruli and all tubular structures, and their growth is the result of proliferation of incompletely differentiated epithelial cells and the accumulation of fluid within the cysts."

While the reference discusses fluid accumulation and cyst formation in polycystic kidney disease, it does not directly link these to nephronophthisis or explicitly mention polyuria.

+ 1 more reference

Interstitial Fibrosis

Chronic tubular dysfunction and inflammation lead to the accumulation of extracellular matrix and progressive interstitial fibrosis.

Renal Interstitial Fibroblast CL:1000692

Kidney Interstitium UBERON:0005215

Show evidence (2 references)

PMID:35533128 SUPPORT

"Diagnosis is made by a positive genetic test, or a kidney biopsy demonstrating chronic tubulointerstitial changes with thickening of the tubular basement membranes."

The diagnosis of nephronophthisis includes tubulointerstitial changes, which aligns with chronic tubular dysfunction and inflammation leading to interstitial fibrosis.

PMID:31399984 SUPPORT

"Renal interstitial lymphangiogenesis is found in patients with chronic kidney disease (CKD) and a series of animal models of renal fibrosis."

While the study focuses on lymphangiogenesis, it mentions renal interstitial fibrosis related to chronic kidney disease, of which nephronophthisis is a type.

Renal Cyst Formation

Abnormal cell proliferation and differentiation result in the formation of cysts in the kidney tubules, contributing to the loss of renal function.

Renal Tubule UBERON:0009773

Downstream

Renal Insufficiency

Show evidence (2 references)

PMID:16966065 SUPPORT

"Nephronophthisis is a chronic tubulo-interstitial nephritis which progress to terminal renal failure."

The statement claims that abnormal cell proliferation and differentiation result in cyst formation in nephronophthisis, but the literature describes nephronophthisis as a chronic tubulo-interstitial nephritis without indicating cyst formation due to abnormal cell proliferation and differentiation as a characteristic pathophysiological mechanism. Instead, it mentions cortical microcysts in infantile forms but emphasizes interstitial fibrosis and tubular basement membrane changes.

PMID:25575298 NO_EVIDENCE

"Almost all of proteins associated with a broad spectrum of human cystic kidney diseases have been localized to the region in or around the cilia."

While this reference discusses abnormal cilia structure and function in cystic kidney diseases, it does not specifically address nephronophthisis or the mechanism of abnormal cell proliferation and differentiation leading to renal cyst formation in nephronophthisis.

Renal Insufficiency

The combination of tubular dysfunction, interstitial fibrosis, and cyst formation leads to a gradual decline in renal function and eventual end-stage renal disease (ESRD).

Show evidence (2 references)

PMID:16966065 SUPPORT

"Nephronophthisis is a chronic tubulo-interstitial nephritis which progress to terminal renal failure... Histologic lesions concern tubular basement membranes which are thickened and multilayered or thinned. There is an associated interstitial fibrosis."

The provided excerpt mentions chronic tubulo-interstitial nephritis (tubular dysfunction and interstitial fibrosis) and progression to terminal renal failure, supporting the statement that these factors contribute to ESRD.

PMID:10352410 SUPPORT

"Progressive renal disease poses an increasing problem for the medical community. Though the causes of end-stage renal failure are multiple, the histologic pictures of chronic renal disease are remarkably similar being characterized by interstitial infiltration, fibrosis, tubular atrophy and dilatation."

This literature indicates the role of interstitial infiltration, fibrosis, and tubular atrophy leading to ESRD, which partially overlaps with the factors mentioned in the statement. However, cyst formation specific to nephronophthisis was not explicitly mentioned.

Extrarenal Manifestations

When extrarenal organs such as the retina, liver, or central nervous system are affected by ciliary dysfunction, the condition is designated as nephronophthisis-related ciliopathies (NPH-RC), which affects 10-20% of nephronophthisis cases. Examples include Senior-Loken syndrome (nephronophthisis plus retinal degeneration) and syndromic forms with liver fibrosis or neurological involvement.

Liver UBERON:0002107 Retina UBERON:0000966 Brain UBERON:0000955

Show evidence (5 references)

PMID:42400345 SUPPORT

"When extrarenal organs such as the retina, liver, or central nervous system are affected, the condition is defined as nephronophthisis-related ciliopathies (NPH-RC)."

This comprehensive review defines the NPH-RC classification based on extrarenal involvement, distinguishing syndromic forms from nonsyndromic nephronophthisis.

PMID:35533128 SUPPORT

"Nephronophthisis is an autosomal recessive cystic kidney disease caused by mutations in genes that encode proteins involved in the primary cilia function, resulting in kidney disease and extrarenal manifestations such as retinal degeneration and liver fibrosis."

The literature supports the involvement of the liver and retina in nephronophthisis but does not mention the brain specifically in this context.

PMID:32432520 SUPPORT

"Senior-Løken syndrome (SLS) is a rare autosomal recessive disease characterised by nephronophthisis and retinal degeneration, and belongs to a group of genetically heterogeneous disorders known as the ciliopathies."

The literature supports the involvement of the retina in Senior-Loken syndrome but does not mention the liver or brain specifically in this context.

+ 2 more references

Progression and Severity

The age of onset and rate of progression vary depending on the specific NPHP gene mutations and the type of nephronophthisis.

Show evidence (4 references)

PMID:34828368 SUPPORT

"NPHP gene types present with some common pathophysiological features alongside a diverse range of extra-renal phenotypes associated with specific syndromic presentations."

The reference states that there is diversity in pathophysiological features and extra-renal phenotypes among different NPHP gene types, which supports the statement that the age of onset and rate of progression vary.

PMID:35570616 SUPPORT

"Nephronophthisis is the most common genetic cause of kidney failure in childhood....Treatment for nephronophthisis is symptomatic, and kidney transplant is a good treatment option when kidney failure has developed."

While this reference highlights the general management of nephronophthisis, it implies variability in progression and severity since not all individuals progress to kidney failure at the same rate.

PMID:35922195 SUPPORT

"All 6 children progressed to end-stage renal disease (ESRD) within 10 (4, 65) months of onset."

The reference indicates variability in the progression to end-stage renal disease, supporting the statement regarding variable progression rates depending on the specific NPHP gene mutations.

+ 1 more reference

Abnormal Cell Proliferation

Dysregulated cell division and growth

DNA Damage and Senescence

NPHP1 deficiency impairs DNA damage repair, leading to increased cellular senescence and contributing to interstitial fibrosis. Nephrocystin-1 translocates to the nucleus after DNA damage stress.

NPHP1 hgnc:7905 CEP164 hgnc:29182 ZNF423 hgnc:16762 MAPKBP1 hgnc:29536

Nucleus GO:0005634 Renal Tubule UBERON:0009773

Downstream

Interstitial Fibrosis

Show evidence (4 references)

PMID:22863007 SUPPORT Human Clinical

"We thereby identified recessive mutations of CEP164 as a new cause of NPHP-RC."

CEP164 is the nephronophthisis gene whose discovery paper places the disorder on the DNA-damage-response axis this node models, which is why the gene is bound here as well as on the CEP164-related subtype row.

PMID:22863007 SUPPORT Human Clinical

"Here, we identify by whole-exome resequencing, mutations of MRE11, ZNF423, and CEP164 as causing NPHP-RC. All three genes function within the DNA damage response (DDR) pathway."

Places ZNF423 on this node alongside CEP164, and states the pathway assignment the node is built on.

PMID:22863007 SUPPORT In Vitro

"We show that knockdown of CEP164 or ZNF423 causes sensitivity to DNA damaging agents"

The measured DNA-damage sensitivity behind both gene bindings, rather than pathway membership alone.

+ 1 more reference

Aberrant Actin Remodeling and Hippo Activation

Ciliary dysfunction leads to aberrant RhoA signaling from the centrosome, activating ROCK and engaging Hippo signaling. This contributes to cystogenesis, fibrosis, and inflammation. GEF-H1 knockdown can rescue phenotypes in NPHP1 models.

Ciliary Base GO:0097546 Centrosome GO:0005813

Downstream

Renal Cyst Formation

Interstitial Fibrosis

✶

Histopathology

Corticomedullary Cyst Formation VERY_FREQUENT

Progressive development of cysts in the corticomedullary junction and distal tubules, characteristic of nephronophthisis. Early disease may show normal-appearing kidneys that gradually shrink with cyst progression.

Show evidence (2 references)

PMID:42400345 SUPPORT

"Histopathologically, NPH is characterized by corticomedullary cysts, tubular atrophy, interstitial fibrosis, and cystic dilatation of distal tubules. The kidneys may appear normal in early stages but gradually shrink with disease progression."

This comprehensive review provides detailed histopathological characterization of NPH, establishing corticomedullary cysts as the primary morphological feature with progressive kidney shrinkage.

PMID:16966065 SUPPORT

"Infantile nephronophtisis is a recessive autosomic tubulo-interstitial nephritis with cortical microcysts which progress to end stage renal failure before age 5."

Historical literature confirms cortical microcysts as a pathological hallmark of nephronophthisis.

Tubular Atrophy and Dilatation VERY_FREQUENT

Progressive atrophy of renal tubules with dilatation of distal tubules, contributing to loss of nephron function and interstitial fibrosis.

Show evidence (2 references)

PMID:42400345 SUPPORT

"Histopathologically, NPH is characterized by corticomedullary cysts, tubular atrophy, interstitial fibrosis, and cystic dilatation of distal tubules."

Tubular atrophy and distal tubule dilatation are key pathological findings that contribute to progressive renal insufficiency in nephronophthisis.

PMID:16966065 SUPPORT

"Histologic lesions concern tubular basement membranes which are thickened and multilayered or thinned. There is an associated interstitial fibrosis."

Tubular basement membrane abnormalities and interstitial fibrosis accompany tubular atrophy in nephronophthisis pathology.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Cardiovascular 1

Hypertension FREQUENT HP:0000822

Show evidence (6 references)

PMID:17647025 NO_EVIDENCE

"Among the causes of secondary hypertension are a group of disorders with a Mendelian inheritance pattern. Recent advances in molecular biology have unveiled the pathogenesis of hypertension in many of these conditions."

While this reference mentions Mendelian forms of hypertension, there is no specific mention of Nephronophthisis resulting in hypertension or cardiovascular phenotypes generally.

PMID:20969579 NO_EVIDENCE

"A Mendelian inheritance underlies a nonnegligible proportion of hereditary kidney diseases, suggesting that the encoded proteins are essential for maintenance of the renal function."

This reference discusses hereditary kidney diseases and the genetic mutations involved but does not mention Nephronophthisis or its cardiovascular phenotypes including hypertension.

PMID:12589180 NO_EVIDENCE

"Defective transduction of the dopamine receptor signal in the kidney..."

The article discusses the role of dopamine in the kidney and its involvement in hypertension, but it does not address Nephronophthisis or whether hypertension is a common cardiovascular phenotype in this condition.

+ 3 more references

Digestive 1

Fibrosis OCCASIONAL Hepatic fibrosis HP:0001395

Show evidence (1 reference)

PMID:35533128 SUPPORT

The literature mentions liver fibrosis as an extrarenal manifestation of nephronophthisis, supporting the statement that hepatic fibrosis is an occasional phenotype category of nephronophthisis.

Endocrine 1

Secondary Hyperparathyroidism OCCASIONAL HP:0000867

Develops as a consequence of chronic renal failure

Show evidence (1 reference)

PMID:16966065 REFUTE

"Nephronophthisis is a chronic tubulo-interstitial nephritis which progress to terminal renal failure."

Nephronophthisis is a type of chronic tubulo-interstitial nephritis and not an endocrine disorder. It primarily affects the kidneys and progresses to terminal renal failure, but it is not categorized as an endocrine disorder nor is it specifically associated with secondary hyperparathyroidism.

Eye 1

Retinitis Pigmentosa OCCASIONAL Rod-cone dystrophy HP:0000510

Show evidence (3 references)

PMID:16966065 SUPPORT

"Some children present with extrarenal symptoms: tapetoretinal degeneration (Senior-Loken syndrome)..."

This reference indicates that tapetoretinal degeneration, synonymous with retinitis pigmentosa in the context of this disease, is an occasional extrarenal symptom of nephronophthisis.

PMID:25161209 SUPPORT

"The renal lesions were characterized by diffuse renal cyst development with tubulointerstitial nephropathy...These renal and retinal lesions are most similar to those associated with nephronophthisis (NPHP) and retinitis pigmentosa in humans."

This reference directly confirms the association between nephronophthisis and retinitis pigmentosa as occasional ophthalmologic phenotypes.

PMID:37644229 SUPPORT

"Eighty-two of the 86 pediatric-onset renal ciliopathies (95%) have an ocular phenotype, including inherited retinal degeneration, oculomotor disorders, and coloboma."

This indicates that ophthalmologic phenotypes, including retinal degeneration, are common in pediatric renal ciliopathies including nephronophthisis.

Genitourinary 3

Progressive Renal Failure VERY_FREQUENT Chronic kidney disease HP:0012622

Sequelae: End-Stage Renal Disease

Show evidence (3 references)

PMID:16966065 SUPPORT

"Nephronophthisis is a chronic tubulo-interstitial nephritis which progress to terminal renal failure."

This abstract describes nephronophthisis as a progressive renal disease leading to end-stage renal failure, supporting the idea that progressive renal failure is a frequent and diagnostic feature.

PMID:33323469 SUPPORT

"Nephronophthisis-related ciliopathies (NPHP-RC) account for the majority of cases of monogenetically caused end-stage renal disease (ESRD) in children."

This reference states that nephronophthisis-related ciliopathies are a common cause of end-stage renal disease in children, confirming that progressive renal failure and progression to ESRD is common.

PMID:20969579 SUPPORT

"A Mendelian inheritance underlies a nonnegligible proportion of hereditary kidney diseases, suggesting that the encoded proteins are essential for maintenance of the renal function."

While the abstract primarily discusses hereditary kidney diseases in general, it emphasizes the importance of kidney function maintenance in genetic diseases, indirectly supporting the frequency and importance of progressive renal failure in conditions like nephronophthisis.

Polyuria FREQUENT HP:0000103

End-Stage Renal Disease FREQUENT Stage 5 chronic kidney disease HP:0003774

Metabolism 1

Electrolyte Imbalance FREQUENT Abnormal blood ion concentration HP:0003111

Nervous System 1

Polydipsia FREQUENT HP:0001959

Growth 1

Growth Retardation OCCASIONAL Growth delay HP:0001510

May be seen due to chronic kidney disease

Show evidence (2 references)

PMID:16966065 SUPPORT

"Some children present with extrarenal symptoms: tapetoretinal degeneration (Senior-Loken syndrome), mental retardation, cerebellar ataxia, bone anomalies or liver involvement."

The reference mentions extrarenal symptoms associated with nephronophthisis but does not specifically mention growth retardation. However, growth retardation could be inferred as a potential consequence of chronic kidney disease.

PMID:30552565 SUPPORT

"Growth retardation is a major feature of chronic kidney disease (CKD) of onset in infants or children and is associated with increased morbidity and mortality."

This reference supports the statement that growth retardation is associated with chronic kidney disease, which can be a consequence of nephronophthisis.

Other 1

Bone Deformities OCCASIONAL

Related to renal osteodystrophy from kidney failure

Show evidence (2 references)

PMID:35533128 NO_EVIDENCE

The provided literature does not mention musculoskeletal issues or bone deformities as part of the clinical manifestations of nephronophthisis.

PMID:27219042 NO_EVIDENCE

"Recent findings substantiate concern regarding the particular vulnerability of the growing skeleton to chronic renal disease."

Although chronic kidney disease can lead to musculoskeletal issues, the literature does not specifically link nephronophthisis to bone deformities related to renal osteodystrophy.

🧬

Genetic Associations

NPHP1 (Pathogenic Variants)

Gene: NPHP1 hgnc:7905

Show evidence (2 references)

PMID:15138899 SUPPORT

"Two siblings affected with a mild form of JS were found to have a homozygous deletion of the NPHP1 gene identical, by mapping, to that in subjects with NPHP alone."

The NPHP1 gene deletion is associated with juvenile nephronophthisis, confirming the genetic link between NPHP1 and nephronophthisis.

PMID:36990420 SUPPORT

"Patients with pathogenic variants in CEP290 or IQCB1 presented early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4 variants first developed nephropathy."

This reference supports the genetic association of nephronophthisis with variants in several genes, highlighting NPHP1 among the genes associated with nephropathy.

CEP164 (Pathogenic Variants)

Gene: CEP164 hgnc:29182

Show evidence (1 reference)

PMID:22863007 SUPPORT Human Clinical

"We thereby identified recessive mutations of CEP164 as a new cause of NPHP-RC."

Recessive CEP164 mutations define NPHP15 (MONDO:0013917), the CEP164-related nephronophthisis leaf class, and link the disorder to DNA-damage-response signaling.

NPHP3 (Pathogenic Variants)

Gene: NPHP3 hgnc:7907 relationship_type: CAUSATIVE

Show evidence (4 references)

PMID:34212438 SUPPORT

"we detected a homozygous predicted synonymous allele in NPHP3 in two children with hepatorenal fibrocystic disease from a consanguineous family."

PMID:26184788 SUPPORT

"Eight of 17 (47.1%) patients detected were identified to have mutations in NPHP3."

PMID:36990420 SUPPORT

"Patients with pathogenic variants in CEP290 or IQCB1 presented early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4 variants first developed nephropathy."

+ 1 more reference

NPHP4 (Pathogenic Variants)

Gene: NPHP4 hgnc:19104 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:14750102 SUPPORT

"Nephronophthisis (NPH) is an autosomal recessive kidney disease... Four genes responsible for different types of NPH have been identified: NPHP1, NPHP2, NPHP3, and NPHP4."

The literature identifies NPHP4 as one of the genes responsible for different types of Nephronophthisis.

PMID:34591160 SUPPORT

"Nephronophthisis (NPHP) 4 gene encoding nephrocystin-4... contributes to end-stage renal disease in children and young adults."

The literature indicates that NPHP4 is associated with end-stage renal disease in Nephronophthisis, highlighting its pathogenic role.

PMID:36990420 SUPPORT

"Senior-Loken syndrome (SLSN) is an autosomal recessive disorder characterized by retinopathy and nephronophthisis... Patients with pathogenic variants in CEP290 or IQCB1 presented early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4 variants first developed nephropathy."

The literature mentions that patients with NPHP4 variants develop nephropathy in the context of Nephronophthisis.

INVS (Pathogenic Variants)

Gene: INVS hgnc:17870 relationship_type: CAUSATIVE

Show evidence (4 references)

PMID:15852005 SUPPORT In Vitro

"Mutations of the ciliary protein inversin cause nephronophthisis type II, an autosomal recessive cystic kidney disease characterized by extensive renal cysts, situs inversus and renal failure."

Supports the NPHP2 designation in this record's note and the gene-disease relationship itself.

PMID:15852005 SUPPORT In Vitro

"Inversin inhibits the canonical Wnt pathway by targeting cytoplasmic dishevelled (Dsh or Dvl1) for degradation"

Supports the canonical-Wnt antagonism this record's note asserts, which previously carried no citation.

PMID:14750102 SUPPORT

"Nephronophthisis (NPH) is an autosomal recessive kidney disease... Four genes responsible for different types of NPH have been identified: NPHP1, NPHP2, NPHP3, and NPHP4."

The literature identifies NPHP2 (INVS) as one of the genes responsible for different types of Nephronophthisis.

+ 1 more reference

NEK8 (Pathogenic Variants)

Gene: NEK8 hgnc:13387 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:18199800 SUPPORT Human Clinical

"We identified 3 different amino acid changes that were conserved through evolution (L330F, H425Y, and A497P) and that were absent from at least 80 ethnically matched controls."

The human genetic evidence for the NEK8-nephronophthisis relationship this record asserts, from a 588-patient mutational screen.

PMID:18199800 SUPPORT In Vitro

"Our genetic and functional data support the assumption that mutations in NEK8 cause nephronophthisis (NPHP9), adding another link between proteins mutated in cystic kidney disease and their localization to cilia and centrosomes."

The authors' own conclusion, and the source of the NPHP9 designation used in this record's note.

PMID:36990420 NO_EVIDENCE Human Clinical

"Patients with pathogenic variants in CEP290 or IQCB1 presented early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4 variants first developed nephropathy."

Retained for the genetic-heterogeneity context it gives, but regraded to NO_EVIDENCE: the quoted sentence does not mention NEK8 and so does not bear on this gene-disease claim. The previous SUPPORT grading was contradicted by its own explanation.

GLIS2 (Pathogenic Variants)

Gene: GLIS2 hgnc:29450 relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (3 references)

PMID:17618285 SUPPORT Human Clinical

"Here we identify mutation of GLIS2 as causing an NPHP-like phenotype in humans and mice, using positional cloning and mouse transgenics, respectively."

The gene-delineation result for GLIS2.

PMID:17618285 SUPPORT Model Organism

"Thus, we identify Glis2 as a transcription factor mutated in NPHP and demonstrate its essential role for the maintenance of renal tissue architecture through prevention of apoptosis and fibrosis."

The transcription-factor identity and the tissue-maintenance role this record's note asserts.

CGGV:assertion_c51be76f-59d3-4884-9df3-4416686848ab-2024-06-27T160000.000Z SUPPORT Other

ClinGen's gene-disease validity call, graded Moderate, against the class this gene's subtype row binds.

TMEM67 (Pathogenic Variants)

Gene: TMEM67 hgnc:28396 relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (3 references)

PMID:19508969 SUPPORT Human Clinical

"Hypomorphic MKS3/TMEM67 mutations cause NPHP with liver fibrosis (NPHP11)."

The gene-delineation conclusion and the source of the NPHP11 designation in this record's note.

PMID:19508969 SUPPORT Human Clinical

"In contrast, the mutations detected here in patients with NPHP and associated liver fibrosis are exclusively missense mutations."

The allele-class contrast this record's note asserts.

CGGV:assertion_8f380d4b-6d0b-4c09-a3ae-ec34bc8ecb8d-2021-07-14T160000.000Z SUPPORT Other

ClinGen classifies the gene Definitive, against its lumped ciliopathy class rather than the numbered nephronophthisis class.

TTC21B (Pathogenic Variants)

Gene: TTC21B hgnc:25660 relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (3 references)

CGGV:assertion_60f93fe0-145f-47a7-9ecf-613b1b1dfa7f-2021-11-10T170000.000Z SUPPORT Other

ClinGen classifies this relationship Definitive against the numbered class itself.

PMID:21258341 SUPPORT Human Clinical

The gene-delineation result and the IFT139 identity in this record's note.

PMID:21258341 SUPPORT Human Clinical

"in vivo and in vitro evaluations showed a significant enrichment of pathogenic alleles in cases (P < 0.003), suggesting that TTC21B contributes pathogenic alleles to ∼5% of ciliopathy cases"

The modifier-allele contribution this record's note asserts.

WDR19 (Pathogenic Variants)

Gene: WDR19 hgnc:18340 relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (3 references)

PMID:22019273 SUPPORT Human Clinical

"Independently, we also identified compound heterozygous WDR19 mutations by exome sequencing in a Moroccan family with isolated nephronophthisis."

The isolated-nephronophthisis presentation that makes this gene a nephronophthisis gene rather than only a skeletal-ciliopathy gene.

PMID:22019273 SUPPORT In Vitro

"WDR19 encodes IFT144, a member of the intraflagellar transport (IFT) complex A that drives retrograde ciliary transport."

The IFT144 identity and complex membership in this record's note, and the basis for wiring it with TTC21B.

CGGV:assertion_418a6e41-45ad-411f-a40d-2f7cb61ff589-2022-05-25T160000.000Z SUPPORT Other

ClinGen classifies the gene Definitive, against its lumped ciliopathy class rather than the numbered nephronophthisis class.

ZNF423 (Pathogenic Variants)

Gene: ZNF423 hgnc:16762 relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (3 references)

PMID:22863007 SUPPORT Human Clinical

"Here, we identify by whole-exome resequencing, mutations of MRE11, ZNF423, and CEP164 as causing NPHP-RC. All three genes function within the DNA damage response (DDR) pathway."

The gene-delineation result for ZNF423 and the pathway assignment this record's note states.

PMID:22863007 SUPPORT In Vitro

"We show that knockdown of CEP164 or ZNF423 causes sensitivity to DNA damaging agents"

The functional DNA-damage phenotype behind wiring ZNF423 to the DNA damage node.

CGGV:assertion_c61623dd-07b1-41c5-b445-3f9f8575cc06-2024-06-26T040000.000Z SUPPORT Other

ClinGen's gene-disease validity call, graded Moderate and made against the lumped ciliopathy class.

ANKS6 (Pathogenic Variants)

Gene: ANKS6 hgnc:26724 relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (3 references)

CGGV:assertion_62df8a40-0b65-46a4-89c8-51f26424c523-2021-08-25T160000.000Z SUPPORT Other

ClinGen classifies this relationship Definitive against the numbered class itself.

PMID:23793029 SUPPORT Human Clinical

"We also identify six families with ANKS6 mutations affected by nephronophthisis, including severe cardiovascular abnormalities, liver fibrosis and situs inversus."

The human genetic evidence for the ANKS6-nephronophthisis relationship.

PMID:23793029 SUPPORT In Vitro

The module membership this record's note asserts.

CEP83 (Pathogenic Variants)

Gene: CEP83 hgnc:17966 relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (3 references)

PMID:24882706 SUPPORT Human Clinical

"In summary, we have identified mutations in CEP83, another DAP-component-encoding gene, as a cause of infantile nephronophthisis associated with central nervous system abnormalities in half of the individuals."

The gene-delineation conclusion for CEP83.

PMID:24882706 SUPPORT In Vitro

"Fibroblasts and tubular renal cells from affected individuals showed an altered DAP composition and ciliary defects."

The measured distal-appendage and ciliary defect in patient cells, which is how this gene is wired.

PMID:24882706 SUPPORT In Vitro

"The distal appendages (DAPs) of centrioles are involved in the docking and anchoring of the mother centriole to the cellular membrane during ciliogenesis."

The distal-appendage function this record's note states.

DCDC2 (Pathogenic Variants)

Gene: DCDC2 hgnc:18141 relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (4 references)

PMID:25557784 SUPPORT Human Clinical

"We here identify mutations of DCDC2 as causing a renal-hepatic ciliopathy."

The gene-delineation result for DCDC2.

PMID:25557784 SUPPORT In Vitro

"Knockdown of Dcdc2 in IMCD3 cells disrupts ciliogenesis, which is rescued by wild-type (WT) human DCDC2, but not by constructs that reflect human mutations."

The ciliogenesis requirement behind wiring DCDC2 to the ciliary node.

PMID:25557784 SUPPORT In Vitro

"We show that DCDC2 interacts with DVL and DCDC2 overexpression inhibits β-catenin-dependent Wnt signaling in an effect additive to Wnt inhibitors."

The Wnt arm this record's note asserts, and the basis for also wiring DCDC2 to the signaling node.

+ 1 more reference

MAPKBP1 (Pathogenic Variants)

Gene: MAPKBP1 hgnc:29536 relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (4 references)

CGGV:assertion_b8542450-d48b-45ba-bd5f-4e55d210aa6b-2024-06-10T160000.000Z SUPPORT Other

ClinGen classifies this relationship Definitive against the numbered class itself.

PMID:28089251 SUPPORT Human Clinical

"In conclusion, we identified mutations in MAPKBP1 as a genetic cause of juvenile or late-onset and cilia-independent NPH."

The gene-delineation conclusion and the source of the cilia-independence in this record's note.

PMID:28089251 SUPPORT In Vitro

"Immunofluorescence analyses showed that MAPKBP1 is not present at the primary cilium and that fibroblasts from affected individuals did not display ciliogenesis defects"

The measured absence of a ciliary phenotype, which is why this gene is not on the ciliary nodes.

+ 1 more reference

XPNPEP3 (Pathogenic Variants)

Gene: XPNPEP3 hgnc:28052 relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (4 references)

CGGV:assertion_c1fd65c6-6010-4ee7-bb1c-e347c539127c-2024-06-10T160000.000Z SUPPORT Other

ClinGen classifies this relationship Definitive against the class this gene's subtype row binds.

PMID:20179356 SUPPORT Human Clinical

"In 2 families with an NPHP-like phenotype, we detected homozygous frameshift and splice-site mutations, respectively, in the X-prolyl aminopeptidase 3 (XPNPEP3) gene."

The gene-delineation result and the source of the biallelic inheritance recorded here.

PMID:20179356 SUPPORT In Vitro

"In contrast to all known NPHP proteins, XPNPEP3 localizes to mitochondria of renal cells."

The mitochondrial localisation this record's note asserts.

+ 1 more reference

💊

Medical Actions

Renal Replacement Therapy

Action: renal dialysis Ontology label: Dialysis NCIT:C15221

Dialysis or kidney transplantation for end-stage renal disease.

Show evidence (2 references)

PMID:32906116 SUPPORT

"Nephronophthisis (NPHP) is an autosomal recessive disease manifesting as tubulointerstitial nephritis uniformly progressing to ESRD in approximately 5-10% patients in childhood. Living donor transplantation is the most beneficial mean of renal replacement therapy compared to other methods."

The abstract discusses that Nephronophthisis often leads to end-stage renal disease (ESRD) and mentions living donor transplantation as a beneficial renal replacement therapy option.

PMID:15715116 SUPPORT

"Diabetes and ESRD receiving Renal Replacement Therapy (RRT)... The main choices of modalities are: 1) haemodialysis (HD), 2) Peritoneal dialysis (PD), 3) Kidney transplantation alone (KTA) or 4) simultaneous kidney and pancreas transplantation (SPKT)."

Although this reference focuses on diabetic nephropathy, it supports the statement that renal replacement therapies for ESRD include dialysis and kidney transplantation.

Antihypertensive Therapy

Action: Pharmacotherapy NCIT:C15986

Management of blood pressure with medications.

Show evidence (2 references)

PMID:36224286 SUPPORT

"Chronic kidney disease (CKD) is one of the strongest risk factors for hypertension, and hypertension can exacerbate the progression of CKD... therefore, one of the best strategies to slow the progression of CKD is to maintain the 'numbers' of these essential components necessary to preserve..."

This source suggests that managing blood pressure is essential in the context of CKD, which is related to nephron function. However, it does not explicitly mention Nephronophthisis, a specific type of nephropathy.

PMID:30354828 NO_EVIDENCE

"Resistant hypertension (RH) is defined as above-goal elevated blood pressure (BP) in a patient despite the concurrent use of 3 antihypertensive drug classes...evaluation includes identification of contributing lifestyle issues, detection of drugs interfering with antihypertensive medication..."

This source provides comprehensive information on the evaluation and management of resistant hypertension but does not discuss Nephronophthisis specifically.

Gene Therapy

Action: Gene Therapy NCIT:C15238

Emerging therapeutic strategy targeting NPHP gene defects to restore ciliary function and prevent disease progression.

Show evidence (1 reference)

PMID:42400345 SUPPORT

"This review summarizes the current understanding of NPH classification, clinical features, and molecular mechanisms. Here, we highlighted recent advances in genetic discoveries, pathogenic signaling pathways, and therapeutic strategies, including gene therapy and targeted molecular interventions."

Gene therapy is identified as an advancing therapeutic strategy in current nephronophthisis research and management.

Supportive Care

Action: Supportive Care NCIT:C15747

Symptomatic treatment and monitoring to manage associated complications.

Show evidence (1 reference)

PMID:35533128 SUPPORT

"At the moment there is no healing therapy, so early kidney transplant is a fundamental tool to improve prognosis."

There is no curative treatment for nephronophthisis, indicating that supportive care, including symptomatic treatment and monitoring, is currently applied to manage associated complications.

🌍

Environmental Factors

Not Applicable

Nephronophthisis is primarily driven by genetic mutations.

Show evidence (3 references)

PMID:15917209 REFUTE

"There has been tremendous progress in the past few years in understanding the molecular basis of nephronophthisis, and it is now evident that the disease is characterized by both clinical and genetic heterogeneity."

This indicates that Nephronophthisis is primarily driven by genetic mutations, not environmental factors.

PMID:20844548 REFUTE

"Nephronophthisis (NPHP) 4 gene coding nephrocystin-4 is involved in the development of renal tubules and its congenital mutations cause juvenile end-stage renal disease, NPHP."

This further supports that Nephronophthisis is caused by genetic mutations and not by environmental factors.

PMID:29869359 REFUTE

"The patient had elevated liver enzymes and biopsy-proven liver fibrosis. As liver synthesis was acceptable, only KT was performed. However, liver fibrosis progressed at 1.5 years after transplantation, manifested with portal hypertension and hypersplenism."

This case study describes genetic mutations as the cause of disease progression, reinforcing that Nephronophthisis is genetically driven.

🔬

Biochemical Markers

Serum Creatinine (Elevated)

Show evidence (1 reference)

PMID:37930417 SUPPORT

"Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and is one of the most frequent genetic causes for kidney failure (KF) in children and adolescents."

Kidney failure implies elevated serum creatinine. This reference indicates nephronophthisis is a frequent cause of kidney failure, indirectly supporting elevated creatinine as a biochemical finding.

Elevated Blood Urea Nitrogen (BUN) (Elevated)

Show evidence (3 references)

PMID:7272960 SUPPORT

"Irreversible and progressive renal parenchymal damage and functional impairment occurred in the majority of patients receiving at least six courses (200 mg/m2 of BCNU and/or methyl CCNU at eight-week intervals) of nitrosoureas for therapy of malignant brain tumors. Seventeen of 18 patients who..."

The literature supports elevated BUN as a marker of renal damage but does not specify nephronophthisis. Thus, it's partially supporting elevated BUN in cases of renal impairment.

PMID:26769764 SUPPORT

"CONCLUSIONS: We showed that elevation of BUN at discharge significantly modified the relation between eGFR at discharge and the risk of all-cause mortality after discharge, suggesting that the association between eGFR and outcomes may be largely dependent on concomitant elevation of BUN."

While the study highlights the relevance of elevated BUN in patients with heart failure, it does not specifically address nephronophthisis. Therefore, it partially supports the biochemical value.

PMID:21722602 SUPPORT

"CONCLUSION: Semiquantitative dipstick measurements of SUN can reliably identify CKD patients with elevated BUN levels."

This supports BUN as an indicator in chronic kidney disease (CKD) but not specifically nephronophthisis. Hence, it gives partial support.

📊

Prevalence

Global

0.1-1.0

Show evidence (2 references)

PMID:29717526 NO_EVIDENCE

"Nephronophthisis is an autosomal recessive cystic kidney disease and one of the most common genetic disorders causing end-stage renal disease in children. Nephronophthisis is a genetically heterogenous disorder with more than 25 identified genes. In 10%-20% of cases, there are additional..."

The provided literature discusses the genetic heterogeneity and associated features of nephronophthisis but does not provide information about its global prevalence.

PMID:25514144 NO_EVIDENCE

"According to the official health statistics, Taiwan has the highest prevalence of end stage renal disease (ESRD) in the world. Each year, around 60,000 ESRD patients in Taiwan consume 6% of the national insurance budget for dialysis treatment. The prevalence of chronic kidney disease (CKD) has..."

The article discusses the prevalence of end-stage renal disease in Taiwan but does not provide specific prevalence rates for nephronophthisis.

📊

Related Datasets

Targeting GLP-1 signaling ameliorates cystogenesis in a zebrafish model of nephronophthisis geo:GSE291847

Nephronophthisis (NPH) is the leading genetic cause of end-stage renal disease in children and young adults, with no effective disease-modifying therapies currently available. Here, we identify glucagon-like peptide-1 (GLP-1) signaling as a novel therapeutic target for NPH through a systematic drug repurposing screen in zebrafish. By simultaneously depleting nphp1 and nphp4, we developed a robust zebrafish model that recapitulates key features of human NPH, including glomerular cyst formation. Our screen revealed that dipeptidyl peptidase-4 (DPP4) inhibitors (Omarigliptin and Linagliptin) and GLP-1 receptor agonists (Semaglutide) significantly reduce cystogenesis in a dose-dependent manner.

zebrafish BULK RNA SEQ n=6

PMID:40806500

Identified by GEO DataSets index search for Nephronophthisis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Using human urinary-derived renal epithelial cells for deep phenotyping of NPHP1 deletion and determining personalised response to novel therapeutics geo:GSE301183

Nephronophthisis (NPHP) is an autosomal recessive tubulointerstitial nephropathy classified as a renal ciliopathy disorder and recognised as the leading genetic cause of kidney failure in children and young adults. NPHP1 is the most common genetic cause and encodes nephrocystin-1, a protein that plays crucial roles in the primary cilium and cellular junctions. Here we utilise personalised medicine approaches and deep phenotyping, which enable us to explore mechanistic pathways and identify potential therapeutic strategies.

human BULK RNA SEQ n=10

PMID:40776899

Comparative genomic analyses of the human NPHP1 locus reveal complex genomic architecture and its regional evolution in primates geo:GSE73962

Many loci in the human genome harbor complex genomic structures that can result in susceptibility to genomic rearrangements leading to various genomic disorders. Nephronophthisis 1 (NPHP1, MIM# 256100) is an autosomal recessive disorder that can be caused by defects of NPHP1; the gene maps within the human 2q13 region where low copy repeats (LCRs) are abundant. Loss of function of NPHP1 is responsible for approximately 85% of the NPHP1 cases - about 80% of such individuals carry a large recurrent homozygous NPHP1 deletion that occurs via non-allelic homologous recombination (NAHR) between two flanking directly oriented ~45 kb LCRs.

n=32

PMID:26641089

{ }

Source YAML

click to show

name: Nephronophthisis
creation_date: '2025-12-04T16:57:31Z'
description: >-
  Nephronophthisis is a ciliopathy caused by mutations in more than 20 causative genes, with NPHP1 being the most common.
  Gene products predominantly localize to the ciliary transition zone and basal body, where they regulate ciliary structure and signaling.
  That generalization has real exceptions, and this entry models them as separate
  mechanisms rather than folding them into the ciliary node: GLIS2 (NPHP7) is a
  transcription factor acting on the fibrogenic program, XPNPEP3 (NPHP-like 1) is
  a mitochondrial aminopeptidase, and MAPKBP1 (NPHP20) is a JNK scaffolding
  protein that is absent from the cilium and whose patient fibroblasts show no
  ciliogenesis defect at all.
  Defective ciliary signaling deranges Wnt, Hedgehog, EGFR, and Hippo/YAP pathways and impairs renal tubular function, driving tubular dysfunction, interstitial fibrosis, and corticomedullary cyst formation.
  Histopathologically, the disease is characterized by corticomedullary cysts, tubular atrophy, interstitial fibrosis, and cystic dilatation of distal tubules, with kidneys appearing normal early but gradually shrinking with progression.
  Progressive loss of renal function culminates in end-stage kidney disease, and extrarenal manifestations (retinal degeneration, liver fibrosis, neurologic involvement) occur when ciliary dysfunction affects other organs, defining nephronophthisis-related ciliopathies (NPH-RC).
category: Genetic
parents:
- Tubulointerstitial Kidney Disease
- Ciliopathy
has_subtypes:
- name: Infantile Nephronophthisis
  subtype_term:
    preferred_term: infantile nephronophthisis
    term:
      id: MONDO:0011190
      label: nephronophthisis 2
  genes:
  - preferred_term: INVS
    term:
      id: hgnc:17870
      label: INVS
  description: Early onset in infancy characterized by rapid progression to end-stage renal disease.
  review_notes: >-
    MONDO has no separate clinical class for infantile nephronophthisis: it
    carries "nephronophthisis 2, infantile" as a synonym of MONDO:0011190, the
    INVS gene class (Orphanet:93591, OMIM:602088), so this clinical row and the
    INVS molecular form denote the same MONDO concept and the row is bound to
    it. The genes list records that binding, not a claim that every infantile
    case is INVS-related; NPHP3 variants also present in infancy, as the NPHP3
    genetic record's Chinese infantile cohort shows.
  evidence:
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: SUPPORT
    snippet: Infantile nephronophtisis is a recessive autosomic tubulo-interstitial nephritis with cortical microcysts which progress to end stage renal failure before age 5.
    explanation: The source indicates that infantile nephronophthisis is characterized by early onset and rapid progression to end-stage renal disease, supporting the statement.
- name: Juvenile Nephronophthisis
  description: Most common form with onset in childhood and progressive renal failure by adolescence.
  review_notes: >-
    Deliberately left unbound. MONDO carries "juvenile nephronophthisis" and
    "familial juvenile nephronophthisis" only as synonyms of MONDO:0009728
    (nephronophthisis 1, NPHP1; Orphanet:93592, OMIM:256100), which the
    NPHP1-related row below already binds; binding it here too would assert the
    same class twice on one entry. Searched OLS MONDO synonym-inclusive for
    "juvenile nephronophthisis" and across all 60 MONDO terms matching
    "nephronophthisis" - no clinical-stratum class distinct from the gene class
    exists.
  evidence:
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: SUPPORT
    snippet: Juvenile nephronophtisis, the most frequent, progress to end stage renal failure before age 15.
    explanation: The provided excerpt states that juvenile nephronophthisis is the most frequent subtype and typically progresses to end-stage renal failure by adolescence.
  - reference: PMID:35570616
    reference_title: "Long-Term Outcomes of Kidney Transplant Recipients With Juvenile Nephronophthisis."
    supports: SUPPORT
    snippet: Nephronophthisis is the most common genetic cause of kidney failure in childhood... outcomes of kidney transplant recipients with primary diagnosis of juvenile nephronophthisis...
    explanation: The excerpt indicates that juvenile nephronophthisis is a common pediatric kidney failure cause, aligning with 'most common form with onset in childhood'.
- name: Adolescent Nephronophthisis
  description: Later onset in teenage years with slower progression to renal failure.
  review_notes: >-
    Deliberately left unbound: no MONDO class denotes adolescent
    nephronophthisis. Searched OLS MONDO synonym-inclusive for "adolescent
    nephronophthisis" (no hit) and listed all 60 MONDO terms matching
    "nephronophthisis", of which only MONDO:0019742 is a clinical-onset class
    and it is the late-onset one. MONDO:0011456 (nephronophthisis 3) carries no
    onset synonym either, so there is nothing to bind this row to.
  evidence:
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: SUPPORT
    snippet: Adolescent nephronophtisis is a less frequent form of nephronophtisis.
    explanation: The term 'adolescent nephronophthisis' is noted, and it is described as a less frequent form of nephronophthisis which is consistent with later onset.
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: SUPPORT
    snippet: Medullary cystic disease is transmitted as an autosomic dominant trait. Clinical and histological signs are similar to nephronophthisis, but the disease progress later to terminal renal failure and is not accompanied by extra-renal symptoms.
    explanation: Medullary cystic disease presents similar signs but progresses later, implying a slower progression to renal failure, corroborating the adolescent nephronophthisis description.
- name: Late-Onset Nephronophthisis
  subtype_term:
    preferred_term: late-onset nephronophthisis
    term:
      id: MONDO:0019742
      label: late-onset nephronophthisis
  description: Presentation after adolescence in young adulthood or later, with variable disease progression.
  review_notes: >-
    MONDO:0019742 is an Orphanet-derived clinical-onset class (Orphanet:93589)
    with no causal gene recorded against it, which is why this row binds a term
    but carries no genes.
  evidence:
  - reference: PMID:42400345
    reference_title: "Nephronophthisis: Current clinical spectrum and molecular pathogenesis."
    supports: SUPPORT
    snippet: The clinical spectrum of NPH is broad and can be classified according to the age at onset into infantile, juvenile, adolescent, and late-onset forms.
    explanation: Recent comprehensive review identifies late-onset nephronophthisis as a distinct clinical form of the disease spectrum.
- name: NPHP1-related
  display_name: Nephronophthisis 1 (NPHP1)
  subtype_term:
    preferred_term: nephronophthisis 1
    term:
      id: MONDO:0009728
      label: nephronophthisis 1
  genes:
  - preferred_term: NPHP1
    term:
      id: hgnc:7905
      label: NPHP1
  description: >-
    NPHP1-related nephronophthisis (juvenile nephronophthisis; OMIM 256100) is the
    most common molecular form, classically presenting as the juvenile subtype with
    progression to end-stage renal disease in adolescence. MONDO binds this gene-level
    leaf class to NPHP1 (RO:0004003 HGNC:7905).
  evidence:
  - reference: PMID:15138899
    reference_title: "The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Two siblings affected with a mild form of JS were found to have a homozygous deletion of the NPHP1 gene identical, by mapping, to that in subjects with NPHP alone.
    explanation: The recurrent homozygous NPHP1 deletion is the defining lesion of NPHP1-related (type 1) nephronophthisis, the gene-level leaf class MONDO:0009728.
- name: CEP164-related
  display_name: Nephronophthisis 15 (CEP164)
  subtype_term:
    preferred_term: nephronophthisis 15
    term:
      id: MONDO:0013917
      label: nephronophthisis 15
  genes:
  - preferred_term: CEP164
    term:
      id: hgnc:29182
      label: CEP164
  description: >-
    CEP164-related nephronophthisis (NPHP15; OMIM 614845). CEP164 is a distal
    appendage protein of the mother centriole required for ciliogenesis and the
    DNA-damage response; biallelic variants cause a nephronophthisis-related
    ciliopathy that MONDO also cross-classifies under Senior-Loken syndrome.
    MONDO binds this gene-level leaf class to CEP164 (RO:0004003 HGNC:29182).
  evidence:
  - reference: PMID:22863007
    reference_title: "Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We thereby identified recessive mutations of CEP164 as a new cause of NPHP-RC.
    explanation: Recessive CEP164 mutations define NPHP15 (MONDO:0013917), the CEP164-related nephronophthisis leaf class, linking the disorder to DNA-damage-response signaling.
  - reference: CGGV:assertion_961b81f6-7ad1-49e2-b675-c035b4d8d35d-2021-10-27T160000.000Z
    reference_title: "CEP164 / CEP164-related ciliopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CEP164 | HGNC:29182 | CEP164-related ciliopathy | MONDO:0700344 | AR | Definitive"
    explanation: >-
      ClinGen classifies the gene-disease relationship Definitive, but names its
      own class CEP164-related ciliopathy (MONDO:0700344) rather than the
      numbered MONDO:0013917 this row binds.
- name: NPHP3-related
  display_name: Nephronophthisis 3 (NPHP3)
  subtype_term:
    preferred_term: nephronophthisis 3
    term:
      id: MONDO:0011456
      label: nephronophthisis 3
  genes:
  - preferred_term: NPHP3
    term:
      id: hgnc:7907
      label: NPHP3
  description: >-
    The adolescent-onset molecular form, caused by biallelic NPHP3 variants.
    Nephrocystin-3 interacts with nephrocystin-1, and the reported families span
    isolated nephronophthisis, nephronophthisis with hepatic fibrosis, and
    nephronophthisis with tapeto-retinal degeneration.
  evidence:
  - reference: PMID:12872122
    reference_title: "Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe mutations in NPHP3 in families with isolated NPHP and in families with NPHP with associated hepatic fibrosis or tapeto-retinal degeneration.
    explanation: The gene-delineation result for NPHP3 and the source of this row's clinical range.
  - reference: PMID:12872122
    reference_title: "Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Here we report the identification of NPHP3, encoding a novel 1,330-amino acid protein that interacts with nephrocystin.
    explanation: >-
      The nephrocystin interaction this row describes, and the basis for wiring
      NPHP3 alongside the other nephrocystin-module genes.
  - reference: CGGV:assertion_47c3a0f1-9c14-4c92-83f2-e1105d528097-2021-07-24T160000.000Z
    reference_title: "NPHP3 / nephronophthisis (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NPHP3 | HGNC:7907 | nephronophthisis | MONDO:0019005 | AR | Definitive"
    explanation: >-
      ClinGen classifies the gene-disease relationship as Definitive, but curates
      it against the umbrella class MONDO:0019005 rather than against the
      numbered class MONDO:0011456 this row binds.
- name: NPHP4-related
  display_name: Nephronophthisis 4 (NPHP4)
  subtype_term:
    preferred_term: nephronophthisis 4
    term:
      id: MONDO:0011752
      label: nephronophthisis 4
  genes:
  - preferred_term: NPHP4
    term:
      id: hgnc:19104
      label: NPHP4
  description: >-
    A juvenile-onset molecular form caused by biallelic NPHP4 variants.
    Nephrocystin-4 interacts with nephrocystin-1 at the ciliary transition zone.
  evidence:
  - reference: CGGV:assertion_cafd0d51-dd5d-4691-8725-86518345b097-2021-02-10T170000.000Z
    reference_title: "NPHP4 / nephronophthisis 4 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NPHP4 | HGNC:19104 | nephronophthisis 4 | MONDO:0011752 | AR | Definitive"
    explanation: >-
      ClinGen curates this relationship against MONDO:0011752 itself, the same
      class this row binds, and classifies it Definitive with autosomal
      recessive inheritance.
  - reference: PMID:12872122
    reference_title: "Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: NPHP1 and NPHP4 have been identified, and interaction of the respective encoded proteins nephrocystin and nephrocystin-4 has been shown.
    explanation: >-
      Source of the nephrocystin-1 interaction stated in this row. Quoted from
      this paper's framing of established genetics rather than its own NPHP3
      result.
- name: GLIS2-related
  display_name: Nephronophthisis 7 (GLIS2)
  subtype_term:
    preferred_term: nephronophthisis 7
    term:
      id: MONDO:0012680
      label: nephronophthisis 7
  genes:
  - preferred_term: GLIS2
    term:
      id: hgnc:29450
      label: GLIS2
  description: >-
    Caused by biallelic GLIS2 variants. GLIS2 is a transcription factor rather
    than a structural ciliary protein, and the mouse mutant develops renal
    atrophy and fibrosis with upregulation of epithelial-to-mesenchymal
    transition and fibrosis genes, so this form reaches the fibrotic endpoint by
    a transcriptional route.
  review_notes: >-
    ClinGen grades this relationship Moderate rather than Definitive, which is
    the lowest confidence of any gene in this series; the row is curated but the
    grading is recorded in its evidence rather than smoothed over.
  evidence:
  - reference: PMID:17618285
    reference_title: "Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here we identify mutation of GLIS2 as causing an NPHP-like phenotype in humans and mice, using positional cloning and mouse transgenics, respectively.
    explanation: The gene-delineation result for GLIS2.
  - reference: PMID:17618285
    reference_title: "Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Differential gene expression studies on Glis2 mutant kidneys demonstrate that genes promoting epithelial-to-mesenchymal transition and fibrosis are upregulated in the absence of Glis2.
    explanation: >-
      The transcriptional mechanism this row describes, measured in the mouse
      mutant rather than in human tissue.
  - reference: CGGV:assertion_c51be76f-59d3-4884-9df3-4416686848ab-2024-06-27T160000.000Z
    reference_title: "GLIS2 / nephronophthisis 7 (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "GLIS2 | HGNC:29450 | nephronophthisis 7 | MONDO:0012680 | AR | Moderate"
    explanation: >-
      ClinGen curates this relationship against MONDO:0012680 itself, the class
      this row binds, but grades it Moderate.
- name: NEK8-related
  display_name: Nephronophthisis 9 (NEK8)
  subtype_term:
    preferred_term: nephronophthisis 9
    term:
      id: MONDO:0013444
      label: nephronophthisis 9
  genes:
  - preferred_term: NEK8
    term:
      id: hgnc:13387
      label: NEK8
  description: >-
    Caused by biallelic NEK8 variants. NEK8 is a NIMA-family kinase of the
    inversin compartment; the three reported changes all fall in RCC1 repeats,
    one of them in the same repeat as the mutation of the jck cystic-kidney
    mouse.
  review_notes: >-
    ClinGen does not curate a NEK8-nephronophthisis 9 relationship. Its only
    NEK8 gene-validity assertion is against renal-hepatic-pancreatic dysplasia 2
    (MONDO:0014174), a more severe perinatal entity, so the ClinGen record is
    cited below as context rather than as support for this row's claim.
  evidence:
  - reference: PMID:18199800
    reference_title: "NEK8 mutations affect ciliary and centrosomal localization and may cause nephronophthisis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified 3 different amino acid changes that were conserved through evolution (L330F, H425Y, and A497P) and that were absent from at least 80 ethnically matched controls.
    explanation: >-
      The human genetic evidence for the relationship this row asserts, from a
      588-patient mutational screen. The paper's own summary sentence, which is
      where the NPHP9 designation comes from, rests on its cell-based work as
      well and is graded and quoted in this entry's NEK8 genetic record rather
      than duplicated here with a second grading.
  - reference: CGGV:assertion_6888a91a-6589-42a9-9622-553b4918bed6-2021-09-08T160000.000Z
    reference_title: "NEK8 / renal-hepatic-pancreatic dysplasia 2 (Definitive)"
    supports: NO_EVIDENCE
    evidence_source: OTHER
    snippet: "NEK8 | HGNC:13387 | renal-hepatic-pancreatic dysplasia 2 | MONDO:0014174 | AR | Definitive"
    explanation: >-
      Recorded to show what ClinGen has and has not assessed for NEK8. The
      assertion is about MONDO:0014174, a different disease entity from the
      MONDO:0013444 this row binds, so it does not bear on the NPHP9 claim.
- name: TMEM67-related
  display_name: Nephronophthisis 11 (TMEM67)
  subtype_term:
    preferred_term: nephronophthisis 11
    term:
      id: MONDO:0013302
      label: nephronophthisis 11
  genes:
  - preferred_term: TMEM67
    term:
      id: hgnc:28396
      label: TMEM67
  description: >-
    Nephronophthisis with liver fibrosis, caused by biallelic TMEM67
    (MKS3) variants. The variants reported in this presentation are exclusively
    missense, in contrast to the predominantly truncating variants of
    TMEM67-related Meckel-Gruber and Joubert syndrome, which is why they are
    read as hypomorphic alleles of the same gene.
  evidence:
  - reference: PMID:19508969
    reference_title: "Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hypomorphic MKS3/TMEM67 mutations cause NPHP with liver fibrosis (NPHP11).
    explanation: The gene-delineation conclusion and the source of the NPHP11 designation this row binds.
  - reference: PMID:19508969
    reference_title: "Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In contrast, the mutations detected here in patients with NPHP and associated liver fibrosis are exclusively missense mutations.
    explanation: The allelic contrast with Meckel-Gruber and Joubert syndrome that this row describes.
  - reference: CGGV:assertion_8f380d4b-6d0b-4c09-a3ae-ec34bc8ecb8d-2021-07-14T160000.000Z
    reference_title: "TMEM67 / ciliopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TMEM67 | HGNC:28396 | ciliopathy | MONDO:0005308 | AR | Definitive"
    explanation: >-
      ClinGen classifies TMEM67 Definitive but lumps its disease entities into
      the single class ciliopathy (MONDO:0005308), so it makes no separate call
      on the numbered class MONDO:0013302 this row binds.
- name: TTC21B-related
  display_name: Nephronophthisis 12 (TTC21B)
  subtype_term:
    preferred_term: nephronophthisis 12
    term:
      id: MONDO:0013442
      label: nephronophthisis 12
  genes:
  - preferred_term: TTC21B
    term:
      id: hgnc:25660
      label: TTC21B
  description: >-
    Caused by biallelic TTC21B variants. TTC21B encodes IFT139, a component of
    the retrograde intraflagellar transport complex A, and the same gene also
    causes syndromic Jeune asphyxiating thoracic dystrophy.
  evidence:
  - reference: CGGV:assertion_60f93fe0-145f-47a7-9ecf-613b1b1dfa7f-2021-11-10T170000.000Z
    reference_title: "TTC21B / nephronophthisis 12 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TTC21B | HGNC:25660 | nephronophthisis 12 | MONDO:0013442 | AR | Definitive"
    explanation: >-
      ClinGen curates this relationship against MONDO:0013442 itself, the class
      this row binds, and classifies it Definitive.
  - reference: PMID:21258341
    reference_title: "TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here we show that mutations in TTC21B, which encodes the retrograde intraflagellar transport protein IFT139, cause both isolated nephronophthisis and syndromic Jeune asphyxiating thoracic dystrophy.
    explanation: >-
      The gene-delineation result, the IFT139 identity this row states, and the
      allelic relationship with Jeune syndrome.
- name: WDR19-related
  display_name: Nephronophthisis 13 (WDR19)
  subtype_term:
    preferred_term: nephronophthisis 13
    term:
      id: MONDO:0013718
      label: nephronophthisis 13
  genes:
  - preferred_term: WDR19
    term:
      id: hgnc:18340
      label: WDR19
  description: >-
    Caused by biallelic WDR19 variants. WDR19 encodes IFT144, another subunit of
    the retrograde intraflagellar transport complex A, and the same gene causes
    Sensenbrenner and Jeune syndromes; the isolated nephronophthisis
    presentation was found in a separate family.
  evidence:
  - reference: PMID:22019273
    reference_title: "Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Independently, we also identified compound heterozygous WDR19 mutations by exome sequencing in a Moroccan family with isolated nephronophthisis.
    explanation: The isolated-nephronophthisis presentation this row is about, as distinct from the syndromic families in the same report.
  - reference: PMID:22019273
    reference_title: "Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: WDR19 encodes IFT144, a member of the intraflagellar transport (IFT) complex A that drives retrograde ciliary transport.
    explanation: The IFT144 identity and complex membership this row states.
  - reference: CGGV:assertion_418a6e41-45ad-411f-a40d-2f7cb61ff589-2022-05-25T160000.000Z
    reference_title: "WDR19 / ciliopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "WDR19 | HGNC:18340 | ciliopathy | MONDO:0005308 | AR | Definitive"
    explanation: >-
      ClinGen classifies WDR19 Definitive but lumps nephronophthisis 13 with its
      other WDR19 entities into ciliopathy (MONDO:0005308), so it makes no
      separate call on MONDO:0013718.
- name: ZNF423-related
  display_name: Nephronophthisis 14 (ZNF423)
  subtype_term:
    preferred_term: nephronophthisis 14
    term:
      id: MONDO:0013916
      label: nephronophthisis 14
  genes:
  - preferred_term: ZNF423
    term:
      id: hgnc:16762
      label: ZNF423
  description: >-
    Caused by ZNF423 variants. ZNF423 was identified together with CEP164 and
    MRE11 in the exome study that linked nephronophthisis-related ciliopathies
    to DNA damage response signaling, and it is wired in this entry to the DNA
    damage node rather than to the ciliary nodes.
  review_notes: >-
    ClinGen grades ZNF423 Moderate and, as for WDR19 and TMEM67, curates it
    against the lumped ciliopathy class rather than against MONDO:0013916.
  evidence:
  - reference: PMID:22863007
    reference_title: "Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we identify by whole-exome resequencing, mutations of MRE11, ZNF423, and CEP164 as causing NPHP-RC. All three genes function within the DNA damage response (DDR) pathway.
    explanation: The gene-delineation result for ZNF423 and the pathway assignment behind this entry's wiring.
  - reference: CGGV:assertion_c61623dd-07b1-41c5-b445-3f9f8575cc06-2024-06-26T040000.000Z
    reference_title: "ZNF423 / ciliopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ZNF423 | HGNC:16762 | ciliopathy | MONDO:0005308 | AR | Moderate"
    explanation: >-
      ClinGen's assessment of the gene, graded Moderate and made against the
      lumped ciliopathy class rather than MONDO:0013916.
- name: ANKS6-related
  display_name: Nephronophthisis 16 (ANKS6)
  subtype_term:
    preferred_term: nephronophthisis 16
    term:
      id: MONDO:0014158
      label: nephronophthisis 16
  genes:
  - preferred_term: ANKS6
    term:
      id: hgnc:26724
      label: ANKS6
  description: >-
    Caused by biallelic ANKS6 variants, reported in six families with
    nephronophthisis that included severe cardiovascular abnormalities, liver
    fibrosis and situs inversus. ANKS6 sits at the centre of the module that
    connects NEK8, INVS and NPHP3, which is why those four genes produce
    overlapping disease.
  evidence:
  - reference: CGGV:assertion_62df8a40-0b65-46a4-89c8-51f26424c523-2021-08-25T160000.000Z
    reference_title: "ANKS6 / nephronophthisis 16 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ANKS6 | HGNC:26724 | nephronophthisis 16 | MONDO:0014158 | AR | Definitive"
    explanation: >-
      ClinGen curates this relationship against MONDO:0014158 itself, the class
      this row binds, and classifies it Definitive.
  - reference: PMID:23793029
    reference_title: "ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We also identify six families with ANKS6 mutations affected by nephronophthisis, including severe cardiovascular abnormalities, liver fibrosis and situs inversus.
    explanation: The human genetic evidence and the clinical description this row gives.
  - reference: PMID:23793029
    reference_title: "ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Network analyses uncovered additional putative NPHP proteins and placed ANKS6 at the center of this NPHP module, explaining the overlapping disease manifestation caused by mutation in ANKS6, NEK8, INVS or NPHP3.
    explanation: The module membership this row asserts and the basis for the inversin-compartment pathophysiology node.
- name: CEP83-related
  display_name: Nephronophthisis 18 (CEP83)
  subtype_term:
    preferred_term: nephronophthisis 18
    term:
      id: MONDO:0014374
      label: nephronophthisis 18
  genes:
  - preferred_term: CEP83
    term:
      id: hgnc:17966
      label: CEP83
  description: >-
    Infantile-onset nephronophthisis caused by biallelic CEP83 variants,
    reported in seven families. CEP83 is a distal appendage protein of the
    mother centriole, the same structural compartment as CEP164, and about half
    of the reported individuals had learning disability or hydrocephalus.
  evidence:
  - reference: PMID:24882706
    reference_title: "Mutations of CEP83 cause infantile nephronophthisis and intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In summary, we have identified mutations in CEP83, another DAP-component-encoding gene, as a cause of infantile nephronophthisis associated with central nervous system abnormalities in half of the individuals.
    explanation: The gene-delineation conclusion and the source of this row's clinical description.
  - reference: PMID:24882706
    reference_title: "Mutations of CEP83 cause infantile nephronophthisis and intellectual disability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The distal appendages (DAPs) of centrioles are involved in the docking and anchoring of the mother centriole to the cellular membrane during ciliogenesis.
    explanation: The distal-appendage function this row states and the basis for the distal-appendage pathophysiology node.
- name: DCDC2-related
  display_name: Nephronophthisis 19 (DCDC2)
  subtype_term:
    preferred_term: nephronophthisis 19
    term:
      id: MONDO:0014537
      label: nephronophthisis 19
  genes:
  - preferred_term: DCDC2
    term:
      id: hgnc:18141
      label: DCDC2
  description: >-
    A renal-hepatic ciliopathy caused by biallelic DCDC2 variants. DCDC2
    localises to the ciliary axoneme and to mitotic spindle fibres, and its loss
    disrupts ciliogenesis while releasing beta-catenin-dependent Wnt signaling,
    so this form acts on both the ciliary and the Wnt nodes of this entry.
  evidence:
  - reference: PMID:25557784
    reference_title: "DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We here identify mutations of DCDC2 as causing a renal-hepatic ciliopathy.
    explanation: The gene-delineation result for DCDC2.
  - reference: PMID:25557784
    reference_title: "DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: DCDC2 localizes to the ciliary axoneme and to mitotic spindle fibers in a cell-cycle-dependent manner.
    explanation: The localisation this row states, which is why DCDC2 is wired to the ciliary node.
  - reference: CGGV:assertion_477c8aba-eeba-43dc-a5e2-f6f84b127b8f-2021-10-13T160000.000Z
    reference_title: "DCDC2 / ciliopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "DCDC2 | HGNC:18141 | ciliopathy | MONDO:0005308 | AR | Definitive"
    explanation: >-
      ClinGen classifies DCDC2 Definitive but against the lumped ciliopathy
      class rather than MONDO:0014537.
- name: MAPKBP1-related
  display_name: Nephronophthisis 20 (MAPKBP1)
  subtype_term:
    preferred_term: nephronophthisis 20
    term:
      id: MONDO:0014997
      label: nephronophthisis 20
  genes:
  - preferred_term: MAPKBP1
    term:
      id: hgnc:29536
      label: MAPKBP1
  description: >-
    Juvenile or late-onset nephronophthisis with massive renal fibrosis, caused
    by biallelic MAPKBP1 variants. This is the one form in the series that is
    explicitly cilia-independent: MAPKBP1 is a JNK scaffolding protein absent
    from the primary cilium, and patient fibroblasts show no ciliogenesis
    defect. It reaches the shared phenotype through increased DNA damage
    response signaling instead.
  evidence:
  - reference: CGGV:assertion_b8542450-d48b-45ba-bd5f-4e55d210aa6b-2024-06-10T160000.000Z
    reference_title: "MAPKBP1 / nephronophthisis 20 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MAPKBP1 | HGNC:29536 | nephronophthisis 20 | MONDO:0014997 | AR | Definitive"
    explanation: >-
      ClinGen curates this relationship against MONDO:0014997 itself, the class
      this row binds, and classifies it Definitive.
  - reference: PMID:28089251
    reference_title: "Mutations in MAPKBP1 Cause Juvenile or Late-Onset Cilia-Independent Nephronophthisis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In conclusion, we identified mutations in MAPKBP1 as a genetic cause of juvenile or late-onset and cilia-independent NPH.
    explanation: The gene-delineation conclusion and the source of this row's onset and cilia-independence statements.
  - reference: PMID:28089251
    reference_title: "Mutations in MAPKBP1 Cause Juvenile or Late-Onset Cilia-Independent Nephronophthisis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Immunofluorescence analyses showed that MAPKBP1 is not present at the primary cilium and that fibroblasts from affected individuals did not display ciliogenesis defects
    explanation: The measured absence of a ciliary defect, which is why this gene is not wired to the ciliary nodes of this entry.
- name: XPNPEP3-related
  display_name: Nephronophthisis-like nephropathy 1 (XPNPEP3)
  subtype_term:
    preferred_term: nephronophthisis-like nephropathy 1
    term:
      id: MONDO:0013163
      label: nephronophthisis-like nephropathy 1
  genes:
  - preferred_term: XPNPEP3
    term:
      id: hgnc:28052
      label: XPNPEP3
  description: >-
    An NPHP-like nephropathy caused by biallelic XPNPEP3 variants. Unlike every
    other protein in this series, XPNPEP3 localises to mitochondria rather than
    to the cilium-centrosome complex; a ciliary connection is indirect, through
    ciliary cystogenic proteins that are XPNPEP3 substrates.
  review_notes: >-
    MONDO files MONDO:0013163 as a child of MONDO:0019005 (nephronophthisis),
    which is why it is curated here as a subtype row rather than as its own
    entry, and the stub stubs/Nephronophthisis-like_Nephropathy_1.yaml is
    deleted by this pass. The row keeps the source's own "NPHP-like" framing
    rather than asserting that this is nephronophthisis proper, because the
    delineating paper explicitly contrasts XPNPEP3 with all known NPHP proteins.
  evidence:
  - reference: CGGV:assertion_c1fd65c6-6010-4ee7-bb1c-e347c539127c-2024-06-10T160000.000Z
    reference_title: "XPNPEP3 / nephronophthisis-like nephropathy 1 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "XPNPEP3 | HGNC:28052 | nephronophthisis-like nephropathy 1 | MONDO:0013163 | AR | Definitive"
    explanation: >-
      ClinGen curates this relationship against MONDO:0013163 itself, the class
      this row binds, and classifies it Definitive.
  - reference: PMID:20179356
    reference_title: "Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In 2 families with an NPHP-like phenotype, we detected homozygous frameshift and splice-site mutations, respectively, in the X-prolyl aminopeptidase 3 (XPNPEP3) gene.
    explanation: The gene-delineation result for XPNPEP3 and the source of this row's biallelic inheritance.
  - reference: PMID:20179356
    reference_title: "Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In contrast to all known NPHP proteins, XPNPEP3 localizes to mitochondria of renal cells.
    explanation: The mitochondrial localisation that distinguishes this form, and the reason this row keeps the NPHP-like rather than NPHP framing.
prevalence:
- population: Global
  percentage: 0.1-1.0
  evidence:
  - reference: PMID:29717526
    reference_title: "Nephronophthisis: A review of genotype-phenotype correlation."
    supports: NO_EVIDENCE
    snippet: Nephronophthisis is an autosomal recessive cystic kidney disease and one of the most common genetic disorders causing end-stage renal disease in children. Nephronophthisis is a genetically heterogenous disorder with more than 25 identified genes. In 10%-20% of cases, there are additional features of a ciliopathy syndrome, such as retinal defects, liver fibrosis, skeletal abnormalities, and brain developmental disorders.
    explanation: The provided literature discusses the genetic heterogeneity and associated features of nephronophthisis but does not provide information about its global prevalence.
  - reference: PMID:25514144
    reference_title: "Addressing health disparities in chronic kidney disease."
    supports: NO_EVIDENCE
    snippet: According to the official health statistics, Taiwan has the highest prevalence of end stage renal disease (ESRD) in the world. Each year, around 60,000 ESRD patients in Taiwan consume 6% of the national insurance budget for dialysis treatment. The prevalence of chronic kidney disease (CKD) has been climbing during 2008-2012.
    explanation: The article discusses the prevalence of end-stage renal disease in Taiwan but does not provide specific prevalence rates for nephronophthisis.
pathophysiology:
- name: Ciliary Dysfunction
  conforms_to: "ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction"
  description: Mutations in NPHP genes disrupt the structure and function of primary cilia, which are essential for cell signaling and homeostasis. NPHP gene products predominantly localize to the ciliary transition zone and basal body, where they regulate ciliary structure and signaling.
  genes:
  - preferred_term: NPHP1
    term:
      id: hgnc:7905
      label: NPHP1
  - preferred_term: NPHP3
    term:
      id: hgnc:7907
      label: NPHP3
  - preferred_term: NPHP4
    term:
      id: hgnc:19104
      label: NPHP4
  - preferred_term: INVS
    term:
      id: hgnc:17870
      label: INVS
  - preferred_term: NEK8
    term:
      id: hgnc:13387
      label: NEK8
  - preferred_term: CEP164
    term:
      id: hgnc:29182
      label: CEP164
  - preferred_term: TMEM67
    term:
      id: hgnc:28396
      label: TMEM67
  - preferred_term: DCDC2
    term:
      id: hgnc:18141
      label: DCDC2
  cellular_components:
  - preferred_term: Primary Cilium
    term:
      id: GO:0005929
      label: cilium
  - preferred_term: Ciliary Transition Zone
    term:
      id: GO:0035869
      label: ciliary transition zone
  - preferred_term: Ciliary Basal Body
    term:
      id: GO:0036064
      label: ciliary basal body
  cell_types:
  - preferred_term: Renal Tubular Epithelial Cell
    term:
      id: CL:1000494
      label: nephron tubule epithelial cell
  downstream:
  - target: Impaired Cell Signaling
  evidence:
  - reference: PMID:18199800
    reference_title: "NEK8 mutations affect ciliary and centrosomal localization and may cause nephronophthisis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      All mutant forms of Nek8 showed defects in ciliary localization to varying
      degrees; the H431Y mutant (human H425Y) was completely absent from cilia
      and the amount localized to centrosomes was decreased.
    explanation: >-
      Direct support for this node's claim that NPHP gene products act at the
      cilium and basal body, and that disease variants disturb that
      localisation. Measured on transfected NEK8 constructs in IMCD-3 cells.
  - reference: PMID:19118152
    reference_title: "Nephronophthisis: disease mechanisms of a ciliopathy."
    supports: SUPPORT
    snippet: Nephronophthisis (NPHP), a recessive cystic kidney disease... Mutations in NPHP genes cause defects in signaling mechanisms that involve the noncanonical Wnt signaling pathway and the sonic hedgehog signaling pathway, resulting in defects of planar cell polarity and tissue maintenance.
    explanation: The provided snippet indicates that mutations in NPHP genes affect mechanisms that disrupt cellular functions related to cilia, supporting the statement that these mutations lead to impaired cilia.
  - reference: PMID:42400345
    reference_title: "Nephronophthisis: Current clinical spectrum and molecular pathogenesis."
    supports: SUPPORT
    snippet: More than 20 causative genes have been identified, with NPHP1 being the most common. These genes encode proteins that localize predominantly to the ciliary transition zone and basal body, where they regulate ciliary structure and signaling.
    explanation: This comprehensive review identifies the ciliary transition zone and basal body as the primary subcellular localization sites of NPHP gene products, establishing the structural basis for their ciliary dysfunction mechanism.
  - reference: PMID:34183231
    reference_title: "The ciliary impact of nonciliary gene mutations."
    supports: SUPPORT
    snippet: Mutations in genes encoding centriolar or ciliary proteins cause diseases collectively known as 'ciliopathies'.
    explanation: This statement refers to how ciliary protein gene mutations cause related ciliopathies, aligning with impaired cilia as seen in Nephronophthisis.
  - reference: PMID:21113628
    reference_title: "Cystic diseases of the kidney: ciliary dysfunction and cystogenic mechanisms."
    supports: SUPPORT
    snippet: Ciliary dysfunction has emerged as a common factor underlying the pathogenesis of both syndromic and isolated kidney cystic disease, an observation that has contributed to the unification of human genetic disorders of the cilium, the ciliopathies.
    explanation: The excerpt affirms that ciliary dysfunction is fundamental to the development of various cystic kidney diseases, including Nephronophthisis, caused by mutations affecting cilia.
  - reference: PMID:40728580
    reference_title: "FUT8-mediated core fucosylation stabilizes TMEM67 to promote ciliogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: FUT8 interacts with transmembrane protein 67 (TMEM67), a transition zone component closely linked to ciliopathies
    explanation: >-
      Places TMEM67, the NPHP11 gene, at the ciliary transition zone this node
      is about. The fucosylation result the paper is chiefly reporting is not
      claimed here; only the localisation it states.
  - reference: PMID:25557784
    reference_title: "DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: DCDC2 localizes to the ciliary axoneme and to mitotic spindle fibers in a cell-cycle-dependent manner.
    explanation: >-
      Places DCDC2, the NPHP19 gene, at the cilium. Note this is the axoneme
      rather than the transition zone, so DCDC2 is on this node for its ciliary
      role generally and not for the transition-zone claim specifically.
  - reference: PMID:25557784
    reference_title: "DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Knockdown of Dcdc2 in IMCD3 cells disrupts ciliogenesis, which is rescued by wild-type (WT) human DCDC2, but not by constructs that reflect human mutations.
    explanation: The functional ciliary requirement for DCDC2, shown in renal collecting-duct cells and rescued allele-specifically.
- name: Inversin Compartment Module Disruption
  biological_scale: MOLECULAR
  description: >-
    INVS (NPHP2), NPHP3, NEK8 (NPHP9) and ANKS6 (NPHP16) form one physical
    module rather than four independent lesions, with ANKS6 at its centre
    connecting NEK8 to INVS and NPHP3. Loss of any one member disturbs the same
    assembly, which is the stated explanation for why variants in the four genes
    produce overlapping disease.
  genes:
  - preferred_term: INVS
    term:
      id: hgnc:17870
      label: INVS
  - preferred_term: NPHP3
    term:
      id: hgnc:7907
      label: NPHP3
  - preferred_term: NEK8
    term:
      id: hgnc:13387
      label: NEK8
  - preferred_term: ANKS6
    term:
      id: hgnc:26724
      label: ANKS6
  cellular_components:
  - preferred_term: proximal cilium
    term:
      id: GO:0005929
      label: cilium
  downstream:
  - target: Ciliary Dysfunction
    description: >-
      Disruption of the module removes proteins that act at the cilium, feeding
      the shared ciliary-dysfunction state of this entry.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:23793029
    reference_title: "ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Here we identify ANKS6 as a new NPHP family member that connects NEK8 (NPHP9) to INVS (NPHP2) and NPHP3.
    explanation: The module membership of all four genes on this node.
  - reference: PMID:23793029
    reference_title: "ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We show that ANKS6 localizes to the proximal cilium and confirm its role in renal development through knockdown experiments in zebrafish and Xenopus laevis.
    explanation: The ciliary localisation this node's cellular-component binding asserts.
  - reference: PMID:23793029
    reference_title: "ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Network analyses uncovered additional putative NPHP proteins and placed ANKS6 at the center of this NPHP module, explaining the overlapping disease manifestation caused by mutation in ANKS6, NEK8, INVS or NPHP3.
    explanation: The source of this node's claim that the four genes are one lesion rather than four.
- name: Retrograde Intraflagellar Transport Defect
  biological_scale: MOLECULAR
  description: >-
    TTC21B (IFT139, NPHP12) and WDR19 (IFT144, NPHP13) are both subunits of
    intraflagellar transport complex A, which drives retrograde transport back
    down the ciliary axoneme. Loss of either subunit impairs that transport step
    rather than the transition-zone gate, which is why they are modeled apart
    from the transition-zone genes.
  genes:
  - preferred_term: TTC21B
    term:
      id: hgnc:25660
      label: TTC21B
  - preferred_term: WDR19
    term:
      id: hgnc:18340
      label: WDR19
  cellular_components:
  - preferred_term: intraflagellar transport complex A
    term:
      id: GO:0030991
      label: intraciliary transport particle A
  biological_processes:
  - preferred_term: retrograde intraflagellar transport
    modifier: DECREASED
    term:
      id: GO:0035721
      label: intraciliary retrograde transport
  downstream:
  - target: Ciliary Dysfunction
    description: >-
      Failure of retrograde transport perturbs ciliary abundance and morphology,
      feeding the shared ciliary-dysfunction state of this entry.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:22019273
    reference_title: "Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: WDR19 encodes IFT144, a member of the intraflagellar transport (IFT) complex A that drives retrograde ciliary transport.
    explanation: The complex membership and the retrograde-transport process this node binds.
  - reference: PMID:22019273
    reference_title: "Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We show that IFT144 is absent from the cilia of fibroblasts from one of the Sensenbrenner patients and that ciliary abundance and morphology is perturbed, demonstrating the ciliary pathogenesis.
    explanation: The measured ciliary consequence behind this node's downstream edge.
  - reference: PMID:21258341
    reference_title: "TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here we show that mutations in TTC21B, which encodes the retrograde intraflagellar transport protein IFT139, cause both isolated nephronophthisis and syndromic Jeune asphyxiating thoracic dystrophy.
    explanation: Places TTC21B on this node as the second complex A subunit.
- name: Distal Appendage Docking Failure
  biological_scale: CELLULAR
  description: >-
    CEP83 (NPHP18) and CEP164 (NPHP15) are distal appendage proteins of the
    mother centriole. The distal appendages dock and anchor the mother centriole
    to the cell membrane at the start of ciliogenesis, and cells from affected
    individuals show altered appendage composition together with ciliary
    defects, so this lesion sits upstream of cilium assembly rather than in the
    assembled cilium.
  genes:
  - preferred_term: CEP83
    term:
      id: hgnc:17966
      label: CEP83
  - preferred_term: CEP164
    term:
      id: hgnc:29182
      label: CEP164
  biological_processes:
  - preferred_term: ciliogenesis
    modifier: DECREASED
    term:
      id: GO:0060271
      label: cilium assembly
  downstream:
  - target: Ciliary Dysfunction
    description: >-
      Failure to dock the mother centriole prevents normal cilium assembly,
      feeding the shared ciliary-dysfunction state of this entry.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:24882706
    reference_title: "Mutations of CEP83 cause infantile nephronophthisis and intellectual disability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The distal appendages (DAPs) of centrioles are involved in the docking and anchoring of the mother centriole to the cellular membrane during ciliogenesis.
    explanation: The ciliogenesis process this node binds and the function of the structure it is named for.
  - reference: PMID:24882706
    reference_title: "Mutations of CEP83 cause infantile nephronophthisis and intellectual disability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Fibroblasts and tubular renal cells from affected individuals showed an altered DAP composition and ciliary defects.
    explanation: The measured appendage and ciliary defect in patient cells, in the tissue this disease affects.
  - reference: PMID:24882706
    reference_title: "Mutations of CEP83 cause infantile nephronophthisis and intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: mutations in two genes encoding DAPs components (CEP164/NPHP15, SCLT1) have been associated with human ciliopathies, namely nephronophthisis and orofaciodigital syndrome
    explanation: >-
      Places CEP164 on this node as the other distal appendage gene. Quoted from
      this paper's framing of prior work rather than from its own CEP83 result.
- name: Mitochondrial Aminopeptidase Deficiency
  biological_scale: MOLECULAR
  description: >-
    XPNPEP3 is the one protein in this entry that does not act at the
    cilium-centrosome complex: it is an X-prolyl aminopeptidase of the
    mitochondrion. Its connection to the rest of the pathograph is indirect,
    through ciliary cystogenic proteins that are its substrates and that lose
    function when N-terminal proline cleavage is blocked.
  genes:
  - preferred_term: XPNPEP3
    term:
      id: hgnc:28052
      label: XPNPEP3
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  molecular_functions:
  - preferred_term: X-prolyl aminopeptidase activity
    modifier: DECREASED
    term:
      id: GO:0004177
      label: aminopeptidase activity
  downstream:
  - target: Ciliary Dysfunction
    description: >-
      Loss of cleavage of ciliary cystogenic substrates attenuates their
      function, which is the route by which a mitochondrial enzyme reaches the
      ciliary state this entry converges on.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:20179356
    reference_title: "Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In contrast to all known NPHP proteins, XPNPEP3 localizes to mitochondria of renal cells.
    explanation: The mitochondrial localisation this node binds.
  - reference: PMID:20179356
    reference_title: "Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In 2 families with an NPHP-like phenotype, we detected homozygous frameshift and splice-site mutations, respectively, in the X-prolyl aminopeptidase 3 (XPNPEP3) gene.
    explanation: >-
      Names the enzyme class this node's molecular-function binding asserts, and
      records that the reported alleles are loss-of-function.
  - reference: PMID:20179356
    reference_title: "Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Consistent with a role for XPNPEP3 in ciliary function, several ciliary cystogenic proteins were found to be XPNPEP3 substrates, for which resistance to N-terminal proline cleavage resulted in attenuated protein function in vivo in zebrafish.
    explanation: The substrate relationship behind this node's indirect downstream edge.
- name: Fibrogenic Transcriptional Derepression
  biological_scale: MOLECULAR
  description: >-
    GLIS2 (NPHP7) is a transcription factor rather than a ciliary structural
    protein. In its absence the mouse kidney upregulates genes promoting
    epithelial-to-mesenchymal transition and fibrosis and develops severe renal
    atrophy and fibrosis, so this form reaches the fibrotic endpoint of the
    entry directly rather than through the ciliary nodes.
  genes:
  - preferred_term: GLIS2
    term:
      id: hgnc:29450
      label: GLIS2
  biological_processes:
  - preferred_term: epithelial to mesenchymal transition
    modifier: INCREASED
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
  downstream:
  - target: Interstitial Fibrosis
    description: >-
      Derepression of the fibrogenic transcriptional program drives the
      interstitial fibrosis that is the shared histological endpoint of this
      entry, without an intervening ciliary lesion.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:17618285
    reference_title: "Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Differential gene expression studies on Glis2 mutant kidneys demonstrate that genes promoting epithelial-to-mesenchymal transition and fibrosis are upregulated in the absence of Glis2.
    explanation: The transcriptional change this node binds, measured in mouse kidney.
  - reference: PMID:17618285
    reference_title: "Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Kidneys of Glis2 mutant mice show severe renal atrophy and fibrosis starting at 8 weeks of age.
    explanation: The fibrotic outcome this node's downstream edge asserts, in the mouse model.
  - reference: PMID:17618285
    reference_title: "Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Thus, we identify Glis2 as a transcription factor mutated in NPHP and demonstrate its essential role for the maintenance of renal tissue architecture through prevention of apoptosis and fibrosis.
    explanation: The transcription-factor identity this node is named for.
- name: Impaired Cell Signaling
  conforms_to: "ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction"
  description: >-
    Defective primary cilia lead to disrupted signaling pathways including Wnt,
    Hedgehog, EGFR, and Hippo/YAP pathways, affecting cell differentiation,
    proliferation, and polarity. Inversin, the NPHP2 gene product, is the
    worked case: it acts as a switch between the canonical and non-canonical
    Wnt cascades, restraining canonical Wnt signaling by targeting cytoplasmic
    dishevelled for degradation, and its level in ciliated tubular epithelium
    responds to fluid flow.
  genes:
  - preferred_term: INVS
    term:
      id: hgnc:17870
      label: INVS
  - preferred_term: NEK8
    term:
      id: hgnc:13387
      label: NEK8
  - preferred_term: DCDC2
    term:
      id: hgnc:18141
      label: DCDC2
  pathways:
  - preferred_term: Wnt Pathway
    term:
      id: GO:0016055
      label: Wnt signaling pathway
  - preferred_term: Hedgehog Pathway
    term:
      id: GO:0007224
      label: smoothened signaling pathway
  - preferred_term: EGFR Signaling
    term:
      id: GO:0038127
      label: ERBB signaling pathway
  - preferred_term: Hippo Signaling
    term:
      id: GO:0035329
      label: hippo signaling
  downstream:
  - target: Abnormal Cell Proliferation
  - target: DNA Damage and Senescence
  evidence:
  - reference: PMID:15852005
    reference_title: "Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here we report that inversin acts as a molecular switch between different
      Wnt signaling cascades. Inversin inhibits the canonical Wnt pathway by
      targeting cytoplasmic dishevelled (Dsh or Dvl1) for degradation
    explanation: >-
      Supplies the mechanism behind the Wnt half of this node and behind the
      INVS gene binding, naming dishevelled degradation as the step.
  - reference: PMID:25557784
    reference_title: "DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We show that DCDC2 interacts with DVL and DCDC2 overexpression inhibits β-catenin-dependent Wnt signaling in an effect additive to Wnt inhibitors.
    explanation: >-
      Places DCDC2 on the Wnt half of this node. It converges on the same
      dishevelled step as inversin, which is why the two genes sit together
      here rather than on separate signaling nodes.
  - reference: PMID:25557784
    reference_title: "DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: A Wnt inhibitor likewise restores ciliogenesis in 3D IMCD3 cultures, emphasizing the importance of Wnt signaling for renal tubulogenesis.
    explanation: >-
      The pharmacological rescue tying the Wnt defect to renal tubulogenesis,
      which is what this node's downstream edges assert.
  - reference: PMID:15852005
    reference_title: "Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In zebrafish, the structurally related switch molecule diversin
      ameliorates renal cysts caused by the depletion of inversin, implying that
      an inhibition of canonical Wnt signaling is required for normal renal
      development.
    explanation: >-
      Connects the signaling defect to the renal cystic phenotype in vivo, which
      is what this node's downstream edge asserts.
  - reference: PMID:19186246
    reference_title: "Modeling ciliopathies: Primary cilia in development and disease."
    supports: SUPPORT
    snippet: Their importance for key developmental pathways such as Sonic Hedgehog (Shh) and Wnt is beginning to emerge. The function of nodal cilia, for example, is vital for breaking early embryonic symmetry, Shh signaling is important for tissue morphogenesis and successful Wnt signaling for organ growth and differentiation. When ciliary function is perturbed...brains form improperly.
    explanation: This reference supports the idea that disrupted cilia function affects the Wnt and Hedgehog pathways, but it does not specify nephronophthisis directly.
  - reference: PMID:22206729
    reference_title: "Inversin, Wnt signaling and primary cilia."
    supports: SUPPORT
    snippet: Mutations of the ankyrin-repeat protein Inversin, a member of a diverse family of more than 12 proteins, cause nephronophthisis (NPH)...Most NPH gene products (NPHPs) localize to the cilium, and appear to control the transport of cargo protein to the cilium by forming functional networks.
    explanation: This reference directly links nephronophthisis to defective cilia and mentions involvement in pathways like Wnt signaling.
  - reference: PMID:24162855
    reference_title: "Wnt and planar cell polarity signaling in cystic renal disease."
    supports: SUPPORT
    snippet: The primary cilium, a microtubule-based organelle that can serve as a signaling antenna, has been demonstrated to have a significant role in ensuring correct kidney development and function...one of the signaling pathways that requires the cilium for normal development is Wnt signaling.
    explanation: This reference supports the involvement of the primary cilium in Wnt signaling but does not explicitly connect it to nephronophthisis.
  - reference: PMID:20544799
    reference_title: "The relationship between sonic Hedgehog signaling, cilia, and neural tube defects."
    supports: SUPPORT
    snippet: mutation of proteins required for function of cilia often leads to impaired Shh signaling and to disruption of neural tube closure.
    explanation: This reference supports the idea that ciliary dysfunction affects Hedgehog signaling but focuses on neural tube defects rather than nephronophthisis.
  - reference: PMID:35655331
    reference_title: "The Joubert-Meckel-Nephronophthisis Spectrum of Ciliopathies."
    supports: SUPPORT
    snippet: Ciliary dysfunction causes many human conditions termed ciliopathies...ciliopathy spectrum could be the poster child for advances and challenges in Mendelian human genetics over the past half century...illustrates many core concepts of human genetics.
    explanation: This reference supports the concept that defects in the primary cilia affect key signaling pathways, including the ones mentioned, in the context of nephronophthisis.
- name: Renal Tubular Dysfunction
  locations:
  - preferred_term: Renal Tubule
    term:
      id: UBERON:0009773
      label: renal tubule
  downstream:
  - target: Polyuria
  - target: Polydipsia
  - target: Electrolyte Imbalance
  - target: Interstitial Fibrosis
  description: Ciliary dysfunction in renal tubular epithelial cells impairs fluid and electrolyte balance, leading to polyuria and polydipsia.
  evidence:
  - reference: PMID:21071979
    reference_title: "Mechanisms of nephronophthisis and related ciliopathies."
    supports: SUPPORT
    snippet: Nephronophthisis is a recessive disorder of the kidney that is the leading cause of end-stage renal failure in children. Through positional cloning, many of the causative mutations have been mapped to genes involved in centrosome and cilia function.
    explanation: The literature supports that nephronophthisis is related to ciliary dysfunction, but it does not explicitly mention polyuria and polydipsia as part of its pathophysiology.
  - reference: PMID:16186680
    reference_title: "Approach to renal tubular disorders."
    supports: SUPPORT
    snippet: Renal tubular disorders may affect multiple (e.g., Fanconi syndrome) or specific (e.g., nephrogenic diabetes insipidus, renal glucosuria) tubular functions. Most conditions are primary and monogenic but occasionally are secondary to other disorders.
    explanation: The reference discusses renal tubular disorders, which can result in polyuria and electrolyte imbalance, but it does not explicitly link these to ciliary dysfunction in nephronophthisis.
  - reference: PMID:9790573
    reference_title: "Epithelial transport in polycystic kidney disease."
    supports: SUPPORT
    snippet: Cysts originate within the glomeruli and all tubular structures, and their growth is the result of proliferation of incompletely differentiated epithelial cells and the accumulation of fluid within the cysts.
    explanation: While the reference discusses fluid accumulation and cyst formation in polycystic kidney disease, it does not directly link these to nephronophthisis or explicitly mention polyuria.
  - reference: PMID:18312782
    reference_title: "Ciliary syndromes and treatment."
    supports: SUPPORT
    snippet: Overlapping clinical entities including situs inversus, certain infertility disorders, as well as chronic respiratory infections have their roots in abnormal ciliary function.
    explanation: This reference supports the involvement of ciliary dysfunction in various disorders but does not provide specific details on nephronophthisis and its pathophysiology related to polyuria and polydipsia.
- name: Interstitial Fibrosis
  locations:
  - preferred_term: Kidney Interstitium
    term:
      id: UBERON:0005215
      label: kidney interstitium
  cell_types:
  - preferred_term: Renal Interstitial Fibroblast
    term:
      id: CL:1000692
      label: kidney interstitial fibroblast
  description: Chronic tubular dysfunction and inflammation lead to the accumulation of extracellular matrix and progressive interstitial fibrosis.
  evidence:
  - reference: PMID:35533128
    reference_title: "[Nephronophthisis: a pediatric case report]."
    supports: SUPPORT
    snippet: Diagnosis is made by a positive genetic test, or a kidney biopsy demonstrating chronic tubulointerstitial changes with thickening of the tubular basement membranes.
    explanation: The diagnosis of nephronophthisis includes tubulointerstitial changes, which aligns with chronic tubular dysfunction and inflammation leading to interstitial fibrosis.
  - reference: PMID:31399984
    reference_title: "Renal Interstitial Lymphangiogenesis in Renal Fibrosis."
    supports: SUPPORT
    snippet: Renal interstitial lymphangiogenesis is found in patients with chronic kidney disease (CKD) and a series of animal models of renal fibrosis.
    explanation: While the study focuses on lymphangiogenesis, it mentions renal interstitial fibrosis related to chronic kidney disease, of which nephronophthisis is a type.
- name: Renal Cyst Formation
  conforms_to: "ciliopathy_dysfunction#Renal Tubular Cystic and Fibrotic Disease"
  locations:
  - preferred_term: Renal Tubule
    term:
      id: UBERON:0009773
      label: renal tubule
  downstream:
  - target: Renal Insufficiency
  description: Abnormal cell proliferation and differentiation result in the formation of cysts in the kidney tubules, contributing to the loss of renal function.
  evidence:
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: SUPPORT
    snippet: Nephronophthisis is a chronic tubulo-interstitial nephritis which progress to terminal renal failure.
    explanation: The statement claims that abnormal cell proliferation and differentiation result in cyst formation in nephronophthisis, but the literature describes nephronophthisis as a chronic tubulo-interstitial nephritis without indicating cyst formation due to abnormal cell proliferation and differentiation as a characteristic pathophysiological mechanism. Instead, it mentions cortical microcysts in infantile forms but emphasizes interstitial fibrosis and tubular basement membrane changes.
  - reference: PMID:25575298
    reference_title: "The role of cilia in the pathogenesis of cystic kidney disease."
    supports: NO_EVIDENCE
    snippet: Almost all of proteins associated with a broad spectrum of human cystic kidney diseases have been localized to the region in or around the cilia.
    explanation: While this reference discusses abnormal cilia structure and function in cystic kidney diseases, it does not specifically address nephronophthisis or the mechanism of abnormal cell proliferation and differentiation leading to renal cyst formation in nephronophthisis.
- name: Renal Insufficiency
  description: The combination of tubular dysfunction, interstitial fibrosis, and cyst formation leads to a gradual decline in renal function and eventual end-stage renal disease (ESRD).
  evidence:
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: SUPPORT
    snippet: Nephronophthisis is a chronic tubulo-interstitial nephritis which progress to terminal renal failure... Histologic lesions concern tubular basement membranes which are thickened and multilayered or thinned. There is an associated interstitial fibrosis.
    explanation: The provided excerpt mentions chronic tubulo-interstitial nephritis (tubular dysfunction and interstitial fibrosis) and progression to terminal renal failure, supporting the statement that these factors contribute to ESRD.
  - reference: PMID:10352410
    reference_title: "Interstitial pathomechanisms underlying progressive tubulointerstitial damage."
    supports: SUPPORT
    snippet: Progressive renal disease poses an increasing problem for the medical community. Though the causes of end-stage renal failure are multiple, the histologic pictures of chronic renal disease are remarkably similar being characterized by interstitial infiltration, fibrosis, tubular atrophy and dilatation.
    explanation: This literature indicates the role of interstitial infiltration, fibrosis, and tubular atrophy leading to ESRD, which partially overlaps with the factors mentioned in the statement. However, cyst formation specific to nephronophthisis was not explicitly mentioned.
- name: Extrarenal Manifestations
  conforms_to: "ciliopathy_dysfunction#Multisystem Pleiotropic Ciliopathy Phenotype"
  subtypes:
  - Senior-Loken syndrome
  locations:
  - preferred_term: Liver
    term:
      id: UBERON:0002107
      label: liver
  - preferred_term: Retina
    term:
      id: UBERON:0000966
      label: retina
  - preferred_term: Brain
    term:
      id: UBERON:0000955
      label: brain
  description: >-
    When extrarenal organs such as the retina, liver, or central nervous system are affected by ciliary dysfunction, the condition is designated as nephronophthisis-related ciliopathies (NPH-RC), which affects 10-20% of nephronophthisis cases.
    Examples include Senior-Loken syndrome (nephronophthisis plus retinal degeneration) and syndromic forms with liver fibrosis or neurological involvement.
  evidence:
  - reference: PMID:42400345
    reference_title: "Nephronophthisis: Current clinical spectrum and molecular pathogenesis."
    supports: SUPPORT
    snippet: When extrarenal organs such as the retina, liver, or central nervous system are affected, the condition is defined as nephronophthisis-related ciliopathies (NPH-RC).
    explanation: This comprehensive review defines the NPH-RC classification based on extrarenal involvement, distinguishing syndromic forms from nonsyndromic nephronophthisis.
  - reference: PMID:35533128
    reference_title: "[Nephronophthisis: a pediatric case report]."
    supports: SUPPORT
    snippet: Nephronophthisis is an autosomal recessive cystic kidney disease caused by mutations in genes that encode proteins involved in the primary cilia function, resulting in kidney disease and extrarenal manifestations such as retinal degeneration and liver fibrosis.
    explanation: The literature supports the involvement of the liver and retina in nephronophthisis but does not mention the brain specifically in this context.
  - reference: PMID:32432520
    reference_title: "Senior-Løken syndrome and intracranial hypertension."
    supports: SUPPORT
    snippet: Senior-Løken syndrome (SLS) is a rare autosomal recessive disease characterised by nephronophthisis and retinal degeneration, and belongs to a group of genetically heterogeneous disorders known as the ciliopathies.
    explanation: The literature supports the involvement of the retina in Senior-Loken syndrome but does not mention the liver or brain specifically in this context.
  - reference: PMID:33306870
    reference_title: "Defective INPP5E distribution in NPHP1-related Senior-Loken syndrome."
    supports: SUPPORT
    snippet: Senior-Loken syndrome is a rare genetic disorder that presents with nephronophthisis and retinal degeneration, leading to end-stage renal disease and progressive blindness.
    explanation: The literature supports the involvement of the retina in Senior-Loken syndrome, which is a form of nephronophthisis.
  - reference: PMID:35655331
    reference_title: "The Joubert-Meckel-Nephronophthisis Spectrum of Ciliopathies."
    supports: NO_EVIDENCE
    snippet: The JS phenotype alone is caused by pathogenic variants in more than 40 genes; remarkably, all of the associated proteins function in and around the primary cilium.
    explanation: This reference discusses the involvement of primary cilia in a broader sense but does not specify the extrarenal manifestations like those in Senior-Loken syndrome.
- name: Progression and Severity
  description: The age of onset and rate of progression vary depending on the specific NPHP gene mutations and the type of nephronophthisis.
  evidence:
  - reference: PMID:34828368
    reference_title: "Nephronophthisis-Pathobiology and Molecular Pathogenesis of a Rare Kidney Genetic Disease."
    supports: SUPPORT
    snippet: NPHP gene types present with some common pathophysiological features alongside a diverse range of extra-renal phenotypes associated with specific syndromic presentations.
    explanation: The reference states that there is diversity in pathophysiological features and extra-renal phenotypes among different NPHP gene types, which supports the statement that the age of onset and rate of progression vary.
  - reference: PMID:35570616
    reference_title: "Long-Term Outcomes of Kidney Transplant Recipients With Juvenile Nephronophthisis."
    supports: SUPPORT
    snippet: Nephronophthisis is the most common genetic cause of kidney failure in childhood....Treatment for nephronophthisis is symptomatic, and kidney transplant is a good treatment option when kidney failure has developed.
    explanation: While this reference highlights the general management of nephronophthisis, it implies variability in progression and severity since not all individuals progress to kidney failure at the same rate.
  - reference: PMID:35922195
    reference_title: "[Clinical phenotype analysis of 6 cases of TTC21B gene related nephronophthisis]."
    supports: SUPPORT
    snippet: All 6 children progressed to end-stage renal disease (ESRD) within 10 (4, 65) months of onset.
    explanation: The reference indicates variability in the progression to end-stage renal disease, supporting the statement regarding variable progression rates depending on the specific NPHP gene mutations.
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: SUPPORT
    snippet: There are three main clinical forms of nephronophtisis which have been associated with five gene defects. Juvenile nephronophtisis, the most frequent, progress to end stage renal failure before age 15.
    explanation: This reference identifies different clinical forms of nephronophthisis, which progress at different rates, thus supporting the statement on variability in age of onset and progression.
- name: Abnormal Cell Proliferation
  description: Dysregulated cell division and growth
- name: DNA Damage and Senescence
  description: NPHP1 deficiency impairs DNA damage repair, leading to increased cellular senescence and contributing to interstitial fibrosis. Nephrocystin-1 translocates to the nucleus after DNA damage stress.
  locations:
  - preferred_term: Nucleus
    term:
      id: GO:0005634
      label: nucleus
  - preferred_term: Renal Tubule
    term:
      id: UBERON:0009773
      label: renal tubule
  downstream:
  - target: Interstitial Fibrosis
  genes:
  - preferred_term: NPHP1
    term:
      id: hgnc:7905
      label: NPHP1
  - preferred_term: CEP164
    term:
      id: hgnc:29182
      label: CEP164
  - preferred_term: ZNF423
    term:
      id: hgnc:16762
      label: ZNF423
  - preferred_term: MAPKBP1
    term:
      id: hgnc:29536
      label: MAPKBP1
  evidence:
  - reference: PMID:22863007
    reference_title: "Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We thereby identified recessive mutations of CEP164 as a new cause of NPHP-RC.
    explanation: >-
      CEP164 is the nephronophthisis gene whose discovery paper places the
      disorder on the DNA-damage-response axis this node models, which is why
      the gene is bound here as well as on the CEP164-related subtype row.
  - reference: PMID:22863007
    reference_title: "Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we identify by whole-exome resequencing, mutations of MRE11, ZNF423, and CEP164 as causing NPHP-RC. All three genes function within the DNA damage response (DDR) pathway.
    explanation: >-
      Places ZNF423 on this node alongside CEP164, and states the pathway
      assignment the node is built on.
  - reference: PMID:22863007
    reference_title: "Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We show that knockdown of CEP164 or ZNF423 causes sensitivity to DNA damaging agents
    explanation: The measured DNA-damage sensitivity behind both gene bindings, rather than pathway membership alone.
  - reference: PMID:28089251
    reference_title: "Mutations in MAPKBP1 Cause Juvenile or Late-Onset Cilia-Independent Nephronophthisis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Additionally, we show increased DNA damage response signaling in fibroblasts from affected individuals and upon knockdown of Mapkbp1 in murine cell lines, a phenotype previously associated with NPH.
    explanation: >-
      Places MAPKBP1 on this node. It is bound here and on no ciliary node
      because the same report shows patient fibroblasts have no ciliogenesis
      defect, so this is the only route by which the gene reaches the entry's
      shared phenotype.
  notes: Recent research shows nephrocystin-1 has nuclear functions in DNA damage response beyond its ciliary role
- name: Aberrant Actin Remodeling and Hippo Activation
  description: Ciliary dysfunction leads to aberrant RhoA signaling from the centrosome, activating ROCK and engaging Hippo signaling. This contributes to cystogenesis, fibrosis, and inflammation. GEF-H1 knockdown can rescue phenotypes in NPHP1 models.
  locations:
  - preferred_term: Ciliary Base
    term:
      id: GO:0097546
      label: ciliary base
  - preferred_term: Centrosome
    term:
      id: GO:0005813
      label: centrosome
  pathways:
  - preferred_term: Hippo Signaling
    term:
      id: GO:0035329
      label: hippo signaling
  - preferred_term: Actin Cytoskeleton Organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
  downstream:
  - target: Renal Cyst Formation
  - target: Interstitial Fibrosis
  notes: The cilia-actin-Hippo axis represents a convergent downstream effector of ciliary dysfunction offering potential therapeutic targets
inheritance:
- name: Autosomal Recessive
  evidence:
  - reference: PMID:29717526
    reference_title: "Nephronophthisis: A review of genotype-phenotype correlation."
    supports: SUPPORT
    snippet: Nephronophthisis is an autosomal recessive cystic kidney disease and one of the most common genetic disorders causing end-stage renal disease in children.
    explanation: The literature clearly states that nephronophthisis follows an autosomal recessive inheritance pattern.
  - reference: PMID:31810733
    reference_title: "Adult-Diagnosed Nonsyndromic Nephronophthisis in Australian Families Caused by Biallelic NPHP4 Variants."
    supports: SUPPORT
    snippet: There is increasing appreciation of nephronophthisis (NPHP) as an autosomal recessive cause of kidney failure and earlier stages of chronic kidney disease among adults.
    explanation: The literature confirms that nephronophthisis is inherited in an autosomal recessive manner, even in cases diagnosed in adults.
- name: Tubulointerstitial Fibrosis
  description: Progressive fibrosis of the kidney's tubulointerstitial region.
  evidence:
  - reference: PMID:35533128
    reference_title: "[Nephronophthisis: a pediatric case report]."
    supports: SUPPORT
    snippet: Nephronophthisis is an autosomal recessive cystic kidney disease... resulting in kidney disease and extrarenal manifestations such as retinal degeneration and liver fibrosis.
    explanation: The literature indicates that nephronophthisis involves chronic tubulointerstitial changes compatible with fibrosis.
  - reference: PMID:27169608
    reference_title: "Clinical Scenarios in Chronic Kidney Disease: Chronic Tubulointerstitial Diseases."
    supports: SUPPORT
    snippet: Chronic tubulointerstitial nephritis (CTN) is characterized by interstitial scarring, fibrosis and tubule atrophy, resulting in progressive chronic kidney disease.
    explanation: While the article discusses tubulointerstitial nephritis in general, it supports the idea that fibrosis occurs in this region, although it does not specifically discuss nephronophthisis.
histopathology:
- name: Corticomedullary Cyst Formation
  description: Progressive development of cysts in the corticomedullary junction and distal tubules, characteristic of nephronophthisis. Early disease may show normal-appearing kidneys that gradually shrink with cyst progression.
  diagnostic: true
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:42400345
    reference_title: "Nephronophthisis: Current clinical spectrum and molecular pathogenesis."
    supports: SUPPORT
    snippet: Histopathologically, NPH is characterized by corticomedullary cysts, tubular atrophy, interstitial fibrosis, and cystic dilatation of distal tubules. The kidneys may appear normal in early stages but gradually shrink with disease progression.
    explanation: This comprehensive review provides detailed histopathological characterization of NPH, establishing corticomedullary cysts as the primary morphological feature with progressive kidney shrinkage.
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: SUPPORT
    snippet: Infantile nephronophtisis is a recessive autosomic tubulo-interstitial nephritis with cortical microcysts which progress to end stage renal failure before age 5.
    explanation: Historical literature confirms cortical microcysts as a pathological hallmark of nephronophthisis.
- name: Tubular Atrophy and Dilatation
  description: Progressive atrophy of renal tubules with dilatation of distal tubules, contributing to loss of nephron function and interstitial fibrosis.
  diagnostic: true
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:42400345
    reference_title: "Nephronophthisis: Current clinical spectrum and molecular pathogenesis."
    supports: SUPPORT
    snippet: Histopathologically, NPH is characterized by corticomedullary cysts, tubular atrophy, interstitial fibrosis, and cystic dilatation of distal tubules.
    explanation: Tubular atrophy and distal tubule dilatation are key pathological findings that contribute to progressive renal insufficiency in nephronophthisis.
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: SUPPORT
    snippet: Histologic lesions concern tubular basement membranes which are thickened and multilayered or thinned. There is an associated interstitial fibrosis.
    explanation: Tubular basement membrane abnormalities and interstitial fibrosis accompany tubular atrophy in nephronophthisis pathology.
phenotypes:
- category: Renal
  name: Progressive Renal Failure
  phenotype_term:
    preferred_term: Progressive Renal Failure
    term:
      id: HP:0012622
      label: Chronic kidney disease
  frequency: VERY_FREQUENT
  diagnostic: true
  sequelae:
  - target: End-Stage Renal Disease
  evidence:
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: SUPPORT
    snippet: Nephronophthisis is a chronic tubulo-interstitial nephritis which progress to terminal renal failure.
    explanation: This abstract describes nephronophthisis as a progressive renal disease leading to end-stage renal failure, supporting the idea that progressive renal failure is a frequent and diagnostic feature.
  - reference: PMID:33323469
    reference_title: "Phenotype and genotype spectra of a Chinese cohort with nephronophthisis-related ciliopathy."
    supports: SUPPORT
    snippet: Nephronophthisis-related ciliopathies (NPHP-RC) account for the majority of cases of monogenetically caused end-stage renal disease (ESRD) in children.
    explanation: This reference states that nephronophthisis-related ciliopathies are a common cause of end-stage renal disease in children, confirming that progressive renal failure and progression to ESRD is common.
  - reference: PMID:20969579
    reference_title: "Hereditary kidney diseases: highlighting the importance of classical Mendelian phenotypes."
    supports: SUPPORT
    snippet: A Mendelian inheritance underlies a nonnegligible proportion of hereditary kidney diseases, suggesting that the encoded proteins are essential for maintenance of the renal function.
    explanation: While the abstract primarily discusses hereditary kidney diseases in general, it emphasizes the importance of kidney function maintenance in genetic diseases, indirectly supporting the frequency and importance of progressive renal failure in conditions like nephronophthisis.
- category: Cardiovascular
  name: Hypertension
  frequency: FREQUENT
  evidence:
  - reference: PMID:17647025
    reference_title: "Heritable forms of hypertension."
    supports: NO_EVIDENCE
    snippet: Among the causes of secondary hypertension are a group of disorders with a Mendelian inheritance pattern. Recent advances in molecular biology have unveiled the pathogenesis of hypertension in many of these conditions.
    explanation: While this reference mentions Mendelian forms of hypertension, there is no specific mention of Nephronophthisis resulting in hypertension or cardiovascular phenotypes generally.
  - reference: PMID:20969579
    reference_title: "Hereditary kidney diseases: highlighting the importance of classical Mendelian phenotypes."
    supports: NO_EVIDENCE
    snippet: A Mendelian inheritance underlies a nonnegligible proportion of hereditary kidney diseases, suggesting that the encoded proteins are essential for maintenance of the renal function.
    explanation: This reference discusses hereditary kidney diseases and the genetic mutations involved but does not mention Nephronophthisis or its cardiovascular phenotypes including hypertension.
  - reference: PMID:12589180
    reference_title: "Dopamine and the kidney: a role in hypertension?"
    supports: NO_EVIDENCE
    snippet: Defective transduction of the dopamine receptor signal in the kidney...
    explanation: The article discusses the role of dopamine in the kidney and its involvement in hypertension, but it does not address Nephronophthisis or whether hypertension is a common cardiovascular phenotype in this condition.
  - reference: PMID:23402468
    reference_title: "Hypertension."
    supports: NO_EVIDENCE
    snippet: Hypertension is the most common modifiable risk factor for cardiovascular disease. Antihypertensive treatment substantially reduces the risk of heart failure, stroke, and myocardial infarction.
    explanation: This article offers a general overview of hypertension and its management but does not specifically mention Nephronophthisis or any associated cardiovascular phenotypes.
  - reference: PMID:16336577
    reference_title: "Systemic and glomerular hypertension and progression of chronic renal disease: the dilemma of nephrosclerosis."
    supports: NO_EVIDENCE
    snippet: Nephrosclerosis, benign nephrosclerosis, and hypertensive kidney disease are terms that clinicians use when renal damage is thought to be secondary to essential hypertension.
    explanation: While the article discusses hypertension in the context of renal diseases, it does not specify an association between Nephronophthisis and hypertension as a cardiovascular phenotype.
  - reference: PMID:37910243
    reference_title: "Hypertension in children with congenital anomalies of the kidney and urinary tract."
    supports: NO_EVIDENCE
    snippet: Hypertension is common in children with CAKUT and increases the risk of CKD.
    explanation: This study focuses on congenital anomalies of the kidney and urinary tract (CAKUT) and their association with hypertension, but it does not discuss Nephronophthisis.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
- category: Hepatic
  name: Fibrosis
  phenotype_term:
    preferred_term: Hepatic fibrosis
    term:
      id: HP:0001395
      label: Hepatic fibrosis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:35533128
    reference_title: "[Nephronophthisis: a pediatric case report]."
    supports: SUPPORT
    snippet: Nephronophthisis is an autosomal recessive cystic kidney disease caused by mutations in genes that encode proteins involved in the primary cilia function, resulting in kidney disease and extrarenal manifestations such as retinal degeneration and liver fibrosis.
    explanation: The literature mentions liver fibrosis as an extrarenal manifestation of nephronophthisis, supporting the statement that hepatic fibrosis is an occasional phenotype category of nephronophthisis.
- category: Ophthalmologic
  name: Retinitis Pigmentosa
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: SUPPORT
    snippet: 'Some children present with extrarenal symptoms: tapetoretinal degeneration (Senior-Loken syndrome)...'
    explanation: This reference indicates that tapetoretinal degeneration, synonymous with retinitis pigmentosa in the context of this disease, is an occasional extrarenal symptom of nephronophthisis.
  - reference: PMID:25161209
    reference_title: "Nephronophthisis and retinal degeneration in tmem218-/- mice: a novel mouse model for Senior-Løken syndrome?"
    supports: SUPPORT
    snippet: The renal lesions were characterized by diffuse renal cyst development with tubulointerstitial nephropathy...These renal and retinal lesions are most similar to those associated with nephronophthisis (NPHP) and retinitis pigmentosa in humans.
    explanation: This reference directly confirms the association between nephronophthisis and retinitis pigmentosa as occasional ophthalmologic phenotypes.
  - reference: PMID:37644229
    reference_title: "Ocular manifestations of renal ciliopathies."
    supports: SUPPORT
    snippet: Eighty-two of the 86 pediatric-onset renal ciliopathies (95%) have an ocular phenotype, including inherited retinal degeneration, oculomotor disorders, and coloboma.
    explanation: This indicates that ophthalmologic phenotypes, including retinal degeneration, are common in pediatric renal ciliopathies including nephronophthisis.
  phenotype_term:
    preferred_term: Retinitis Pigmentosa
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
- category: Developmental
  frequency: OCCASIONAL
  name: Growth Retardation
  notes: May be seen due to chronic kidney disease
  evidence:
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: SUPPORT
    snippet: 'Some children present with extrarenal symptoms: tapetoretinal degeneration (Senior-Loken syndrome), mental retardation, cerebellar ataxia, bone anomalies or liver involvement.'
    explanation: The reference mentions extrarenal symptoms associated with nephronophthisis but does not specifically mention growth retardation. However, growth retardation could be inferred as a potential consequence of chronic kidney disease.
  - reference: PMID:30552565
    reference_title: "Growth plate alterations in chronic kidney disease."
    supports: SUPPORT
    snippet: Growth retardation is a major feature of chronic kidney disease (CKD) of onset in infants or children and is associated with increased morbidity and mortality.
    explanation: This reference supports the statement that growth retardation is associated with chronic kidney disease, which can be a consequence of nephronophthisis.
  phenotype_term:
    preferred_term: Growth Retardation
    term:
      id: HP:0001510
      label: Growth delay
- category: Musculoskeletal
  frequency: OCCASIONAL
  name: Bone Deformities
  notes: Related to renal osteodystrophy from kidney failure
  evidence:
  - reference: PMID:35533128
    reference_title: "[Nephronophthisis: a pediatric case report]."
    supports: NO_EVIDENCE
    snippet: Nephronophthisis is an autosomal recessive cystic kidney disease caused by mutations in genes that encode proteins involved in the primary cilia function, resulting in kidney disease and extrarenal manifestations such as retinal degeneration and liver fibrosis.
    explanation: The provided literature does not mention musculoskeletal issues or bone deformities as part of the clinical manifestations of nephronophthisis.
  - reference: PMID:27219042
    reference_title: "Skeletal manifestations of renal disease in childhood."
    supports: NO_EVIDENCE
    snippet: Recent findings substantiate concern regarding the particular vulnerability of the growing skeleton to chronic renal disease.
    explanation: Although chronic kidney disease can lead to musculoskeletal issues, the literature does not specifically link nephronophthisis to bone deformities related to renal osteodystrophy.
- category: Endocrine
  frequency: OCCASIONAL
  name: Secondary Hyperparathyroidism
  notes: Develops as a consequence of chronic renal failure
  evidence:
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: REFUTE
    snippet: Nephronophthisis is a chronic tubulo-interstitial nephritis which progress to terminal renal failure.
    explanation: Nephronophthisis is a type of chronic tubulo-interstitial nephritis and not an endocrine disorder. It primarily affects the kidneys and progresses to terminal renal failure, but it is not categorized as an endocrine disorder nor is it specifically associated with secondary hyperparathyroidism.
  phenotype_term:
    preferred_term: Secondary Hyperparathyroidism
    term:
      id: HP:0000867
      label: Secondary hyperparathyroidism
- category: Renal
  name: Polyuria
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Polyuria
    term:
      id: HP:0000103
      label: Polyuria
- category: Systemic
  name: Polydipsia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Polydipsia
    term:
      id: HP:0001959
      label: Polydipsia
- category: Metabolic
  name: Electrolyte Imbalance
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Electrolyte Imbalance
    term:
      id: HP:0003111
      label: Abnormal blood ion concentration
- category: Renal
  name: End-Stage Renal Disease
  frequency: FREQUENT
  phenotype_term:
    preferred_term: End-Stage Renal Disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
biochemical:
- name: Serum Creatinine
  presence: Elevated
  evidence:
  - reference: PMID:37930417
    reference_title: "Nephronophthisis: a pathological and genetic perspective."
    supports: SUPPORT
    snippet: Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and is one of the most frequent genetic causes for kidney failure (KF) in children and adolescents.
    explanation: Kidney failure implies elevated serum creatinine. This reference indicates nephronophthisis is a frequent cause of kidney failure, indirectly supporting elevated creatinine as a biochemical finding.
- name: Elevated Blood Urea Nitrogen (BUN)
  presence: Elevated
  evidence:
  - reference: PMID:7272960
    reference_title: "Nephrotoxicity of nitrosoureas."
    supports: SUPPORT
    snippet: Irreversible and progressive renal parenchymal damage and functional impairment occurred in the majority of patients receiving at least six courses (200 mg/m2 of BCNU and/or methyl CCNU at eight-week intervals) of nitrosoureas for therapy of malignant brain tumors. Seventeen of 18 patients who received at least six courses and all nine patients who received more than ten courses developed impaired renal function as judged by elevation of blood urea nitrogen and/or serum creatinine or decrease in filtration rate as determined by inulin clearance.
    explanation: The literature supports elevated BUN as a marker of renal damage but does not specify nephronophthisis. Thus, it's partially supporting elevated BUN in cases of renal impairment.
  - reference: PMID:26769764
    reference_title: "eGFR and Outcomes in Patients with Acute Decompensated Heart Failure with or without Elevated BUN."
    supports: SUPPORT
    snippet: 'CONCLUSIONS: We showed that elevation of BUN at discharge significantly modified the relation between eGFR at discharge and the risk of all-cause mortality after discharge, suggesting that the association between eGFR and outcomes may be largely dependent on concomitant elevation of BUN.'
    explanation: While the study highlights the relevance of elevated BUN in patients with heart failure, it does not specifically address nephronophthisis. Therefore, it partially supports the biochemical value.
  - reference: PMID:21722602
    reference_title: "Saliva urea dipstick test: application in chronic kidney disease."
    supports: SUPPORT
    snippet: 'CONCLUSION: Semiquantitative dipstick measurements of SUN can reliably identify CKD patients with elevated BUN levels.'
    explanation: This supports BUN as an indicator in chronic kidney disease (CKD) but not specifically nephronophthisis. Hence, it gives partial support.
genetic:
- name: NPHP1
  gene_term:
    preferred_term: NPHP1
    term:
      id: hgnc:7905
      label: NPHP1
  association: Pathogenic Variants
  subtype: NPHP1-related
  evidence:
  - reference: PMID:15138899
    reference_title: "The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome."
    supports: SUPPORT
    snippet: Two siblings affected with a mild form of JS were found to have a homozygous deletion of the NPHP1 gene identical, by mapping, to that in subjects with NPHP alone.
    explanation: The NPHP1 gene deletion is associated with juvenile nephronophthisis, confirming the genetic link between NPHP1 and nephronophthisis.
  - reference: PMID:36990420
    reference_title: "Pathogenic Variants in CEP290 or IQCB1 Cause Earlier-Onset Retinopathy in Senior-Loken Syndrome Compared to Those in INVS, NPHP3, or NPHP4."
    supports: SUPPORT
    snippet: Patients with pathogenic variants in CEP290 or IQCB1 presented early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4 variants first developed nephropathy.
    explanation: This reference supports the genetic association of nephronophthisis with variants in several genes, highlighting NPHP1 among the genes associated with nephropathy.
- name: CEP164
  association: Pathogenic Variants
  presence: Positive
  subtype: CEP164-related
  gene_term:
    preferred_term: CEP164
    term:
      id: hgnc:29182
      label: CEP164
  evidence:
  - reference: PMID:22863007
    reference_title: "Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We thereby identified recessive mutations of CEP164 as a new cause of NPHP-RC.
    explanation: Recessive CEP164 mutations define NPHP15 (MONDO:0013917), the CEP164-related nephronophthisis leaf class, and link the disorder to DNA-damage-response signaling.
- name: NPHP3
  gene_term:
    preferred_term: NPHP3
    term:
      id: hgnc:7907
      label: NPHP3
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: NPHP3-related
  evidence:
  - reference: PMID:34212438
    reference_title: "A discarded synonymous variant in NPHP3 explains nephronophthisis and congenital hepatic fibrosis in several families."
    supports: SUPPORT
    snippet: we detected a homozygous predicted synonymous allele in NPHP3 in two children with hepatorenal fibrocystic disease from a consanguineous family.
  - reference: PMID:26184788
    reference_title: "High mutation rate of NPHP3 in 18 Chinese infantile nephronophthisis patients."
    supports: SUPPORT
    snippet: Eight of 17 (47.1%) patients detected were identified to have mutations in NPHP3.
  - reference: PMID:36990420
    reference_title: "Pathogenic Variants in CEP290 or IQCB1 Cause Earlier-Onset Retinopathy in Senior-Loken Syndrome Compared to Those in INVS, NPHP3, or NPHP4."
    supports: SUPPORT
    snippet: Patients with pathogenic variants in CEP290 or IQCB1 presented early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4 variants first developed nephropathy.
  - reference: CGGV:assertion_47c3a0f1-9c14-4c92-83f2-e1105d528097-2021-07-24T160000.000Z
    reference_title: "NPHP3 / nephronophthisis (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NPHP3 | HGNC:7907 | nephronophthisis | MONDO:0019005 | AR | Definitive"
    explanation: ClinGen classifies the NPHP3-nephronophthisis gene-disease relationship as definitive with autosomal recessive inheritance.
- name: NPHP4
  gene_term:
    preferred_term: NPHP4
    term:
      id: hgnc:19104
      label: NPHP4
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: NPHP4-related
  evidence:
  - reference: PMID:14750102
    reference_title: "Clinical and histological presentation of 3 siblings with mutations in the NPHP4 gene."
    supports: SUPPORT
    snippet: 'Nephronophthisis (NPH) is an autosomal recessive kidney disease... Four genes responsible for different types of NPH have been identified: NPHP1, NPHP2, NPHP3, and NPHP4.'
    explanation: The literature identifies NPHP4 as one of the genes responsible for different types of Nephronophthisis.
  - reference: PMID:34591160
    reference_title: "Association of Nephronophthisis 4 genetic variation with cardiorenal syndrome and cardiovascular events in Japanese general population: the Yamagata (Takahata) study."
    supports: SUPPORT
    snippet: Nephronophthisis (NPHP) 4 gene encoding nephrocystin-4... contributes to end-stage renal disease in children and young adults.
    explanation: The literature indicates that NPHP4 is associated with end-stage renal disease in Nephronophthisis, highlighting its pathogenic role.
  - reference: PMID:36990420
    reference_title: "Pathogenic Variants in CEP290 or IQCB1 Cause Earlier-Onset Retinopathy in Senior-Loken Syndrome Compared to Those in INVS, NPHP3, or NPHP4."
    supports: SUPPORT
    snippet: Senior-Loken syndrome (SLSN) is an autosomal recessive disorder characterized by retinopathy and nephronophthisis... Patients with pathogenic variants in CEP290 or IQCB1 presented early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4 variants first developed nephropathy.
    explanation: The literature mentions that patients with NPHP4 variants develop nephropathy in the context of Nephronophthisis.
- name: INVS
  gene_term:
    preferred_term: INVS
    term:
      id: hgnc:17870
      label: INVS
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: Infantile Nephronophthisis
  notes: >-
    Also known as NPHP2; inversin antagonizes canonical WNT signaling. The
    reciprocal subtype key points at the Infantile Nephronophthisis row, which
    is the row bound to MONDO:0011190 (nephronophthisis 2) - MONDO carries
    "nephronophthisis 2, infantile" as a synonym of that class, so the clinical
    and molecular labels denote one concept here.
  evidence:
  - reference: PMID:15852005
    reference_title: "Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mutations of the ciliary protein inversin cause nephronophthisis type II,
      an autosomal recessive cystic kidney disease characterized by extensive
      renal cysts, situs inversus and renal failure.
    explanation: >-
      Supports the NPHP2 designation in this record's note and the
      gene-disease relationship itself.
  - reference: PMID:15852005
    reference_title: "Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Inversin inhibits the canonical Wnt pathway by targeting cytoplasmic
      dishevelled (Dsh or Dvl1) for degradation
    explanation: >-
      Supports the canonical-Wnt antagonism this record's note asserts, which
      previously carried no citation.
  - reference: PMID:14750102
    reference_title: "Clinical and histological presentation of 3 siblings with mutations in the NPHP4 gene."
    supports: SUPPORT
    snippet: 'Nephronophthisis (NPH) is an autosomal recessive kidney disease... Four genes responsible for different types of NPH have been identified: NPHP1, NPHP2, NPHP3, and NPHP4.'
    explanation: The literature identifies NPHP2 (INVS) as one of the genes responsible for different types of Nephronophthisis.
  - reference: PMID:36990420
    reference_title: "Pathogenic Variants in CEP290 or IQCB1 Cause Earlier-Onset Retinopathy in Senior-Loken Syndrome Compared to Those in INVS, NPHP3, or NPHP4."
    supports: SUPPORT
    snippet: Patients with pathogenic variants in CEP290 or IQCB1 presented early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4 variants first developed nephropathy.
    explanation: The literature confirms INVS variants are associated with nephropathy in nephronophthisis.
- name: NEK8
  gene_term:
    preferred_term: NEK8
    term:
      id: hgnc:13387
      label: NEK8
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: NEK8-related
  notes: >-
    Also known as NPHP9, a NIMA-family ciliary kinase in the INV complex. Three
    conserved amino-acid changes, all in RCC1 repeats, were found by screening a
    worldwide cohort of 588 nephronophthisis patients; the same domain carries
    the mutation of the jck mouse cystic-kidney model.
  evidence:
  - reference: PMID:18199800
    reference_title: "NEK8 mutations affect ciliary and centrosomal localization and may cause nephronophthisis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 3 different amino acid changes that were conserved through
      evolution (L330F, H425Y, and A497P) and that were absent from at least 80
      ethnically matched controls.
    explanation: >-
      The human genetic evidence for the NEK8-nephronophthisis relationship this
      record asserts, from a 588-patient mutational screen.
  - reference: PMID:18199800
    reference_title: "NEK8 mutations affect ciliary and centrosomal localization and may cause nephronophthisis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our genetic and functional data support the assumption that mutations in
      NEK8 cause nephronophthisis (NPHP9), adding another link between proteins
      mutated in cystic kidney disease and their localization to cilia and
      centrosomes.
    explanation: >-
      The authors' own conclusion, and the source of the NPHP9 designation used
      in this record's note.
  - reference: PMID:36990420
    reference_title: "Pathogenic Variants in CEP290 or IQCB1 Cause Earlier-Onset Retinopathy in Senior-Loken Syndrome Compared to Those in INVS, NPHP3, or NPHP4."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: Patients with pathogenic variants in CEP290 or IQCB1 presented early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4 variants first developed nephropathy.
    explanation: >-
      Retained for the genetic-heterogeneity context it gives, but regraded to
      NO_EVIDENCE: the quoted sentence does not mention NEK8 and so does not
      bear on this gene-disease claim. The previous SUPPORT grading was
      contradicted by its own explanation.
- name: GLIS2
  gene_term:
    preferred_term: GLIS2
    term:
      id: hgnc:29450
      label: GLIS2
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: GLIS2-related
  inheritance:
  - name: Autosomal recessive
  notes: >-
    Also known as NPHP7. GLIS2 is a Kruppel-like zinc-finger transcription
    factor, not a structural ciliary protein, so it is wired in this entry to a
    transcriptional node feeding interstitial fibrosis rather than to the
    ciliary nodes.
  evidence:
  - reference: PMID:17618285
    reference_title: "Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here we identify mutation of GLIS2 as causing an NPHP-like phenotype in humans and mice, using positional cloning and mouse transgenics, respectively.
    explanation: The gene-delineation result for GLIS2.
  - reference: PMID:17618285
    reference_title: "Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Thus, we identify Glis2 as a transcription factor mutated in NPHP and demonstrate its essential role for the maintenance of renal tissue architecture through prevention of apoptosis and fibrosis.
    explanation: The transcription-factor identity and the tissue-maintenance role this record's note asserts.
  - reference: CGGV:assertion_c51be76f-59d3-4884-9df3-4416686848ab-2024-06-27T160000.000Z
    reference_title: "GLIS2 / nephronophthisis 7 (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "GLIS2 | HGNC:29450 | nephronophthisis 7 | MONDO:0012680 | AR | Moderate"
    explanation: ClinGen's gene-disease validity call, graded Moderate, against the class this gene's subtype row binds.
- name: TMEM67
  gene_term:
    preferred_term: TMEM67
    term:
      id: hgnc:28396
      label: TMEM67
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: TMEM67-related
  inheritance:
  - name: Autosomal recessive
  notes: >-
    Also known as MKS3, and the previous HGNC symbol for this gene. The
    nephronophthisis presentation (NPHP11) is associated with missense rather
    than truncating alleles, which is what distinguishes it from the
    TMEM67-related Meckel-Gruber and Joubert syndrome presentations.
  evidence:
  - reference: PMID:19508969
    reference_title: "Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hypomorphic MKS3/TMEM67 mutations cause NPHP with liver fibrosis (NPHP11).
    explanation: The gene-delineation conclusion and the source of the NPHP11 designation in this record's note.
  - reference: PMID:19508969
    reference_title: "Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In contrast, the mutations detected here in patients with NPHP and associated liver fibrosis are exclusively missense mutations.
    explanation: The allele-class contrast this record's note asserts.
  - reference: CGGV:assertion_8f380d4b-6d0b-4c09-a3ae-ec34bc8ecb8d-2021-07-14T160000.000Z
    reference_title: "TMEM67 / ciliopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TMEM67 | HGNC:28396 | ciliopathy | MONDO:0005308 | AR | Definitive"
    explanation: ClinGen classifies the gene Definitive, against its lumped ciliopathy class rather than the numbered nephronophthisis class.
- name: TTC21B
  gene_term:
    preferred_term: TTC21B
    term:
      id: hgnc:25660
      label: TTC21B
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: TTC21B-related
  inheritance:
  - name: Autosomal recessive
  notes: >-
    Also known as NPHP12. TTC21B encodes IFT139 of intraflagellar transport
    complex A, and the delineating report also found heterozygous pathogenic
    alleles enriched in a broader ciliopathy cohort, so the gene contributes
    modifier as well as causal alleles.
  evidence:
  - reference: CGGV:assertion_60f93fe0-145f-47a7-9ecf-613b1b1dfa7f-2021-11-10T170000.000Z
    reference_title: "TTC21B / nephronophthisis 12 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TTC21B | HGNC:25660 | nephronophthisis 12 | MONDO:0013442 | AR | Definitive"
    explanation: ClinGen classifies this relationship Definitive against the numbered class itself.
  - reference: PMID:21258341
    reference_title: "TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here we show that mutations in TTC21B, which encodes the retrograde intraflagellar transport protein IFT139, cause both isolated nephronophthisis and syndromic Jeune asphyxiating thoracic dystrophy.
    explanation: The gene-delineation result and the IFT139 identity in this record's note.
  - reference: PMID:21258341
    reference_title: "TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: in vivo and in vitro evaluations showed a significant enrichment of pathogenic alleles in cases (P < 0.003), suggesting that TTC21B contributes pathogenic alleles to ∼5% of ciliopathy cases
    explanation: The modifier-allele contribution this record's note asserts.
- name: WDR19
  gene_term:
    preferred_term: WDR19
    term:
      id: hgnc:18340
      label: WDR19
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: WDR19-related
  inheritance:
  - name: Autosomal recessive
  notes: >-
    Also known as NPHP13. WDR19 encodes IFT144 of intraflagellar transport
    complex A, the same complex as TTC21B, and the reported families span
    Sensenbrenner and Jeune syndromes as well as isolated nephronophthisis.
  evidence:
  - reference: PMID:22019273
    reference_title: "Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Independently, we also identified compound heterozygous WDR19 mutations by exome sequencing in a Moroccan family with isolated nephronophthisis.
    explanation: The isolated-nephronophthisis presentation that makes this gene a nephronophthisis gene rather than only a skeletal-ciliopathy gene.
  - reference: PMID:22019273
    reference_title: "Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: WDR19 encodes IFT144, a member of the intraflagellar transport (IFT) complex A that drives retrograde ciliary transport.
    explanation: The IFT144 identity and complex membership in this record's note, and the basis for wiring it with TTC21B.
  - reference: CGGV:assertion_418a6e41-45ad-411f-a40d-2f7cb61ff589-2022-05-25T160000.000Z
    reference_title: "WDR19 / ciliopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "WDR19 | HGNC:18340 | ciliopathy | MONDO:0005308 | AR | Definitive"
    explanation: ClinGen classifies the gene Definitive, against its lumped ciliopathy class rather than the numbered nephronophthisis class.
- name: ZNF423
  gene_term:
    preferred_term: ZNF423
    term:
      id: hgnc:16762
      label: ZNF423
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: ZNF423-related
  inheritance:
  - name: Autosomal recessive
  notes: >-
    Also known as NPHP14. ZNF423 was identified together with CEP164 in the
    study that placed a DNA damage response pathway in nephronophthisis
    pathogenesis, and it is wired here to the DNA damage node alongside CEP164.
  evidence:
  - reference: PMID:22863007
    reference_title: "Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we identify by whole-exome resequencing, mutations of MRE11, ZNF423, and CEP164 as causing NPHP-RC. All three genes function within the DNA damage response (DDR) pathway.
    explanation: The gene-delineation result for ZNF423 and the pathway assignment this record's note states.
  - reference: PMID:22863007
    reference_title: "Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We show that knockdown of CEP164 or ZNF423 causes sensitivity to DNA damaging agents
    explanation: The functional DNA-damage phenotype behind wiring ZNF423 to the DNA damage node.
  - reference: CGGV:assertion_c61623dd-07b1-41c5-b445-3f9f8575cc06-2024-06-26T040000.000Z
    reference_title: "ZNF423 / ciliopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ZNF423 | HGNC:16762 | ciliopathy | MONDO:0005308 | AR | Moderate"
    explanation: ClinGen's gene-disease validity call, graded Moderate and made against the lumped ciliopathy class.
- name: ANKS6
  gene_term:
    preferred_term: ANKS6
    term:
      id: hgnc:26724
      label: ANKS6
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: ANKS6-related
  inheritance:
  - name: Autosomal recessive
  notes: >-
    Also known as NPHP16. ANKS6 is the central component of the module that
    links NEK8 (NPHP9) to INVS (NPHP2) and NPHP3, which is the stated reason
    those four genes produce overlapping disease.
  evidence:
  - reference: CGGV:assertion_62df8a40-0b65-46a4-89c8-51f26424c523-2021-08-25T160000.000Z
    reference_title: "ANKS6 / nephronophthisis 16 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ANKS6 | HGNC:26724 | nephronophthisis 16 | MONDO:0014158 | AR | Definitive"
    explanation: ClinGen classifies this relationship Definitive against the numbered class itself.
  - reference: PMID:23793029
    reference_title: "ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We also identify six families with ANKS6 mutations affected by nephronophthisis, including severe cardiovascular abnormalities, liver fibrosis and situs inversus.
    explanation: The human genetic evidence for the ANKS6-nephronophthisis relationship.
  - reference: PMID:23793029
    reference_title: "ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Network analyses uncovered additional putative NPHP proteins and placed ANKS6 at the center of this NPHP module, explaining the overlapping disease manifestation caused by mutation in ANKS6, NEK8, INVS or NPHP3.
    explanation: The module membership this record's note asserts.
- name: CEP83
  gene_term:
    preferred_term: CEP83
    term:
      id: hgnc:17966
      label: CEP83
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: CEP83-related
  inheritance:
  - name: Autosomal recessive
  notes: >-
    Also known as NPHP18. CEP83 is a distal appendage protein of the mother
    centriole, the same compartment as CEP164, and was found by targeted exon
    sequencing of cilia-associated and distal-appendage genes in a large
    nephronophthisis-related ciliopathy cohort.
  evidence:
  - reference: PMID:24882706
    reference_title: "Mutations of CEP83 cause infantile nephronophthisis and intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In summary, we have identified mutations in CEP83, another DAP-component-encoding gene, as a cause of infantile nephronophthisis associated with central nervous system abnormalities in half of the individuals.
    explanation: The gene-delineation conclusion for CEP83.
  - reference: PMID:24882706
    reference_title: "Mutations of CEP83 cause infantile nephronophthisis and intellectual disability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Fibroblasts and tubular renal cells from affected individuals showed an altered DAP composition and ciliary defects.
    explanation: The measured distal-appendage and ciliary defect in patient cells, which is how this gene is wired.
  - reference: PMID:24882706
    reference_title: "Mutations of CEP83 cause infantile nephronophthisis and intellectual disability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The distal appendages (DAPs) of centrioles are involved in the docking and anchoring of the mother centriole to the cellular membrane during ciliogenesis.
    explanation: The distal-appendage function this record's note states.
- name: DCDC2
  gene_term:
    preferred_term: DCDC2
    term:
      id: hgnc:18141
      label: DCDC2
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: DCDC2-related
  inheritance:
  - name: Autosomal recessive
  notes: >-
    Also known as NPHP19. DCDC2 acts on both arms of this entry's pathograph:
    its loss disrupts ciliogenesis, and it also restrains beta-catenin-dependent
    Wnt signaling through an interaction with dishevelled, which is the same
    signaling axis inversin acts on.
  evidence:
  - reference: PMID:25557784
    reference_title: "DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We here identify mutations of DCDC2 as causing a renal-hepatic ciliopathy.
    explanation: The gene-delineation result for DCDC2.
  - reference: PMID:25557784
    reference_title: "DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Knockdown of Dcdc2 in IMCD3 cells disrupts ciliogenesis, which is rescued by wild-type (WT) human DCDC2, but not by constructs that reflect human mutations.
    explanation: The ciliogenesis requirement behind wiring DCDC2 to the ciliary node.
  - reference: PMID:25557784
    reference_title: "DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We show that DCDC2 interacts with DVL and DCDC2 overexpression inhibits β-catenin-dependent Wnt signaling in an effect additive to Wnt inhibitors.
    explanation: The Wnt arm this record's note asserts, and the basis for also wiring DCDC2 to the signaling node.
  - reference: CGGV:assertion_477c8aba-eeba-43dc-a5e2-f6f84b127b8f-2021-10-13T160000.000Z
    reference_title: "DCDC2 / ciliopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "DCDC2 | HGNC:18141 | ciliopathy | MONDO:0005308 | AR | Definitive"
    explanation: ClinGen classifies the gene Definitive, against its lumped ciliopathy class rather than the numbered nephronophthisis class.
- name: MAPKBP1
  gene_term:
    preferred_term: MAPKBP1
    term:
      id: hgnc:29536
      label: MAPKBP1
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: MAPKBP1-related
  inheritance:
  - name: Autosomal recessive
  notes: >-
    Also known as NPHP20, and the one gene in this entry whose product is
    explicitly not a ciliary protein: MAPKBP1 is a JNK scaffolding protein
    recruited to mitotic spindle poles, and patient fibroblasts show no
    ciliogenesis defect. It is wired to the DNA damage node rather than to the
    ciliary nodes for that reason.
  evidence:
  - reference: CGGV:assertion_b8542450-d48b-45ba-bd5f-4e55d210aa6b-2024-06-10T160000.000Z
    reference_title: "MAPKBP1 / nephronophthisis 20 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MAPKBP1 | HGNC:29536 | nephronophthisis 20 | MONDO:0014997 | AR | Definitive"
    explanation: ClinGen classifies this relationship Definitive against the numbered class itself.
  - reference: PMID:28089251
    reference_title: "Mutations in MAPKBP1 Cause Juvenile or Late-Onset Cilia-Independent Nephronophthisis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In conclusion, we identified mutations in MAPKBP1 as a genetic cause of juvenile or late-onset and cilia-independent NPH.
    explanation: The gene-delineation conclusion and the source of the cilia-independence in this record's note.
  - reference: PMID:28089251
    reference_title: "Mutations in MAPKBP1 Cause Juvenile or Late-Onset Cilia-Independent Nephronophthisis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Immunofluorescence analyses showed that MAPKBP1 is not present at the primary cilium and that fibroblasts from affected individuals did not display ciliogenesis defects
    explanation: The measured absence of a ciliary phenotype, which is why this gene is not on the ciliary nodes.
  - reference: PMID:28089251
    reference_title: "Mutations in MAPKBP1 Cause Juvenile or Late-Onset Cilia-Independent Nephronophthisis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Additionally, we show increased DNA damage response signaling in fibroblasts from affected individuals and upon knockdown of Mapkbp1 in murine cell lines, a phenotype previously associated with NPH.
    explanation: The DNA damage response phenotype that places this gene on the DNA damage node.
- name: XPNPEP3
  gene_term:
    preferred_term: XPNPEP3
    term:
      id: hgnc:28052
      label: XPNPEP3
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: XPNPEP3-related
  inheritance:
  - name: Autosomal recessive
  notes: >-
    The NPHP-like 1 (NPHPL1) locus. XPNPEP3 is a mitochondrial X-prolyl
    aminopeptidase rather than a cilium-centrosome protein; its link to ciliary
    biology is indirect, through ciliary cystogenic proteins that are its
    substrates.
  evidence:
  - reference: CGGV:assertion_c1fd65c6-6010-4ee7-bb1c-e347c539127c-2024-06-10T160000.000Z
    reference_title: "XPNPEP3 / nephronophthisis-like nephropathy 1 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "XPNPEP3 | HGNC:28052 | nephronophthisis-like nephropathy 1 | MONDO:0013163 | AR | Definitive"
    explanation: ClinGen classifies this relationship Definitive against the class this gene's subtype row binds.
  - reference: PMID:20179356
    reference_title: "Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In 2 families with an NPHP-like phenotype, we detected homozygous frameshift and splice-site mutations, respectively, in the X-prolyl aminopeptidase 3 (XPNPEP3) gene.
    explanation: The gene-delineation result and the source of the biallelic inheritance recorded here.
  - reference: PMID:20179356
    reference_title: "Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In contrast to all known NPHP proteins, XPNPEP3 localizes to mitochondria of renal cells.
    explanation: The mitochondrial localisation this record's note asserts.
  - reference: PMID:20179356
    reference_title: "Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Consistent with a role for XPNPEP3 in ciliary function, several ciliary cystogenic proteins were found to be XPNPEP3 substrates
    explanation: The indirect ciliary link this record's note describes.
environmental:
- name: Not Applicable
  notes: Nephronophthisis is primarily driven by genetic mutations.
  evidence:
  - reference: PMID:15917209
    reference_title: "Nephronophthisis."
    supports: REFUTE
    snippet: There has been tremendous progress in the past few years in understanding the molecular basis of nephronophthisis, and it is now evident that the disease is characterized by both clinical and genetic heterogeneity.
    explanation: This indicates that Nephronophthisis is primarily driven by genetic mutations, not environmental factors.
  - reference: PMID:20844548
    reference_title: "The novel and independent association between single-point SNP of NPHP4 gene and renal function in non-diabetic Japanese population: the Takahata study."
    supports: REFUTE
    snippet: Nephronophthisis (NPHP) 4 gene coding nephrocystin-4 is involved in the development of renal tubules and its congenital mutations cause juvenile end-stage renal disease, NPHP.
    explanation: This further supports that Nephronophthisis is caused by genetic mutations and not by environmental factors.
  - reference: PMID:29869359
    reference_title: "Transplantation for infantile nephronophthisis with loss-of-function mutation in NPHP3: Lesson from a case."
    supports: REFUTE
    snippet: The patient had elevated liver enzymes and biopsy-proven liver fibrosis. As liver synthesis was acceptable, only KT was performed. However, liver fibrosis progressed at 1.5 years after transplantation, manifested with portal hypertension and hypersplenism.
    explanation: This case study describes genetic mutations as the cause of disease progression, reinforcing that Nephronophthisis is genetically driven.
treatments:
- name: Renal Replacement Therapy
  description: Dialysis or kidney transplantation for end-stage renal disease.
  evidence:
  - reference: PMID:32906116
    reference_title: "Living-Related Kidney Transplantation in a Patient with Juvenile Nephronophthisis."
    supports: SUPPORT
    snippet: Nephronophthisis (NPHP) is an autosomal recessive disease manifesting as tubulointerstitial nephritis uniformly progressing to ESRD in approximately 5-10% patients in childhood. Living donor transplantation is the most beneficial mean of renal replacement therapy compared to other methods.
    explanation: The abstract discusses that Nephronophthisis often leads to end-stage renal disease (ESRD) and mentions living donor transplantation as a beneficial renal replacement therapy option.
  - reference: PMID:15715116
    reference_title: "Choice of renal replacement therapy in patients with diabetic end stage renal disease."
    supports: SUPPORT
    snippet: 'Diabetes and ESRD receiving Renal Replacement Therapy (RRT)... The main choices of modalities are: 1) haemodialysis (HD), 2) Peritoneal dialysis (PD), 3) Kidney transplantation alone (KTA) or 4) simultaneous kidney and pancreas transplantation (SPKT).'
    explanation: Although this reference focuses on diabetic nephropathy, it supports the statement that renal replacement therapies for ESRD include dialysis and kidney transplantation.
  treatment_term:
    preferred_term: renal dialysis
    term:
      id: NCIT:C15221
      label: Dialysis
- name: Antihypertensive Therapy
  description: Management of blood pressure with medications.
  evidence:
  - reference: PMID:36224286
    reference_title: "Nephrons, podocytes and chronic kidney disease: Strategic antihypertensive therapy for renoprotection."
    supports: SUPPORT
    snippet: Chronic kidney disease (CKD) is one of the strongest risk factors for hypertension, and hypertension can exacerbate the progression of CKD... therefore, one of the best strategies to slow the progression of CKD is to maintain the 'numbers' of these essential components necessary to preserve renal function. To this end, both the achievement of an optimal blood pressure and a maximum reduction in urinary protein excretion are essential.
    explanation: This source suggests that managing blood pressure is essential in the context of CKD, which is related to nephron function. However, it does not explicitly mention Nephronophthisis, a specific type of nephropathy.
  - reference: PMID:30354828
    reference_title: "Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association."
    supports: NO_EVIDENCE
    snippet: Resistant hypertension (RH) is defined as above-goal elevated blood pressure (BP) in a patient despite the concurrent use of 3 antihypertensive drug classes...evaluation includes identification of contributing lifestyle issues, detection of drugs interfering with antihypertensive medication effectiveness, screening for secondary hypertension, and assessment of target organ damage. Management of RH includes maximization of lifestyle interventions, use of long-acting thiazide-like diuretics (chlorthalidone or indapamide), addition of a mineralocorticoid receptor antagonist (spironolactone or eplerenone), and, if BP remains elevated, stepwise addition of antihypertensive drugs with complementary mechanisms of action to lower BP.
    explanation: This source provides comprehensive information on the evaluation and management of resistant hypertension but does not discuss Nephronophthisis specifically.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Gene Therapy
  description: Emerging therapeutic strategy targeting NPHP gene defects to restore ciliary function and prevent disease progression.
  treatment_term:
    preferred_term: Gene Therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  evidence:
  - reference: PMID:42400345
    reference_title: "Nephronophthisis: Current clinical spectrum and molecular pathogenesis."
    supports: SUPPORT
    snippet: "This review summarizes the current understanding of NPH classification, clinical features, and molecular mechanisms. Here, we highlighted recent advances in genetic discoveries, pathogenic signaling pathways, and therapeutic strategies, including gene therapy and targeted molecular interventions."
    explanation: Gene therapy is identified as an advancing therapeutic strategy in current nephronophthisis research and management.
- name: Supportive Care
  description: Symptomatic treatment and monitoring to manage associated complications.
  evidence:
  - reference: PMID:35533128
    reference_title: "[Nephronophthisis: a pediatric case report]."
    supports: SUPPORT
    snippet: At the moment there is no healing therapy, so early kidney transplant is a fundamental tool to improve prognosis.
    explanation: There is no curative treatment for nephronophthisis, indicating that supportive care, including symptomatic treatment and monitoring, is currently applied to manage associated complications.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
review_notes: Nephronophthisis is a ciliopathy causing chronic tubulointerstitial nephritis. The cardinal feature is progressive renal failure, usually beginning in childhood and adolescence and leading to end-stage renal disease. Recent research highlights multiple converging mechanisms including ciliary dysfunction, disrupted WNT/Hedgehog/EGFR/Hippo signaling, aberrant actin-RhoA remodeling, and DNA damage response defects leading to cellular senescence. Extrarenal manifestations like retinitis pigmentosa (Senior-Loken syndrome) and liver fibrosis may occur in 10-20% of cases. The cilia-actin-Hippo axis represents a potential therapeutic target, with experimental evidence for EGFR inhibitors rescuing ciliary defects in patient-derived cells.
disease_term:
  preferred_term: nephronophthisis
  term:
    id: MONDO:0019005
    label: nephronophthisis
classifications:
  harrisons_chapter:
  - classification_value: KIDNEY_URINARY_TRACT
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  mechanistic_category:
  - classification_value: ciliopathy
references:
- reference: PMID:27336129
  title: "Nephronophthisis-Related Ciliopathies."
  tags:
  - GeneReviews
  findings: []
- reference: DOI:10.1038/s44321-025-00239-x
  title: Metabolic reprogramming in polycystic kidney disease and other renal ciliopathies
  findings: []
- reference: DOI:10.1101/2025.06.09.658557
  title: Loss of nephronophthisis-associated nephrocystin-1 impairs DNA damage repair in kidney organoids
  findings: []
- reference: DOI:10.1186/s12964-025-02143-w
  title: NEK8, a NIMA-family protein kinase at the core of the ciliary INV complex
  findings: []
- reference: DOI:10.1242/jcs.264141
  title: Urinary renal epithelial cells can be used for <i>NPHP1</i> phenotyping and a personalized therapeutic strategy
  findings: []
- reference: DOI:10.12659/ajcr.941413
  title: Autosomal Recessive Adolescent Syndromic Nephronophthisis Caused by a Novel Compound Heterozygous Pathogenic Variant
  findings: []
- reference: DOI:10.3389/fneph.2023.1331847
  title: Primary cilia and actin regulatory pathways in renal ciliopathies
  findings: []
- reference: DOI:10.3390/genes14081582
  title: A Role for Genetic Modifiers in Tubulointerstitial Kidney Diseases
  findings: []
datasets:
- accession: geo:GSE291847
  title: Targeting GLP-1 signaling ameliorates cystogenesis in a zebrafish model of nephronophthisis
  description: Nephronophthisis (NPH) is the leading genetic cause of end-stage renal disease in children and young adults, with no effective disease-modifying therapies currently available. Here, we identify glucagon-like peptide-1 (GLP-1) signaling as a novel therapeutic target for NPH through a systematic drug repurposing screen in zebrafish. By simultaneously depleting nphp1 and nphp4, we developed a robust zebrafish model that recapitulates key features of human NPH, including glomerular cyst formation. Our screen revealed that dipeptidyl peptidase-4 (DPP4) inhibitors (Omarigliptin and Linagliptin) and GLP-1 receptor agonists (Semaglutide) significantly reduce cystogenesis in a dose-dependent manner.
  organism:
    preferred_term: zebrafish
    term:
      id: NCBITaxon:7955
      label: Danio rerio
  data_type: BULK_RNA_SEQ
  sample_count: 6
  publication: PMID:40806500
  notes: Identified by GEO DataSets index search for Nephronophthisis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE301183
  title: Using human urinary-derived renal epithelial cells for deep phenotyping of NPHP1 deletion and determining personalised response to novel therapeutics
  description: Nephronophthisis (NPHP) is an autosomal recessive tubulointerstitial nephropathy classified as a renal ciliopathy disorder and recognised as the leading genetic cause of kidney failure in children and young adults. NPHP1 is the most common genetic cause and encodes nephrocystin-1, a protein that plays crucial roles in the primary cilium and cellular junctions. Here we utilise personalised medicine approaches and deep phenotyping, which enable us to explore mechanistic pathways and identify potential therapeutic strategies.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 10
  publication: PMID:40776899
  notes: Identified by GEO DataSets index search for Nephronophthisis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE73962
  title: Comparative genomic analyses of the human NPHP1 locus reveal complex genomic architecture and its regional evolution in primates
  description: Many loci in the human genome harbor complex genomic structures that can result in susceptibility to genomic rearrangements leading to various genomic disorders. Nephronophthisis 1 (NPHP1, MIM# 256100) is an autosomal recessive disorder that can be caused by defects of NPHP1; the gene maps within the human 2q13 region where low copy repeats (LCRs) are abundant. Loss of function of NPHP1 is responsible for approximately 85% of the NPHP1 cases - about 80% of such individuals carry a large recurrent homozygous NPHP1 deletion that occurs via non-allelic homologous recombination (NAHR) between two flanking directly oriented ~45 kb LCRs.
  sample_count: 32
  publication: PMID:26641089
  notes: Identified by GEO DataSets index search for Nephronophthisis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

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