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Classifications

Harrison's Part

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Inheritance

1

Autosomal recessive HP:0000007

Molecularly characterized patients in the cited families are homozygous; available parental testing supports recessive segregation. For two heterozygous parents, each pregnancy has a 25% risk of an affected child, 50% probability of a carrier and 25% probability of an unaffected noncarrier. The untested deceased G173V-family sibling should not be counted as molecularly confirmed.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:36245711 SUPPORT Human Clinical

"Parents were heterozygous carriers of the respective variant."

Carrier parents of homozygous affected children, including the ARHGDIA family.

CGGV:assertion_0e529f2b-21ac-44b2-981e-048e92e377a1-2022-05-24T180000.000Z SUPPORT Other

ClinGen records the mode of inheritance as AR.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/ SUPPORT REVIEW SYNTHESIS Other

"each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic ... carrier ... and a 25% chance of being unaffected and not a carrier."

General autosomal recessive SRNS counseling when both parents carry a causative allele.

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Mechanistic Hypotheses

1

Cellular actin and motility changes produce glomerular lesions

arhgdia_cellular_glomerular_injury EMERGING

The studies propose that disturbed actin organization and podocyte migration produce foot-process injury and developmental glomerular disease; the specific intervening steps are incompletely established.

Pathograph links

Podocyte Actin Cytoskeleton Derangement -> Podocyte Foot Process Effacement INDIRECT UNKNOWN INTERMEDIATES The authors propose that aberrant projections and reduced cell size alter the slit diaphragm; the step from cultured-podocyte morphology to effaced foot processes in vivo has not been shown directly for ARHGDIA.

Dysregulated Podocyte Motility -> Diffuse Mesangial Sclerosis INDIRECT UNKNOWN INTERMEDIATES Impaired migration during podocyte development is proposed to contribute to disease; the developmental glomerular lesion seen in patients is diffuse mesangial sclerosis. The intermediate steps between the cellular defect and the lesion are not characterized.

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Discussions and Knowledge Gaps

5

Does RhoGDIalpha loss make podocytes more migratory or less?

CONTROVERSY arhgdia_motility_direction

Attached to

pathophysiology#Dysregulated Podocyte Motility

The Gee group found enhanced migration of human podocytes after ARHGDIA knockdown or mutant overexpression, reversible with RAC1 inhibitors. The Gupta and Auguste studies found impaired motility in mouse podocytes and in patient fibroblasts. Auguste et al. attribute the difference to design: Gee overexpressed mutants on a background of endogenous wild-type RhoGDIalpha, whereas they knocked down the endogenous protein and re-expressed the mutant. Both groups agree that RAC1 is hyperactivated and that podocyte motility is abnormal; the entry therefore records the process as dysregulated rather than increased or decreased. The design explanation remains incomplete because Gee also observed enhanced migration after siRNA knockdown. Species, assay and expression differences may contribute.

Show evidence (1 reference)

PMID:26726844 SUPPORT In Vitro

"These differences may be explained by the WT GDIα present in the human podocytes used by Gee et al. since they overexpressed the mutants without knocking down the endogenous GDIα"

The authors' explanation for the discrepancy.

Is RHOA activation part of the mechanism, or is the disease RAC1 (and CDC42) driven?

CONTROVERSY arhgdia_rhoa_role

Attached to

pathophysiology#Variable RHOA Activation pathophysiology#Variable CDC42 Activation pathophysiology#RAC1 Hyperactivation in Podocytes

RhoA was hyperactivated in the Gupta knockdown podocytes and patient fibroblasts, but not in the Gee human podocyte assays, not in the Arhgdia-null mouse kidney, and only modestly and inconsistently in the Auguste allele panel. RHO inhibitors had no effect in the zebrafish model, where RAC1 inhibitors did. The weight of evidence favors RAC1, but no study has measured RHOA activation in patient podocytes.

What is the outcome of kidney transplantation, including post-transplant recurrence, in ARHGDIA disease?

KNOWLEDGE GAP arhgdia_transplant_recurrence

Attached to

treatments#Kidney Transplantation

The single reported graft failed from venous thrombosis and never functioned. A podocyte-intrinsic genetic lesion would predict that the donor kidney is unaffected, but no ARHGDIA-specific post-transplant data exist in the sources used here, and the entry does not infer a recurrence rate from other forms of monogenic SRNS.

What causes the variable neurologic phenotype, and is there reproductive involvement in humans?

KNOWLEDGE GAP arhgdia_extrarenal_phenotype

Attached to

phenotypes#Intellectual Disability animal_models#Arhgdia knockout mouse

Gee Table 1 documents intellectual disability in the two genotyped G173V siblings and the R120X infant, with hearing loss in one G173V sibling and seizures and cortical blindness in the R120X infant. The p.Gly168Arg child was described as developmentally normal at 11 months. Few patients and early deaths limit assessment of neurologic and reproductive outcomes. Infertility in male knockout mice has not been established as a human phenotype in these reports.

Show evidence (2 references)

PMID:23867502 SUPPORT Human Clinical

"It is not clear whether individuals with ARHGDIA mutations also have abnormal reproductive phenotypes"

The founding authors state the reproductive question as open.

PMID:10498891 SUPPORT Model Organism

"Rho GDIalpha -/- male mice were infertile and showed impaired spermatogenesis with vacuolar degeneration of seminiferous tubules in their testes."

The mouse phenotype that raises the question.

Is ARHGDIA disease loss of function or gain of function?

INTERPRETATION arhgdia_mechanism_wording

Attached to

pathophysiology#Biallelic ARHGDIA Loss of Function

ClinGen's evidence summary states the mechanism of pathogenicity as gain of function. The primary studies it cites show loss of RhoGDIalpha function (recessive, including a nonsense allele, with loss of GTPase binding) whose consequence is gain of RAC1 activity. The entry records loss of function on the variant and increased activity on the RAC1 node, which is what the functional data show; the ClinGen wording is best read as describing the downstream GTPase state.

Show evidence (1 reference)

CGGV:assertion_0e529f2b-21ac-44b2-981e-048e92e377a1-2022-05-24T180000.000Z SUPPORT Other

"The mechanism of pathogenicity is Gain of Function."

The ClinGen statement discussed here.

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Pathophysiology

12

Biallelic ARHGDIA Loss of Function

Biallelic ARHGDIA variants are associated with recessive nephrotic syndrome. Functional studies support impaired RhoGDIalpha regulation for p.Asp185del, p.Arg120Ter and p.Gly173Val, with residual binding varying by allele and assay. The later p.Gly168Arg and c.275-1G>A variants were reported as likely pathogenic without equivalent functional testing.

ARHGDIA hgnc:678

Genetic context ARHGDIA hgnc:678 variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Rho GDP-dissociation inhibitor activity GO:0005094 ↓ DECREASED

Experimental models

Patient-derived fibroblasts (p.Asp185del) PRIMARY CELL CULTURE Endogenous mutant protein, mislocalized, with Rho-GTPase hyperactivation.

Downstream

Impaired RhoGDIalpha-GTPase Interaction Characterized variants impair GTPase interaction or its regulatory consequences, with retained partial binding reported for G173V.

Reduced Total Rho GTPase Protein Abundance

Podocyte Actin Cytoskeleton Derangement Actin abnormalities follow loss of RhoGDIalpha regulation, but specific contributions of the affected GTPases are unresolved.

Show evidence (2 references)

PMID:23434736 SUPPORT In Vitro

"The proband's fibroblasts demonstrated mislocalisation of RhoGDIα to the nucleus, hyperactivation of the three Rho-GTPases, and impaired cell motility, suggesting that the in-frame deletion leads to a loss of function."

Patient-derived fibroblasts carrying p.Asp185del show the functional consequence expected of a null allele.

PMID:23867502 SUPPORT In Vitro

"ARHGDIA mutations (R120X and G173V) from individuals with SRNS abrogated interaction with RHO GTPases and increased active GTP-bound RAC1 and CDC42, but not RHOA, indicating that RAC1 and CDC42 are more relevant to the pathogenesis of this SRNS variant than RHOA."

Both patient alleles from the second founding report lose GTPase binding in cultured human podocytes.

Impaired RhoGDIalpha-GTPase Interaction

The p.Asp185del and p.Arg120Ter proteins fail to interact with the tested Rho-family GTPases in binding assays. G173V loses detectable interaction in one experimental system but retains partial binding in another. Binding and inhibition therefore should not be treated as interchangeable readouts, nor as uniformly absent for every allele.

RAC1 hgnc:9801 CDC42 hgnc:1736 RHOA hgnc:667

Downstream

RAC1 Hyperactivation in Podocytes Impaired RhoGDIalpha regulation is associated with altered GTPase activation; intermediate exchange and inactivation factors and allele-specific binding effects remain unresolved.

Variable CDC42 Activation Impaired RhoGDIalpha regulation is associated with altered GTPase activation; intermediate exchange and inactivation factors and allele-specific binding effects remain unresolved.

Variable RHOA Activation RHOA regulation differs between the cell and animal systems; release from RhoGDIalpha does not invariably activate RHOA.

Show evidence (1 reference)

PMID:26726844 SUPPORT In Vitro

"WT GDIα and G173V GDIα co-immunoprecipitated with all 3 Rho-GTPases, but the ΔD185 GDIα and R120X GDIα did not."

Co-immunoprecipitation in HEK293T cells distinguishes binding behavior among the three studied variants.

RAC1 Hyperactivation in Podocytes

The best-supported proximal effector. RAC1 activity rises in podocytes carrying any of the three characterized alleles, in ARHGDIA-knockdown podocytes, in patient lymphoblasts, and in the kidneys of Arhgdia-null mice (where RhoA did not rise). RhoGDIalpha expression normally increases as podocytes mature while active Rac1 falls, so the lesion removes a maturation-linked brake on Rac1.

podocyte CL:0000653

RAC1 hgnc:9801

Rac protein signal transduction GO:0016601 ↑ INCREASED

Experimental models

ARHGDIA-depleted or mutant-reconstituted podocyte lines CELL LINE RAC1 activation is reproduced with all three characterized alleles.

Animal models

arhgdia morphant zebrafish Zebrafish rescues RAC1 inhibition partly reduced edema; RHO inhibitors had no effect, supporting RAC1 over RHOA as the effector.

Downstream

Dysregulated Podocyte Motility Pharmacological RAC1 inhibition reverses the motility phenotype of ARHGDIA-deficient podocytes, placing RAC1 on the causal path.

Renal Mineralocorticoid Receptor Overactivation Cell experiments implicate p21-activated kinase phosphorylation and mineralocorticoid-receptor nuclear accumulation; mouse Rac inhibition reduces renal receptor overactivity without a change in systemic aldosterone.

Sensitization of Podocytes to Inflammatory Injury In ARHGDIA-knockdown podocytes, the exaggerated p38 response to LPS is Rac1-dependent.

Show evidence (3 references)

PMID:23867502 SUPPORT In Vitro

"ARHGDIA loss of function increases the active states of RAC1 and CDC42 by 168% and 185%, respectively, but has no such effect on RHOA"

siRNA knockdown in cultured human podocytes.

PMID:23867502 SUPPORT In Vitro

"we demonstrated by GST pulldown that active RAC1 is spontaneously elevated in EBV-transformed lymphoblasts from patient A1432-21 with an ARHGDIA mutation"

The same effect in cells from an affected individual.

PMID:26726844 SUPPORT Model Organism

"In the developing kidney, GDIα expression increased as podocytes matured. Conversely, active Rac1 was detected only in immature, but not in mature, podocytes."

Developmental expression data in mouse kidney, which place the RhoGDIalpha brake on Rac1 at podocyte maturation - relevant to the congenital and infantile onset.

Variable CDC42 Activation

CDC42 activity increased after ARHGDIA knockdown in human and mouse podocytes. In mutant-reconstituted mouse podocytes, changes were smaller and not consistently significant. Its independent contribution to the clinical phenotype remains unresolved.

CDC42 hgnc:1736

Cdc42 protein signal transduction GO:0032488 ↕ DYSREGULATED

Downstream

Podocyte Actin Cytoskeleton Derangement Whether CDC42 or RHOA activation contributes independently of RAC1 is not established; see the RhoA discussion.

Show evidence (2 references)

PMID:23867502 SUPPORT In Vitro

"ARHGDIA loss of function increases the active states of RAC1 and CDC42 by 168% and 185%, respectively, but has no such effect on RHOA"

Human podocyte knockdown supports CDC42 activation in that system.

PMID:26726844 SUPPORT In Vitro

"Cdc42 hyperactivity only in GDIα KD cells."

The 2016 study distinguishes statistically significant knockdown effects from the variable mutant-reconstitution results.

Podocyte Actin Cytoskeleton Derangement

RhoGDIalpha-knockdown and mutant-reconstituted mouse podocytes showed reduced filamentous-to-globular actin ratios and altered morphology. This is not reproduced simply by constitutively active RAC1, which increased the ratio in the same study; combined GTPase imbalance and cell context matter.

Cellular actin and motility changes produce glomerular lesions

podocyte CL:0000653

actin cytoskeleton organization GO:0030036 ⚠ ABNORMAL

Downstream

Podocyte Foot Process Effacement The authors propose that aberrant projections and reduced cell size alter the slit diaphragm; the step from cultured-podocyte morphology to effaced foot processes in vivo has not been shown directly for ARHGDIA.

Show evidence (1 reference)

PMID:26726844 SUPPORT In Vitro

"The mutant podocytes also showed impaired actin polymerization, smaller cell size, and increased cellular projections."

Cytoskeletal and morphological phenotype of podocytes carrying patient alleles.

Renal Mineralocorticoid Receptor Overactivation

In Arhgdia-null mice, Rac1 enhances mineralocorticoid receptor signalling in the kidney without any change in circulating aldosterone, and MR blockade suppresses the albuminuria. This arm is established in the mouse and in cultured cells only.

podocyte CL:0000653

nuclear receptor-mediated mineralocorticoid signaling pathway GO:0031959 ↑ INCREASED

Animal models

Arhgdia knockout mouse Mouse rescues A Rac-specific inhibitor and mineralocorticoid receptor blockade each reduced renal damage in the knockout.

Downstream

Glomerular Filtration Barrier Failure MR blockade reduces albuminuria and histological damage in the knockout.

Show evidence (1 reference)

PMID:19029984 SUPPORT In Vitro

"CA-Rac1 facilitated mineralocorticoid receptor nuclear accumulation also in podocytes via p21-activated kinase phosphorylation."

The cellular mechanism, shown with constitutively active Rac1 in podocytes.

Sensitization of Podocytes to Inflammatory Injury

RhoGDIalpha-depleted podocytes respond to lipopolysaccharide with exaggerated p38 MAPK phosphorylation and greater loss of synaptopodin, an actin-associated podocyte protein. This proposes a route by which an environmental insult could compound the inherited lesion; it has been shown in cultured podocytes only.

podocyte CL:0000653

Downstream

Podocyte Actin Cytoskeleton Derangement p38-dependent, proteasome- and cathepsin L-mediated synaptopodin degradation removes an actin-associated podocyte protein.

Show evidence (1 reference)

PMID:25503727 SUPPORT In Vitro

"In GDIα knockdown podocytes, the same events were triggered, but the levels of synaptopodin after LPS treatment were significantly lower than in control podocytes."

Greater synaptopodin loss under the same injury.

Podocyte Foot Process Effacement

Diffuse podocyte foot process effacement was demonstrated by electron microscopy of the p.Asp185del proband's biopsy. Slit-diaphragm disruption is a proposed link from cellular abnormalities to protein leakage, rather than a separately measured lesion in that biopsy.

podocyte CL:0000653

Downstream

Glomerular Filtration Barrier Failure

Podocyte Foot Process Effacement on Electron Microscopy

Show evidence (1 reference)

PMID:23434736 SUPPORT Human Clinical

"Electron micrograph images from the patient's kidney biopsy (C) show diffuse foot process effacement (arrow), thinning of the glomerular basement membrane (arrowhead), and swollen endothelial cells (Endo)."

Ultrastructure of the proband's biopsy.

Glomerular Filtration Barrier Failure

Loss of glomerular protein retention. Reproduced in Arhgdia-null mice (massive proteinuria, death from renal failure within a year) and in arhgdia morphant zebrafish (proteinuria and whole-body edema).

podocyte CL:0000653

glomerular filtration GO:0003094 ⚠ ABNORMAL

renal glomerulus UBERON:0000074

Animal models

Arhgdia knockout mouse Mouse recapitulates Heavy proteinuria and fatal renal failure after initial viability.

arhgdia morphant zebrafish Zebrafish recapitulates Edema and measured proteinuria in larvae.

Drosophila nephrocyte RhoGDI knockdown Drosophila partially recapitulates Altered nephrocyte handling of a secreted protein provides a functional analog rather than a direct filtration-barrier assay.

Downstream

Nephrotic-Range Proteinuria

Hypoalbuminemia Urinary protein loss depletes serum albumin.

Generalized Edema Hypoalbuminemia lowers plasma oncotic pressure.

Nephrotic Syndrome

Show evidence (2 references)

PMID:10498891 SUPPORT Model Organism

"Rho GDIalpha -/- mice were initially viable but developed massive proteinuria mimicking nephrotic syndrome, leading to death due to renal failure within a year."

Constitutive knockout reproduces the barrier failure.

PMID:23867502 SUPPORT Model Organism

"The proteinuric effect of the arhgdia MO was confirmed using an established zebrafish proteinuria ELISA assay"

Zebrafish knockdown produces measured proteinuria.

Reduced Total Rho GTPase Protein Abundance

Total RAC1, RHOA and CDC42 protein levels were reduced in RhoGDIalpha-knockdown and mutant-reconstituted mouse podocytes and restored by wild-type replacement. This is distinct from increased activity of the remaining GTPase pool. The study interpreted the result as reduced protection from degradation.

Show evidence (1 reference)

PMID:26726844 SUPPORT In Vitro

"The GDIα KD podocytes had decreased levels of Rac1, RhoA, and Cdc42 compared with control podocytes"

Total protein abundance was measured; loss of protection from proteasomal degradation is the authors' interpretation.

Variable RHOA Activation

RHOA activity increased in patient fibroblasts and some mouse podocyte experiments, including the p.Asp185del model, but not in the Gee human podocyte knockdown experiments or the knockout mouse kidney. Its contribution is model-dependent and cannot be inferred from RAC1 activation alone.

RHOA hgnc:667

Downstream

Podocyte Actin Cytoskeleton Derangement Whether CDC42 or RHOA activation contributes independently of RAC1 is not established; see the RhoA discussion.

Show evidence (2 references)

PMID:23434736 SUPPORT In Vitro

"When RhoGDIα was knocked down in podocytes, RhoA, Rac1, and Cdc42 were hyperactivated and podocyte motility was impaired."

Mouse podocyte knockdown supports RHOA activation.

PMID:23867502 REFUTE In Vitro

"ARHGDIA loss of function increases the active states of RAC1 and CDC42 by 168% and 185%, respectively, but has no such effect on RHOA"

No corresponding RHOA activation in the human podocyte experiment.

Dysregulated Podocyte Motility

Podocyte motility is altered after ARHGDIA perturbation. Human siRNA knockdown and mutant-overexpression experiments found enhanced migration, whereas mouse knockdown and mutant-replacement experiments found slower migration. The direction depends on the experimental system and is not a uniform disease feature.

Cellular actin and motility changes produce glomerular lesions

podocyte CL:0000653

podocyte cell migration GO:0090521 ↕ DYSREGULATED

Downstream

Diffuse Mesangial Sclerosis Impaired migration during podocyte development is proposed to contribute to disease; the developmental glomerular lesion seen in patients is diffuse mesangial sclerosis. The intermediate steps between the cellular defect and the lesion are not characterized.

Show evidence (2 references)

PMID:26726844 SUPPORT In Vitro

"All three mutant GDIα proteins resulted in slow podocyte motility, suggesting that podocytes are sensitive to the relative balance of Rho-GTPase activity."

Motility was slowed in the three mutant-reconstituted lines tested in this study.

PMID:23867502 SUPPORT In Vitro

"Podocytes transfected with ARHGDIA siRNA exhibited more active migration compared with those transfected with scrambled siRNA."

Motility is disturbed in the opposite direction in human podocyte knockdown.

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Pathograph

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

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Phenotypes

16

Cardiovascular 1

Hypertension HP:0000822

Show evidence (1 reference)

PMID:35060086 SUPPORT Human Clinical

"She had stage 2 hypertension."

Single-case observation.

Ear 1

Sensorineural hearing impairment HP:0000407

Show evidence (1 reference)

url:https://www.jci.org/articles/view/69134/files/pdf SUPPORT Human Clinical

"-21: ID, SNHL ... SNHL, sensorineural hearing loss."

Gee et al. (2013), PMID:23867502, Table 1 in the full PDF. The row identifies the affected sibling and the footnote expands SNHL.

Eye 1

Cortical blindness Cerebral visual impairment HP:0100704

Show evidence (2 references)

url:https://www.jci.org/articles/view/69134/files/pdf SUPPORT Human Clinical

"14 d CNS ID, seizures, (DMS; 1 mo), cortical ESKD 6 wk blindness, died at 6 mo"

Gee et al. (2013), PMID:23867502, Table 1 in the full PDF. Seizures and cortical blindness occur in the same infant; renal and extrarenal columns were checked in the rendered table.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/ SUPPORT REVIEW SYNTHESIS Other

"ARHGDIA ... AR ... Seizures ... cortical blindness"

The ARHGDIA row of the syndromic genetic SRNS table lists seizures and cortical blindness.

Genitourinary 8

Nephrotic Syndrome HP:0000100

Show evidence (7 references)

PMID:23434736 SUPPORT Human Clinical

"The proband presented at 3 weeks of age with generalised oedema and was found to have severe hypoalbuminaemia and proteinuria and was diagnosed with congenital nephrotic syndrome."

Neonatal presentation in the first sister.

PMID:23434736 SUPPORT Human Clinical

"The second child was diagnosed with congenital nephrotic syndrome on day 16 of life when her laboratory studies revealed severe hypoalbuminaemia with proteinuria"

Neonatal presentation in the second sister.

PMID:23867502 SUPPORT Human Clinical

"we detected a homozygous mutation (c.358C>T;p.R120X) in an infant (A4578-21) with congenital NS"

Congenital presentation with the nonsense allele.

+ 4 more references

Steroid Resistance Steroid-resistant nephrotic syndrome HP:0012588

Show evidence (3 references)

PMID:35060086 SUPPORT Human Clinical

"Despite 8 wk of daily prednisolone, she had not attained remission."

The only documented steroid trial in a genetically confirmed patient.

ORPHA:656 SUPPORT Other

"OMIM:615244 | Broader"

Orphanet maps OMIM:615244 (NPHS8) to its hereditary steroid-resistant nephrotic syndrome entry as a broader term; there is no ARHGDIA-specific Orphanet code.

PMID:36245711 SUPPORT Human Clinical

"The clinical diagnosis of SRNS was defined as absence of complete remission after 4 weeks of daily prednisone therapy at a dose of 60 mg/m2 per day for all affected individuals."

Cohort eligibility included the ARHGDIA case; this is not a detailed individual treatment record.

Nephrotic-Range Proteinuria HP:0012593

Show evidence (1 reference)

PMID:23434736 SUPPORT Human Clinical

"The proband presented at 3 weeks of age with generalised oedema and was found to have severe hypoalbuminaemia and proteinuria and was diagnosed with congenital nephrotic syndrome."

Heavy proteinuria at presentation.

Diffuse Mesangial Sclerosis HP:0001967

Sequelae: Kidney Failure

Show evidence (3 references)

PMID:23434736 SUPPORT Human Clinical

"A renal biopsy was performed at 1 month of age and this showed severe glomerular changes consistent with diffuse mesangial sclerosis"

DMS in the p.Asp185del proband.

PMID:23867502 SUPPORT Human Clinical

"We performed homozygosity mapping (HM) in a family (A1432) of Ashkenazi Jewish origin in whom 2 siblings had early-onset SRNS with renal histology of DMS."

DMS in the G173V sibling pair.

PMID:23867502 SUPPORT Human Clinical

"This infant also exhibited renal histology of DMS"

DMS in the R120X infant.

Podocyte Foot Process Effacement on Electron Microscopy HP:0031266

Show evidence (1 reference)

PMID:23434736 SUPPORT Human Clinical

"Electron micrograph images from the patient's kidney biopsy (C) show diffuse foot process effacement (arrow), thinning of the glomerular basement membrane (arrowhead), and swollen endothelial cells (Endo)."

Ultrastructural finding in the proband.

Thin Glomerular Basement Membrane HP:0012577

Show evidence (1 reference)

PMID:23434736 SUPPORT Human Clinical

"Electron micrograph images from the patient's kidney biopsy (C) show diffuse foot process effacement (arrow), thinning of the glomerular basement membrane (arrowhead), and swollen endothelial cells (Endo)."

Single-biopsy observation.

Renal Tubular Atrophy HP:0000092

Show evidence (1 reference)

PMID:23867502 SUPPORT Human Clinical

"Right kidney explanted at 2 months of age reveals on H&E staining advanced tubular dilation, atrophy, and casts"

Histology of the explanted kidney.

Kidney Failure Stage 5 chronic kidney disease HP:0003774

Course: PROGRESSIVE

Show evidence (3 references)

PMID:23434736 SUPPORT Human Clinical

"The patient rapidly deteriorated and developed end stage renal failure at 3 months of age that was treated by haemodialysis."

Kidney failure within months of birth.

PMID:35060086 SUPPORT REVIEW SYNTHESIS Human Clinical

"These cases had infantile-onset; showed diffuse mesangial sclerosis on renal biopsy; and rapidly progressed to end-stage renal disease (ESRD) or died"

The case report's summary of the earlier ARHGDIA cases, which it cites rather than reports.

url:https://www.jci.org/articles/view/69134/files/pdf SUPPORT Human Clinical

"-21 2.4 yr -21: SRNS, -21: ID, SNHL ESKD 2.4 yr, ... -23 1 yr -23: SRNS, -23: ID ESKD 3 yr"

Gee et al. (2013), PMID:23867502, Table 1 in the full PDF. Age at kidney failure in the G173V family; this is not uniformly an infantile outcome.

Metabolism 3

Hypoalbuminemia HP:0003073

Show evidence (1 reference)

PMID:23434736 SUPPORT Human Clinical

"The second child was diagnosed with congenital nephrotic syndrome on day 16 of life when her laboratory studies revealed severe hypoalbuminaemia with proteinuria"

Severe hypoalbuminemia in the neonatal period.

Generalized Edema HP:0007430

Show evidence (2 references)

PMID:23434736 SUPPORT Human Clinical

"The proband presented at 3 weeks of age with generalised oedema and was found to have severe hypoalbuminaemia and proteinuria and was diagnosed with congenital nephrotic syndrome."

Generalized edema at presentation.

PMID:35060086 SUPPORT Human Clinical

"At presentation, she had periorbital, pedal edema, severe ascites, and vulval edema."

Anasarca in the later-onset infant.

Hypercholesterolemia HP:0003124

Show evidence (1 reference)

PMID:35060086 SUPPORT Human Clinical

"Hypoalbuminemia (2.1 g/dL), hyper- cholesterolemia (270 mg/dL), and nephrotic-range proteinu- ria (Up:Uc 5.5) without microscopic hematuria were noted."

The published PDF contains line-wrapped hyphenation; the observation is a single-patient laboratory finding.

Nervous System 2

Intellectual Disability HP:0001249

Show evidence (2 references)

PMID:23867502 SUPPORT Human Clinical

"3 of 4 (75%) individuals from 2 independent families had neurological phenotypes including intellectual disability (Table 1)"

Neurological involvement in the original Gee family series; the full PDF table identifies the affected individuals.

PMID:35060086 NO_EVIDENCE Human Clinical

"An 11-mo-old developmentally normal girl was referred for evaluation of anasarca for the preceding 3 mo."

No developmental abnormality was reported at this early assessment; not evidence against neurologic involvement in the disease generally.

Seizures HP:0001250

Show evidence (2 references)

url:https://www.jci.org/articles/view/69134/files/pdf SUPPORT Human Clinical

"14 d CNS ID, seizures, (DMS; 1 mo), cortical ESKD 6 wk blindness, died at 6 mo"

Gee et al. (2013), PMID:23867502, Table 1 in the full PDF. Seizures and cortical blindness occur in the same infant; renal and extrarenal columns were checked in the rendered table.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/ SUPPORT REVIEW SYNTHESIS Other

"ARHGDIA ... AR ... Seizures ... cortical blindness"

The ARHGDIA row of the syndromic genetic SRNS table lists seizures and cortical blindness.

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Genetic Associations

1

ARHGDIA

Gene: ARHGDIA hgnc:678 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

CGGV:assertion_0e529f2b-21ac-44b2-981e-048e92e377a1-2022-05-24T180000.000Z SUPPORT Other

ClinGen (Glomerulopathy GCEP, 2022) classifies the gene-disease relationship for this MONDO term as Moderate.

PMID:36245711 SUPPORT Human Clinical

"Congenital cases are often caused by disease-causing variants in NPHS1 and we identified such variants in two cases as well as disease-causing variants in SGPL1 or ARHGDIA in one case, respectively."

ARHGDIA accounted for one congenital case among 30 consanguineous Iranian SRNS families, consistent with a rare contributor.

url:https://www.jci.org/articles/view/69134/files/pdf SUPPORT Human Clinical

"A4578 Moroccan Yes ARHGDIA c.358C>T p.R120X 4 (Hom, M, F)"

Gee et al. (2013), PMID:23867502, Table 1 in the full PDF. The family row reports origin, consanguinity and heterozygous parental segregation; these details were absent from the cached HTML body.

Variants (5)

c.553_555del (p.Asp185del)

In-frame deletion of one of three consecutive aspartate residues (183-185) at the GTPase-binding interface; homozygous in two Pakistani sisters with congenital nephrotic syndrome. The deleted residue cannot be assigned, so the variant is named for position 185.

Show evidence (1 reference)

PMID:23434736 SUPPORT Human Clinical

"The sisters harbour a homozygous in-frame deletion that is predicted to remove a highly conserved aspartic acid residue within the interface where the protein, RhoGDIα, interacts with the Rho family of small GTPases (c.553_555del(p.Asp185del))."

Identifies the allele and its position.

c.518G>T (p.Gly173Val)

Missense, homozygous in two Ashkenazi Jewish siblings; associated with the later onset. Retains partial GTPase binding in one study but still fails to restrain RAC1.

Show evidence (1 reference)

PMID:23867502 SUPPORT Human Clinical

"Using WER, we detected in both siblings a homozygous missense mutation (c.518G>T;p.G173V) of ARHGDIA (RefSeq accession number NM_001185077.1)"

Identifies the allele and the reference transcript.

c.358C>T (p.Arg120Ter)

Nonsense, homozygous in an infant with congenital nephrotic syndrome.

Show evidence (1 reference)

PMID:23867502 SUPPORT Human Clinical

"we detected a homozygous mutation (c.358C>T;p.R120X) in an infant (A4578-21) with congenital NS"

Identifies the allele.

p.Gly168Arg

Homozygous missense in exon 6, reported as likely pathogenic by clinical exome sequencing in an 11-month-old South Indian girl; not functionally tested.

Show evidence (1 reference)

PMID:35060086 SUPPORT Human Clinical

"exome sequencing revealed homozygous missense likely-pathogenic variation in exon 6 of ARHGDIA gene"

Identifies the allele class and zygosity.

c.275-1G>A

Canonical splice-acceptor variant, homozygous and classified likely pathogenic, in a child with congenital onset from an Iranian SRNS cohort; not functionally tested.

Show evidence (2 references)

PMID:36245711 SUPPORT Human Clinical

"one allele was a −1 canonical splice site variant in ARHGDIA"

Identifies the allele class.

PMID:36245711 SUPPORT Human Clinical

"ARHGDIA NM_004309.6 | c.275-1G>A; p.(?) | Homo"

Table 1 identifies the reference transcript and splice allele; the actual splice product was not measured.

💊

Medical Actions

8

Corticosteroid Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: prednisolone CHEBI:8378

Platform: Small molecule

Prednisolone failed in the reported p.Gly168Arg case. GeneReviews advises avoiding continued ineffective prednisolone/prednisone after SRNS is established. Decisions about other immunosuppression in genetically diagnosed SRNS require individual assessment.

Mechanism Target:

Nephrotic Syndrome — No remission after eight weeks of daily prednisolone.

Show evidence (1 reference)

PMID:35060086 REFUTE Human Clinical

"Despite 8 wk of daily prednisolone, she had not attained remission."

Refutes a steroid response in this patient.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/ SUPPORT REVIEW SYNTHESIS Other

"Once the diagnosis of SRNS is established, ineffective prednisolone/prednisone treatment should be avoided."

General genetic SRNS guidance supports stopping ineffective treatment; not all congenital ARHGDIA patients received a steroid trial.

Dialysis

Action: renal dialysis Ontology label: Dialysis NCIT:C15221

Platform: Device

Haemodialysis from three months of age in the neonatal proband; peritoneal dialysis in the 11-month-old, who remained anuric and died 18 days later.

Mechanism Target:

BYPASSES Kidney Failure — Replaces excretory function without altering the podocyte lesion.

Show evidence (2 references)

PMID:23434736 SUPPORT Human Clinical

"The patient rapidly deteriorated and developed end stage renal failure at 3 months of age that was treated by haemodialysis."

Dialysis in early infancy.

PMID:35060086 SUPPORT Human Clinical

"We initiated peritoneal dialysis, but she remained anuric and eventually died 18 d later"

Peritoneal dialysis, with a fatal outcome.

Kidney Transplantation

Action: kidney transplantation Ontology label: Kidney Transplantation NCIT:C15265

Platform: Surgery

Kidney transplantation is part of the management of genetic SRNS. In the reported p.Asp185del proband, a deceased-donor graft at age two never functioned because of venous thrombosis. This event does not establish recurrent ARHGDIA nephropathy, and the cited cases do not provide a genotype-specific recurrence estimate.

Mechanism Target:

BYPASSES Kidney Failure — Would replace the kidney carrying the podocyte lesion.

Show evidence (2 references)

PMID:23434736 SUPPORT Human Clinical

"She received a cadaveric renal transplant at the age of 2 years, but the graft never functioned due to venous thrombosis in the transplant, and so the patient remains on dialysis."

The only reported transplant, a technical graft loss.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/ SUPPORT REVIEW SYNTHESIS Other

"All genetic SRNS can be corrected with kidney transplantation."

General genetic SRNS guidance; ARHGDIA-specific transplant outcome evidence remains limited.

Renin-angiotensin-aldosterone system inhibition

Platform: Small molecule

GeneReviews recommends renin-angiotensin-aldosterone system inhibitors to reduce proteinuria in established SRNS. Treatment requires specialist assessment of blood pressure, kidney function and volume status; this is general genetic SRNS care, not an ARHGDIA-specific clinical efficacy estimate.

Mechanism Target:

Nephrotic-Range Proteinuria

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/ SUPPORT REVIEW SYNTHESIS Other

"Instead affected individuals should be treated with renin-angiotensin-aldosterone system inhibitors (RAASi) to reduce proteinuria."

General SRNS management baseline.

Supportive renal care

Action: Supportive Care NCIT:C15747

Platform: Other

General genetic SRNS management includes prompt hypertension treatment, cautious diuretic use and management of chronic kidney disease. Vitamin D and thyroid hormone replacement are considered according to clinical need. Renal replacement is required when kidney failure develops.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/ SUPPORT REVIEW SYNTHESIS Other

"Prompt detection and treatment of hypertension"

GeneReviews management section.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/ SUPPORT REVIEW SYNTHESIS Other

"Cautious use of diuretics, vitamin D, and thyroid hormone substitution"

General management guidance; not a claim that every ARHGDIA patient needs each replacement.

Family screening and genetic counseling

Action: Genetic Counseling NCIT:C15240

Platform: Other

Offer at-risk first-degree relatives urine testing for proteinuria and targeted testing once familial variants are identified. Counsel on autosomal recessive recurrence and reproductive options. Potential related kidney donors require genetic and clinical evaluation; heterozygous carriers of recessive SRNS alleles may be assessed as possible donors.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/ SUPPORT REVIEW SYNTHESIS Other

"First degree relatives, including sibs, should be offered urine analysis for proteinuria."

Early family assessment baseline.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/ SUPPORT REVIEW SYNTHESIS Other

"Carrier testing for at-risk relatives requires prior identification of the ... SRNS-causing pathogenic variants in the family."

GeneReviews requires identification of familial variants to guide carrier testing.

Experimental RAC1 inhibition

Platform: Small molecule

RAC1 inhibitors reversed enhanced migration of ARHGDIA-knockdown human podocytes and partially reduced edema and proteinuria in zebrafish morphants. Rac inhibition also reduced renal injury in knockout mice. These are preclinical interventions, with no established ARHGDIA-specific clinical efficacy.

Mechanism Target:

RAC1 Hyperactivation in Podocytes — Pharmacological inhibition of the implicated GTPase pathway.

Show evidence (2 references)

PMID:23867502 SUPPORT Model Organism

"We found that RAC1 inhibitors were partially effective in our zebrafish model in reducing edema from 70% in untreated arhgdia knockdown zebrafish to 47% for the RAC1 inhibitor-treated fish"

Partial edema rescue in morphants; no human efficacy inferred.

PMID:23867502 SUPPORT In Vitro

"the addition to podocyte cultures of either one of the RAC1 inhibitors reversed the migratory phenotype"

Pharmacological reversal of the human podocyte knockdown phenotype.

Experimental eplerenone treatment

Action: eplerenone therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: eplerenone NCIT:C47513

Platform: Small molecule

The mineralocorticoid-receptor antagonist eplerenone partially reduced edema in arhgdia morphant zebrafish, from 70% to 54% in the reported experiment. Mineralocorticoid-receptor blockade also reduced albuminuria and histological injury in Arhgdia-null mice. No ARHGDIA-specific patient response is established.

Mechanism Target:

Renal Mineralocorticoid Receptor Overactivation

Show evidence (2 references)

PMID:23867502 SUPPORT Model Organism

"54% for eplerenone-treated fish, whereas RHO inhibitors (RHO inhibitor 1, Y-27632, and fasudil) showed no effect"

Partial morphant rescue; the untreated edema proportion was 70%.

PMID:19029984 SUPPORT Model Organism

"albuminuria and histological changes in Arhgdia(-/-) mice were suppressed by mineralocorticoid receptor blockade"

Mouse evidence for blockade of this pathway.

🔬

Diagnosis

2

Molecular genetic testing

A nephrotic-syndrome multigene panel including ARHGDIA or exome/genome sequencing can establish the molecular diagnosis, with parental testing to confirm segregation. Panel content varies, so inclusion of this rare gene should be checked. Renal and extrarenal assessment helps interpret candidate variants; diffuse mesangial sclerosis alone does not identify the causal gene.

molecular genetic testing NCIT:C15709

Show evidence (3 references)

PMID:23867502 SUPPORT Human Clinical

"In summary, our findings of ARHGDIA mutation implicate the RHO small GTPase RAC1/CDC42 in the pathogenesis of human NS and permit a noninvasive, causation-based diagnosis."

The founding report's framing of genetic testing as the diagnostic route.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/ SUPPORT REVIEW SYNTHESIS Other

"Molecular genetic testing ... can include a combination of ... targeted testing (single-gene testing or ... ) and comprehensive ... testing"

GeneReviews describes gene-targeted and comprehensive genomic testing strategies; the relevant linked terms are omitted from this HTML quote.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/ SUPPORT REVIEW SYNTHESIS Other

"Some panels may not include newly discovered and/or rare genes associated with genetic SRNS."

Check the actual laboratory panel content rather than assuming ARHGDIA coverage.

Kidney biopsy

Shows diffuse mesangial sclerosis with foot process effacement. It identifies the lesion rather than its cause, and in the fulminant infantile course it may not be feasible.

kidney biopsy NCIT:C51699

Show evidence (2 references)

PMID:23434736 SUPPORT Human Clinical

"A renal biopsy was performed at 1 month of age and this showed severe glomerular changes consistent with diffuse mesangial sclerosis"

Biopsy findings in the proband.

PMID:35060086 SUPPORT Human Clinical

"Renal biopsy could not be performed."

Biopsy was not possible in the later, critically ill case.

🧫

Experimental Models

2

ARHGDIA-depleted or mutant-reconstituted podocyte lines CELL_LINE

Cultured human podocytes with ARHGDIA siRNA or mutant overexpression (Gee), and mouse podocytes with shRNA knockdown alone or reconstituted with each patient allele (Gupta; Auguste).

Publication

PMID:26726844

Pathograph links

RAC1 Hyperactivation in Podocytes recapitulates fidelity: high observes: molecular RAC1 activation is reproduced with all three characterized alleles.

Limitations: Immortalized podocytes in two dimensions; the direction of the motility phenotype differs between the human-overexpression and mouse-replacement designs.

Show evidence (1 reference)

PMID:26726844 SUPPORT In Vitro

"Among the 3 prototypical Rho-GTPases, Rac1 was markedly hyperactivated in podocytes with any of the 3 mutant forms of GDIα while the activation of RhoA and Cdc42 was modest and variable."

Allele-by-allele reproduction of the effector step.

Patient-derived fibroblasts (p.Asp185del) PRIMARY_CELL_CULTURE

Skin fibroblasts from the homozygous p.Asp185del proband.

Publication

PMID:23434736

Pathograph links

Biallelic ARHGDIA Loss of Function recapitulates fidelity: moderate observes: cellular Endogenous mutant protein, mislocalized, with Rho-GTPase hyperactivation.

Limitations: Fibroblasts are not podocytes, and the actin response to RhoGDIalpha loss is reported to differ between the two cell types.

Show evidence (1 reference)

PMID:23434736 SUPPORT In Vitro

"The proband's fibroblasts demonstrated mislocalisation of RhoGDIα to the nucleus, hyperactivation of the three Rho-GTPases, and impaired cell motility, suggesting that the in-frame deletion leads to a loss of function."

The patient-cell readout.

🐁

Animal Models

3

Arhgdia knockout mouse

The constitutive null developed massive proteinuria and died of renal failure within a year, with tubular degeneration and dilatation; males were infertile. A later study in the same line showed increased renal Rac1 (not RhoA) and mineralocorticoid receptor signalling, reduced by a Rac inhibitor, and suppression of albuminuria by mineralocorticoid receptor blockade.

Species

Mouse

Genotype

Arhgdia-/- (constitutive)

Publication

PMID:10498891

Pathograph links

Glomerular Filtration Barrier Failure recapitulates fidelity: moderate observes: organism Heavy proteinuria and fatal renal failure after initial viability.

Limitations: Renal injury develops over months in this constitutive model. The 1999 abstract emphasizes tubular degeneration, while the 2013 human paper summarizes mouse glomerulosclerosis and foot-process injury from earlier work. This does not establish identity with the diffuse mesangial sclerosis of human biopsies. The reproductive phenotype has no established human counterpart in these case reports.

Show evidence (1 reference)

PMID:10498891 SUPPORT Model Organism

"Rho GDIalpha -/- mice were initially viable but developed massive proteinuria mimicking nephrotic syndrome, leading to death due to renal failure within a year."

Establishes the renal phenotype of the null.

Renal Mineralocorticoid Receptor Overactivation rescues fidelity: moderate observes: organism A Rac-specific inhibitor and mineralocorticoid receptor blockade each reduced renal damage in the knockout.

Limitations: Preclinical only. No Rac1 inhibitor or mineralocorticoid receptor antagonist has been reported in a patient with ARHGDIA disease, and the rescue was in a model with a slower course than the human disease.

Show evidence (1 reference)

PMID:19029984 SUPPORT Model Organism

"Furthermore, albuminuria and histological changes in Arhgdia(-/-) mice were suppressed by mineralocorticoid receptor blockade, confirming the pathological role of Rac1-mineralocorticoid receptor interaction."

The in vivo rescue.

arhgdia morphant zebrafish

Knockdown produced periorbital and whole-body edema in 70% of embryos at 120 hours post-fertilization, with proteinuria; RAC1 inhibitors and eplerenone partly reduced the edema, while RHO inhibitors did not.

Species

Zebrafish

Genotype

arhgdia morpholino knockdown (translation-blocking and splice-blocking)

Publication

PMID:23867502

Pathograph links

Glomerular Filtration Barrier Failure recapitulates fidelity: moderate observes: organism Edema and measured proteinuria in larvae.

Limitations: Transient morpholino knockdown in a pronephros; glomerular histology and podocyte ultrastructure are not reported in the cached text.

Show evidence (1 reference)

PMID:23867502 SUPPORT Model Organism

"Coinjection of the p53 control MO with an MO targeting the translation initiation site of zebrafish arhgdia caused the nephrosis phenotype of periorbital and total body edema in 70% of embryos at 120 hpf"

Establishes the phenotype and its penetrance.

RAC1 Hyperactivation in Podocytes rescues fidelity: low observes: organism RAC1 inhibition partly reduced edema; RHO inhibitors had no effect, supporting RAC1 over RHOA as the effector.

Limitations: Partial effect only (70% to 47% of embryos with edema), and RAC1 activity was not measured in the fish. Preclinical only.

Show evidence (2 references)

PMID:23867502 SUPPORT Model Organism

"We found that RAC1 inhibitors were partially effective in our zebrafish model in reducing edema from 70% in untreated arhgdia knockdown zebrafish to 47% for the RAC1 inhibitor-treated fish"

Quantifies the partial rescue.

+ 1 more reference

Drosophila nephrocyte RhoGDI knockdown

Reduced uptake of a secreted ANF-GFP fusion protein in pericardial nephrocytes after RhoGDI knockdown. This supports a role in nephrocyte function but does not directly measure mammalian glomerular filtration or recapitulate the clinical syndrome.

Species

Drosophila

Genotype

Nephrocyte knockdown of RhoGDI (CG7823)

Publication

PMID:23867502

Pathograph links

Glomerular Filtration Barrier Failure partially recapitulates fidelity: low Altered nephrocyte handling of a secreted protein provides a functional analog rather than a direct filtration-barrier assay.

Show evidence (1 reference)

PMID:23867502 SUPPORT Model Organism

"knockdown of Drosophila RhoGDI (CG7823) in nephrocytes reduced the uptake ability of the secreted fusion protein of rat atrial natriuretic factor (ANF) and GFP"

Primary functional assay in fly nephrocytes.

{ }

Source YAML

click to show

name: ARHGDIA-Related Steroid-Resistant Nephrotic Syndrome
description: >-
  Autosomal recessive nephrotic syndrome caused by biallelic ARHGDIA variants that impair Rho GDP-dissociation inhibitor alpha (RhoGDIalpha). Characterized alleles disturb regulation of Rho-family GTPases, with consistent RAC1 hyperactivation in podocyte models and model-dependent effects on CDC42, RHOA and cell motility. Podocyte injury disrupts the glomerular filtration barrier. Reported onset ranges from the neonatal period to early childhood, with diffuse mesangial sclerosis in biopsied patients and progression to kidney failure that can occur in infancy or childhood. Intellectual disability, seizures, cortical blindness and hearing impairment have been reported in selected patients. Pharmacological RAC1 and mineralocorticoid-receptor inhibition has shown preclinical effects; clinical efficacy specific to ARHGDIA disease is unestablished.
category: Mendelian
disease_term:
  preferred_term: nephrotic syndrome, type 8
  term:
    id: MONDO:0014099
    label: nephrotic syndrome, type 8
synonyms:
- NPHS8
- nephrotic syndrome, type 8
- ARHGDIA nephrotic syndrome
- nephrotic syndrome caused by mutation in ARHGDIA
creation_date: "2026-09-23T15:40:00Z"
parents:
- Familial Idiopathic Steroid-Resistant Nephrotic Syndrome
classifications:
  harrisons_chapter:
  - classification_value: KIDNEY_URINARY_TRACT
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
references:
- reference: PMID:34436835
  title: Genetic Steroid-Resistant Nephrotic Syndrome Overview.
  tags:
  - GeneReviews

- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
  title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
- reference: url:https://www.jci.org/articles/view/69134/files/pdf
  title: https://www.jci.org/articles/view/69134/files/pdf
pathophysiology:
- name: Biallelic ARHGDIA Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic ARHGDIA variants are associated with recessive nephrotic syndrome. Functional studies support impaired RhoGDIalpha regulation for p.Asp185del, p.Arg120Ter and p.Gly173Val, with residual binding varying by allele and assay. The later p.Gly168Arg and c.275-1G>A variants were reported as likely pathogenic without equivalent functional testing.
  genes:
  - preferred_term: ARHGDIA
    term:
      id: hgnc:678
      label: ARHGDIA
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    gene:
      preferred_term: ARHGDIA
      term:
        id: hgnc:678
        label: ARHGDIA
  molecular_functions:
  - preferred_term: Rho GDP-dissociation inhibitor activity
    modifier: DECREASED
    term:
      id: GO:0005094
      label: Rho GDP-dissociation inhibitor activity
  evidence:
  - reference: PMID:23434736
    reference_title: "ARHGDIA: a novel gene implicated in nephrotic syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The proband's fibroblasts demonstrated mislocalisation of RhoGDIα to the nucleus,
      hyperactivation of the three Rho-GTPases, and impaired cell motility, suggesting that
      the in-frame deletion leads to a loss of function.
    explanation: >-
      Patient-derived fibroblasts carrying p.Asp185del show the functional consequence
      expected of a null allele.
  - reference: PMID:23867502
    reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ARHGDIA mutations (R120X and G173V) from individuals with SRNS abrogated interaction
      with RHO GTPases and increased active GTP-bound RAC1 and CDC42, but not RHOA,
      indicating that RAC1 and CDC42 are more relevant to the pathogenesis of this SRNS
      variant than RHOA.
    explanation: >-
      Both patient alleles from the second founding report lose GTPase binding in
      cultured human podocytes.
  downstream:
  - target: Impaired RhoGDIalpha-GTPase Interaction
    causal_link_type: DIRECT
    description: >-
      Characterized variants impair GTPase interaction or its regulatory consequences, with retained partial binding reported for G173V.
    evidence:
    - reference: PMID:23434736
      reference_title: "ARHGDIA: a novel gene implicated in nephrotic syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        When transfected in HEK293T cells, the mutant RhoGDIα was unable to bind to the
        Rho-GTPases, RhoA, Rac1, and Cdc42, unlike the wild-type construct.
      explanation: Direct binding assay for the in-frame deletion allele.

  - target: Reduced Total Rho GTPase Protein Abundance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26726844
      reference_title: Disease-causing mutations of RhoGDIα induce Rac1 hyperactivation in podocytes.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The GDIα KD podocytes had decreased levels of Rac1, RhoA, and Cdc42 compared with control podocytes
      explanation: Total protein abundance was measured; loss of protection from proteasomal degradation is the authors' interpretation.
  - target: Podocyte Actin Cytoskeleton Derangement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Actin abnormalities follow loss of RhoGDIalpha regulation, but specific contributions of the affected GTPases are unresolved.
    evidence:
    - reference: PMID:26726844
      reference_title: Disease-causing mutations of RhoGDIα induce Rac1 hyperactivation in podocytes.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The mutant podocytes also showed impaired actin polymerization, smaller cell size,
        and increased cellular projections.
      explanation: Cytoskeletal and morphological phenotype of podocytes carrying patient alleles.
- name: Impaired RhoGDIalpha-GTPase Interaction
  biological_scale: MOLECULAR
  description: >-
    The p.Asp185del and p.Arg120Ter proteins fail to interact with the tested Rho-family GTPases in binding assays. G173V loses detectable interaction in one experimental system but retains partial binding in another. Binding and inhibition therefore should not be treated as interchangeable readouts, nor as uniformly absent for every allele.
  genes:
  - preferred_term: RAC1
    term:
      id: hgnc:9801
      label: RAC1
  - preferred_term: CDC42
    term:
      id: hgnc:1736
      label: CDC42
  - preferred_term: RHOA
    term:
      id: hgnc:667
      label: RHOA
  evidence:
  - reference: PMID:26726844
    reference_title: Disease-causing mutations of RhoGDIα induce Rac1 hyperactivation in podocytes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: WT GDIα and G173V GDIα co-immunoprecipitated with all 3 Rho-GTPases, but the ΔD185 GDIα and R120X GDIα did not.
    explanation: Co-immunoprecipitation in HEK293T cells distinguishes binding behavior among the three studied variants.
  downstream:
  - target: RAC1 Hyperactivation in Podocytes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Impaired RhoGDIalpha regulation is associated with altered GTPase activation; intermediate exchange and inactivation factors and allele-specific binding effects remain unresolved.
    evidence:
    - reference: PMID:26726844
      reference_title: Disease-causing mutations of RhoGDIα induce Rac1 hyperactivation in podocytes.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Among the 3 prototypical Rho-GTPases, Rac1 was markedly hyperactivated in
        podocytes with any of the 3 mutant forms of GDIα while the activation of RhoA and
        Cdc42 was modest and variable.
      explanation: Consistent RAC1 activation across the three functionally tested alleles.
  - target: Variable CDC42 Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired RhoGDIalpha regulation is associated with altered GTPase activation; intermediate exchange and inactivation factors and allele-specific binding effects remain unresolved.

    evidence:
    - reference: PMID:26726844
      reference_title: Disease-causing mutations of RhoGDIα induce Rac1 hyperactivation in podocytes.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Among the 3 prototypical Rho-GTPases, Rac1 was markedly hyperactivated in
        podocytes with any of the 3 mutant forms of GDIα while the activation of RhoA and
        Cdc42 was modest and variable.
      explanation: Mutant-reconstituted podocytes show modest, variable CDC42 activation. This supports a context-dependent association with altered RhoGDIalpha regulation, not a uniform direct effect of binding loss.
  - target: Variable RHOA Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: RHOA regulation differs between the cell and animal systems; release from RhoGDIalpha does not invariably activate RHOA.
    evidence:
    - reference: PMID:26726844
      reference_title: Disease-causing mutations of RhoGDIα induce Rac1 hyperactivation in podocytes.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Among the 3 prototypical Rho-GTPases, Rac1 was markedly hyperactivated in
        podocytes with any of the 3 mutant forms of GDIα while the activation of RhoA and
        Cdc42 was modest and variable.
      explanation: Mutant-reconstituted podocytes show modest, variable RHOA activation; the binding defect does not establish invariant activation.
    - reference: PMID:23867502
      reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
      supports: REFUTE
      evidence_source: IN_VITRO
      snippet: ARHGDIA loss of function increases the active states of RAC1 and CDC42 by 168% and 185%, respectively, but has no such effect on RHOA
      explanation: No corresponding RHOA activation in the human podocyte experiment.
- name: RAC1 Hyperactivation in Podocytes
  biological_scale: MOLECULAR
  description: >-
    The best-supported proximal effector. RAC1 activity rises in podocytes carrying any
    of the three characterized alleles, in ARHGDIA-knockdown podocytes, in patient
    lymphoblasts, and in the kidneys of Arhgdia-null mice (where RhoA did not rise).
    RhoGDIalpha expression normally increases as podocytes mature while active Rac1
    falls, so the lesion removes a maturation-linked brake on Rac1.
  genes:
  - preferred_term: RAC1
    term:
      id: hgnc:9801
      label: RAC1
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  biological_processes:
  - preferred_term: Rac protein signal transduction
    modifier: INCREASED
    term:
      id: GO:0016601
      label: Rac protein signal transduction
  evidence:
  - reference: PMID:23867502
    reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ARHGDIA loss of function increases the active states of RAC1 and CDC42 by 168% and
      185%, respectively, but has no such effect on RHOA
    explanation: siRNA knockdown in cultured human podocytes.
  - reference: PMID:23867502
    reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we demonstrated by GST pulldown that active RAC1 is spontaneously elevated in
      EBV-transformed lymphoblasts from patient A1432-21 with an ARHGDIA mutation
    explanation: The same effect in cells from an affected individual.
  - reference: PMID:26726844
    reference_title: Disease-causing mutations of RhoGDIα induce Rac1 hyperactivation in podocytes.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In the developing kidney, GDIα expression increased as podocytes matured.
      Conversely, active Rac1 was detected only in immature, but not in mature,
      podocytes.
    explanation: >-
      Developmental expression data in mouse kidney, which place the RhoGDIalpha brake on
      Rac1 at podocyte maturation - relevant to the congenital and infantile onset.
  downstream:
  - target: Dysregulated Podocyte Motility
    causal_link_type: DIRECT
    description: >-
      Pharmacological RAC1 inhibition reverses the motility phenotype of
      ARHGDIA-deficient podocytes, placing RAC1 on the causal path.
    evidence:
    - reference: PMID:23867502
      reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Moreover, the mutations enhanced migration of cultured human podocytes; however,
        enhanced migration was reversed by treatment with RAC1 inhibitors.
      explanation: Inhibitor reversal is what makes the RAC1 step causal rather than correlative.
  - target: Renal Mineralocorticoid Receptor Overactivation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Cell experiments implicate p21-activated kinase phosphorylation and mineralocorticoid-receptor nuclear accumulation; mouse Rac inhibition reduces renal receptor overactivity without a change in systemic aldosterone.
    evidence:
    - reference: PMID:19029984
      reference_title: "Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Pharmacological intervention with a Rac-specific small-molecule inhibitor
        diminished mineralocorticoid receptor overactivity and renal damage in this model.
      explanation: >-
        Rac inhibition lowers MR activity in the knockout, so the MR effect lies
        downstream of Rac1.
  - target: Sensitization of Podocytes to Inflammatory Injury
    causal_link_type: DIRECT
    description: >-
      In ARHGDIA-knockdown podocytes, the exaggerated p38 response to LPS is
      Rac1-dependent.
    evidence:
    - reference: PMID:25503727
      reference_title: Loss of Rho-GDIα sensitizes podocytes to lipopolysaccharide-mediated injury.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        GDIα knockdown podocytes showed more pronounced and sustained p38 phosphorylation
        in response to LPS compared with control podocytes, and this was blunted
        significantly by the Rac1 inhibitor.
      explanation: Rac1 inhibition blunts the sensitized response.

- name: Variable CDC42 Activation
  biological_scale: MOLECULAR
  description: >-
    CDC42 activity increased after ARHGDIA knockdown in human and mouse podocytes. In mutant-reconstituted mouse podocytes, changes were smaller and not consistently significant. Its independent contribution to the clinical phenotype remains unresolved.
  genes:
  - preferred_term: CDC42
    term:
      id: hgnc:1736
      label: CDC42
  biological_processes:
  - preferred_term: Cdc42 protein signal transduction
    modifier: DYSREGULATED
    term:
      id: GO:0032488
      label: Cdc42 protein signal transduction
  evidence:
  - reference: PMID:23867502
    reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: ARHGDIA loss of function increases the active states of RAC1 and CDC42 by 168% and 185%, respectively, but has no such effect on RHOA
    explanation: Human podocyte knockdown supports CDC42 activation in that system.
  - reference: PMID:26726844
    reference_title: Disease-causing mutations of RhoGDIα induce Rac1 hyperactivation in podocytes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Cdc42 hyperactivity only in GDIα KD cells.
    explanation: The 2016 study distinguishes statistically significant knockdown effects from the variable mutant-reconstitution results.
  downstream:
  - target: Podocyte Actin Cytoskeleton Derangement
    causal_link_type: UNKNOWN
    description: >-
      Whether CDC42 or RHOA activation contributes independently of RAC1 is not
      established; see the RhoA discussion.

- name: Podocyte Actin Cytoskeleton Derangement
  biological_scale: CELLULAR
  conforms_to: "nephrotic_podocyte_injury#Podocyte Injury"
  description: >-
    RhoGDIalpha-knockdown and mutant-reconstituted mouse podocytes showed reduced filamentous-to-globular actin ratios and altered morphology. This is not reproduced simply by constitutively active RAC1, which increased the ratio in the same study; combined GTPase imbalance and cell context matter.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  biological_processes:
  - preferred_term: actin cytoskeleton organization
    modifier: ABNORMAL
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
  evidence:
  - reference: PMID:26726844
    reference_title: Disease-causing mutations of RhoGDIα induce Rac1 hyperactivation in podocytes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The mutant podocytes also showed impaired actin polymerization, smaller cell size,
      and increased cellular projections.
    explanation: Cytoskeletal and morphological phenotype of podocytes carrying patient alleles.
  downstream:
  - target: Podocyte Foot Process Effacement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The authors propose that aberrant projections and reduced cell size alter the slit
      diaphragm; the step from cultured-podocyte morphology to effaced foot processes in
      vivo has not been shown directly for ARHGDIA.
    evidence:
    - reference: PMID:26726844
      reference_title: Disease-causing mutations of RhoGDIα induce Rac1 hyperactivation in podocytes.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The increased number of cellular protrusions may result in an aberrant podocyte
        morphology that alters the morphology of the slit diaphragms, thereby allowing
        protein leakage into the urine.
      explanation: >-
        The authors' proposed link, stated as a possibility; this is why the edge is
        marked as having unknown intermediates.
    hypothesis_groups:
    - arhgdia_cellular_glomerular_injury
- name: Renal Mineralocorticoid Receptor Overactivation
  biological_scale: MOLECULAR
  description: >-
    In Arhgdia-null mice, Rac1 enhances mineralocorticoid receptor signalling in the kidney
    without any change in circulating aldosterone, and MR blockade suppresses the
    albuminuria. This arm is established in the mouse and in cultured cells only.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  biological_processes:
  - preferred_term: nuclear receptor-mediated mineralocorticoid signaling pathway
    modifier: INCREASED
    term:
      id: GO:0031959
      label: nuclear receptor-mediated mineralocorticoid signaling pathway
  evidence:
  - reference: PMID:19029984
    reference_title: "Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      CA-Rac1 facilitated mineralocorticoid receptor nuclear accumulation also in
      podocytes via p21-activated kinase phosphorylation.
    explanation: The cellular mechanism, shown with constitutively active Rac1 in podocytes.
  downstream:
  - target: Glomerular Filtration Barrier Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: MR blockade reduces albuminuria and histological damage in the knockout.
    evidence:
    - reference: PMID:19029984
      reference_title: "Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Furthermore, albuminuria and histological changes in Arhgdia(-/-) mice were
        suppressed by mineralocorticoid receptor blockade, confirming the pathological
        role of Rac1-mineralocorticoid receptor interaction.
      explanation: Pharmacological interruption of this node reduces the barrier defect in vivo.

- name: Sensitization of Podocytes to Inflammatory Injury
  biological_scale: CELLULAR
  description: >-
    RhoGDIalpha-depleted podocytes respond to lipopolysaccharide with exaggerated p38 MAPK
    phosphorylation and greater loss of synaptopodin, an actin-associated podocyte
    protein. This proposes a route by which an environmental insult could compound the
    inherited lesion; it has been shown in cultured podocytes only.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  evidence:
  - reference: PMID:25503727
    reference_title: Loss of Rho-GDIα sensitizes podocytes to lipopolysaccharide-mediated injury.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In GDIα knockdown podocytes, the same events were triggered, but the levels of
      synaptopodin after LPS treatment were significantly lower than in control
      podocytes.
    explanation: Greater synaptopodin loss under the same injury.
  downstream:
  - target: Podocyte Actin Cytoskeleton Derangement
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      p38-dependent, proteasome- and cathepsin L-mediated synaptopodin degradation removes
      an actin-associated podocyte protein.
    evidence:
    - reference: PMID:25503727
      reference_title: Loss of Rho-GDIα sensitizes podocytes to lipopolysaccharide-mediated injury.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        These experiments reveal a common pathway by which heritable and environmental
        risk factors converge to injure podocytes, from Rac1 hyperactivation to p38
        phosphorylation and synaptopodin degradation via the ubiquitin-proteasome pathway
        and cathepsin L.
      explanation: The authors' summary of the intermediate steps.

- name: Podocyte Foot Process Effacement
  biological_scale: CELLULAR
  description: >-
    Diffuse podocyte foot process effacement was demonstrated by electron microscopy of the p.Asp185del proband's biopsy. Slit-diaphragm disruption is a proposed link from cellular abnormalities to protein leakage, rather than a separately measured lesion in that biopsy.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  evidence:
  - reference: PMID:23434736
    reference_title: "ARHGDIA: a novel gene implicated in nephrotic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electron micrograph images from the patient's kidney biopsy (C) show diffuse foot
      process effacement (arrow), thinning of the glomerular basement membrane
      (arrowhead), and swollen endothelial cells (Endo).
    explanation: Ultrastructure of the proband's biopsy.
  downstream:
  - target: Glomerular Filtration Barrier Failure
    causal_link_type: DIRECT
  - target: Podocyte Foot Process Effacement on Electron Microscopy
    causal_link_type: DIRECT

- name: Glomerular Filtration Barrier Failure
  biological_scale: TISSUE
  conforms_to: "nephrotic_podocyte_injury#Glomerular Filtration Barrier Breakdown"
  description: >-
    Loss of glomerular protein retention. Reproduced in Arhgdia-null mice (massive
    proteinuria, death from renal failure within a year) and in arhgdia morphant
    zebrafish (proteinuria and whole-body edema).
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  locations:
  - preferred_term: renal glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  biological_processes:
  - preferred_term: glomerular filtration
    modifier: ABNORMAL
    term:
      id: GO:0003094
      label: glomerular filtration
  evidence:
  - reference: PMID:10498891
    reference_title: Progressive impairment of kidneys and reproductive organs in mice lacking Rho GDIalpha.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Rho GDIalpha -/- mice were initially viable but developed massive proteinuria
      mimicking nephrotic syndrome, leading to death due to renal failure within a year.
    explanation: Constitutive knockout reproduces the barrier failure.
  - reference: PMID:23867502
    reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The proteinuric effect of the arhgdia MO was confirmed using an established
      zebrafish proteinuria ELISA assay
    explanation: Zebrafish knockdown produces measured proteinuria.
  downstream:
  - target: Nephrotic-Range Proteinuria
    causal_link_type: DIRECT
  - target: Hypoalbuminemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Urinary protein loss depletes serum albumin.
  - target: Generalized Edema
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Hypoalbuminemia lowers plasma oncotic pressure.
  - target: Nephrotic Syndrome
    causal_link_type: DIRECT

- name: Reduced Total Rho GTPase Protein Abundance
  biological_scale: MOLECULAR
  description: >-
    Total RAC1, RHOA and CDC42 protein levels were reduced in RhoGDIalpha-knockdown and mutant-reconstituted mouse podocytes and restored by wild-type replacement. This is distinct from increased activity of the remaining GTPase pool. The study interpreted the result as reduced protection from degradation.
  evidence:
  - reference: PMID:26726844
    reference_title: Disease-causing mutations of RhoGDIα induce Rac1 hyperactivation in podocytes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The GDIα KD podocytes had decreased levels of Rac1, RhoA, and Cdc42 compared with control podocytes
    explanation: Total protein abundance was measured; loss of protection from proteasomal degradation is the authors' interpretation.
- name: Variable RHOA Activation
  biological_scale: MOLECULAR
  description: >-
    RHOA activity increased in patient fibroblasts and some mouse podocyte experiments, including the p.Asp185del model, but not in the Gee human podocyte knockdown experiments or the knockout mouse kidney. Its contribution is model-dependent and cannot be inferred from RAC1 activation alone.
  genes:
  - preferred_term: RHOA
    term:
      id: hgnc:667
      label: RHOA
  evidence:
  - reference: PMID:23434736
    reference_title: "ARHGDIA: a novel gene implicated in nephrotic syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: When RhoGDIα was knocked down in podocytes, RhoA, Rac1, and Cdc42 were hyperactivated and podocyte motility was impaired.
    explanation: Mouse podocyte knockdown supports RHOA activation.
  - reference: PMID:23867502
    reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: ARHGDIA loss of function increases the active states of RAC1 and CDC42 by 168% and 185%, respectively, but has no such effect on RHOA
    explanation: No corresponding RHOA activation in the human podocyte experiment.
  downstream:
  - target: Podocyte Actin Cytoskeleton Derangement
    causal_link_type: UNKNOWN
    description: >-
      Whether CDC42 or RHOA activation contributes independently of RAC1 is not
      established; see the RhoA discussion.

- name: Dysregulated Podocyte Motility
  biological_scale: CELLULAR
  description: >-
    Podocyte motility is altered after ARHGDIA perturbation. Human siRNA knockdown and mutant-overexpression experiments found enhanced migration, whereas mouse knockdown and mutant-replacement experiments found slower migration. The direction depends on the experimental system and is not a uniform disease feature.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  biological_processes:
  - preferred_term: podocyte cell migration
    modifier: DYSREGULATED
    term:
      id: GO:0090521
      label: podocyte cell migration
  evidence:
  - reference: PMID:26726844
    reference_title: Disease-causing mutations of RhoGDIα induce Rac1 hyperactivation in podocytes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      All three mutant GDIα proteins resulted in slow podocyte motility, suggesting that
      podocytes are sensitive to the relative balance of Rho-GTPase activity.
    explanation: Motility was slowed in the three mutant-reconstituted lines tested in this study.
  - reference: PMID:23867502
    reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Podocytes transfected with ARHGDIA siRNA exhibited more active migration compared
      with those transfected with scrambled siRNA.
    explanation: Motility is disturbed in the opposite direction in human podocyte knockdown.
  downstream:
  - target: Diffuse Mesangial Sclerosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired migration during podocyte development is proposed to contribute to disease;
      the developmental glomerular lesion seen in patients is diffuse mesangial sclerosis.
      The intermediate steps between the cellular defect and the lesion are not
      characterized.
    evidence:
    - reference: PMID:26726844
      reference_title: Disease-causing mutations of RhoGDIα induce Rac1 hyperactivation in podocytes.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        impaired cell migration during podocyte development likely contributes to the
        pathogenesis of NS in patients with GDIα mutations
      explanation: The authors' developmental framing; a hypothesis, not a demonstration.

    hypothesis_groups:
    - arhgdia_cellular_glomerular_injury
phenotypes:
- category: Renal
  name: Nephrotic Syndrome
  description: >-
    Presentation ranges from congenital nephrotic syndrome to early-childhood onset. Gee Table 1 records onset at 2.4 years and one year in the genotyped G173V siblings, and at 14 days in the R120X infant. The additional affected G173V-family sibling had onset at one year but no DNA available. The p.Gly168Arg infant had three months of anasarca before referral at 11 months. These few families suggest allele-associated variation without establishing a precise genotype-prognosis rule.
  phenotype_term:
    preferred_term: Nephrotic syndrome
    term:
      id: HP:0000100
      label: Nephrotic syndrome
  evidence:
  - reference: PMID:23434736
    reference_title: "ARHGDIA: a novel gene implicated in nephrotic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband presented at 3 weeks of age with generalised oedema and was found to
      have severe hypoalbuminaemia and proteinuria and was diagnosed with congenital
      nephrotic syndrome.
    explanation: Neonatal presentation in the first sister.
  - reference: PMID:23434736
    reference_title: "ARHGDIA: a novel gene implicated in nephrotic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The second child was diagnosed with congenital nephrotic syndrome on day 16 of life
      when her laboratory studies revealed severe hypoalbuminaemia with proteinuria
    explanation: Neonatal presentation in the second sister.
  - reference: PMID:23867502
    reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we detected a homozygous mutation (c.358C>T;p.R120X) in an infant (A4578-21) with
      congenital NS
    explanation: Congenital presentation with the nonsense allele.
  - reference: PMID:26726844
    reference_title: Disease-causing mutations of RhoGDIα induce Rac1 hyperactivation in podocytes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      patients with the G173V mutation developed NS later in childhood (at one year of age
      or older) compared to patients with the ΔD185 and R120X mutations (within the first
      3 months of life)
    explanation: >-
      Allele-dependent age at onset, summarized from the two founding reports by the
      authors of an in vitro study.
  - reference: CGGV:assertion_0e529f2b-21ac-44b2-981e-048e92e377a1-2022-05-24T180000.000Z
    reference_title: "ARHGDIA / nephrotic syndrome, type 8 (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The clinical presentation is with the nephrotic syndrome soon after birth.
    explanation: ClinGen Glomerulopathy GCEP summary of the presentation.

  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
    reference_title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: The initial manifestation of nephrotic syndrome is severe proteinuria defined as presence of the following
    explanation: GeneReviews supplies the general nephrotic-syndrome clinical baseline; patient onset comes from ARHGDIA-specific reports.
  - reference: url:https://www.jci.org/articles/view/69134/files/pdf
    reference_title: https://www.jci.org/articles/view/69134/files/pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '-21 2.4 yr -21: SRNS, -21: ID, SNHL ... -23 1 yr -23: SRNS, -23: ID'
    explanation: Gee et al. (2013), PMID:23867502, Table 1 in the full PDF. The two genotyped G173V siblings have distinct ages at onset; the intervening sibling row is marked no data or DNA available.
- category: Renal
  name: Steroid Resistance
  description: >-
    Eight weeks of daily prednisolone failed to induce remission in the p.Gly168Arg case. The Iranian cohort including the ARHGDIA splice-variant case defined SRNS by failure of complete remission after four weeks of daily prednisone. Steroid treatment was not documented for every congenital patient, so the disease-group label does not imply an observed steroid trial in all individuals.
  phenotype_term:
    preferred_term: Steroid-resistant nephrotic syndrome
    term:
      id: HP:0012588
      label: Steroid-resistant nephrotic syndrome
  evidence:
  - reference: PMID:35060086
    reference_title: Homozygous ARHGDIA Gene Mutation in an 11-Month-Old Infant with Steroid-Resistant Nephrotic Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Despite 8 wk of daily prednisolone, she had not attained remission.
    explanation: The only documented steroid trial in a genetically confirmed patient.
  - reference: ORPHA:656
    reference_title: "Hereditary steroid-resistant nephrotic syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:615244 | Broader"
    explanation: >-
      Orphanet maps OMIM:615244 (NPHS8) to its hereditary steroid-resistant nephrotic
      syndrome entry as a broader term; there is no ARHGDIA-specific Orphanet code.

  - reference: PMID:36245711
    reference_title: High detection rate for disease-causing variants in a cohort of 30 Iranian pediatric steroid resistant nephrotic syndrome cases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The clinical diagnosis of SRNS was defined as absence of complete remission after 4 weeks of daily prednisone therapy at a dose of 60 mg/m2 per day for all affected individuals.
    explanation: Cohort eligibility included the ARHGDIA case; this is not a detailed individual treatment record.
- category: Renal
  name: Nephrotic-Range Proteinuria
  phenotype_term:
    preferred_term: Nephrotic range proteinuria
    term:
      id: HP:0012593
      label: Nephrotic range proteinuria
  evidence:
  - reference: PMID:23434736
    reference_title: "ARHGDIA: a novel gene implicated in nephrotic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband presented at 3 weeks of age with generalised oedema and was found to
      have severe hypoalbuminaemia and proteinuria and was diagnosed with congenital
      nephrotic syndrome.
    explanation: Heavy proteinuria at presentation.

- category: Renal
  name: Hypoalbuminemia
  phenotype_term:
    preferred_term: Hypoalbuminemia
    term:
      id: HP:0003073
      label: Hypoalbuminemia
  evidence:
  - reference: PMID:23434736
    reference_title: "ARHGDIA: a novel gene implicated in nephrotic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The second child was diagnosed with congenital nephrotic syndrome on day 16 of life
      when her laboratory studies revealed severe hypoalbuminaemia with proteinuria
    explanation: Severe hypoalbuminemia in the neonatal period.

- category: Cardiovascular
  name: Generalized Edema
  description: >-
    Generalized edema in the neonatal proband; anasarca with periorbital, pedal and vulval
    edema and severe ascites in the 11-month-old.
  phenotype_term:
    preferred_term: Generalized edema
    term:
      id: HP:0007430
      label: Generalized edema
  evidence:
  - reference: PMID:23434736
    reference_title: "ARHGDIA: a novel gene implicated in nephrotic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband presented at 3 weeks of age with generalised oedema and was found to
      have severe hypoalbuminaemia and proteinuria and was diagnosed with congenital
      nephrotic syndrome.
    explanation: Generalized edema at presentation.
  - reference: PMID:35060086
    reference_title: Homozygous ARHGDIA Gene Mutation in an 11-Month-Old Infant with Steroid-Resistant Nephrotic Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At presentation, she had periorbital, pedal edema, severe ascites, and vulval
      edema.
    explanation: Anasarca in the later-onset infant.

- category: Cardiovascular
  name: Hypertension
  description: >-
    Stage 2 hypertension was documented in the p.Gly168Arg infant, whose serum creatinine was 3.25 mg/dL at presentation.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:35060086
    reference_title: Homozygous ARHGDIA Gene Mutation in an 11-Month-Old Infant with Steroid-Resistant Nephrotic Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She had stage 2 hypertension.
    explanation: Single-case observation.

- category: Renal
  name: Diffuse Mesangial Sclerosis
  description: >-
    The biopsy lesion in every reported case with histology: small, hypercellular
    glomeruli with increased matrix and contracted tufts surrounded by immature or
    vacuolated podocytes. The 11-month-old could not be biopsied.
  phenotype_term:
    preferred_term: Diffuse mesangial sclerosis
    term:
      id: HP:0001967
      label: Diffuse mesangial sclerosis
  evidence:
  - reference: PMID:23434736
    reference_title: "ARHGDIA: a novel gene implicated in nephrotic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A renal biopsy was performed at 1 month of age and this showed severe glomerular
      changes consistent with diffuse mesangial sclerosis
    explanation: DMS in the p.Asp185del proband.
  - reference: PMID:23867502
    reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed homozygosity mapping (HM) in a family (A1432) of Ashkenazi Jewish
      origin in whom 2 siblings had early-onset SRNS with renal histology of DMS.
    explanation: DMS in the G173V sibling pair.
  - reference: PMID:23867502
    reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This infant also exhibited renal histology of DMS
    explanation: DMS in the R120X infant.
  sequelae:
  - target: Kidney Failure
    description: Progression of the developmental glomerular lesion.

- category: Renal
  name: Podocyte Foot Process Effacement on Electron Microscopy
  description: >-
    Diffuse effacement on the one reported electron-microscopy study.
  phenotype_term:
    preferred_term: Podocyte foot process effacement
    term:
      id: HP:0031266
      label: Podocyte foot process effacement
  evidence:
  - reference: PMID:23434736
    reference_title: "ARHGDIA: a novel gene implicated in nephrotic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electron micrograph images from the patient's kidney biopsy (C) show diffuse foot
      process effacement (arrow), thinning of the glomerular basement membrane
      (arrowhead), and swollen endothelial cells (Endo).
    explanation: Ultrastructural finding in the proband.

- category: Renal
  name: Thin Glomerular Basement Membrane
  phenotype_term:
    preferred_term: Thin glomerular basement membrane
    term:
      id: HP:0012577
      label: Thin glomerular basement membrane
  evidence:
  - reference: PMID:23434736
    reference_title: "ARHGDIA: a novel gene implicated in nephrotic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electron micrograph images from the patient's kidney biopsy (C) show diffuse foot
      process effacement (arrow), thinning of the glomerular basement membrane
      (arrowhead), and swollen endothelial cells (Endo).
    explanation: Single-biopsy observation.

- category: Renal
  name: Renal Tubular Atrophy
  description: >-
    Tubular dilation, atrophy and casts in the kidney explanted from the R120X infant at
    two months of age.
  phenotype_term:
    preferred_term: Renal tubular atrophy
    term:
      id: HP:0000092
      label: Renal tubular atrophy
  evidence:
  - reference: PMID:23867502
    reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Right kidney explanted at 2 months of age reveals on H&E staining advanced tubular
      dilation, atrophy, and casts
    explanation: Histology of the explanted kidney.

- category: Renal
  name: Kidney Failure
  description: >-
    Progression can be rapid: the R120X infant reached end-stage kidney disease at six weeks and the p.Asp185del proband at three months. The two genotyped G173V siblings reached end-stage kidney disease at 2.4 and three years. The p.Gly168Arg infant remained anuric after peritoneal dialysis and died at 11 months.
  phenotype_term:
    preferred_term: Stage 5 chronic kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:23434736
    reference_title: "ARHGDIA: a novel gene implicated in nephrotic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient rapidly deteriorated and developed end stage renal failure at 3 months
      of age that was treated by haemodialysis.
    explanation: Kidney failure within months of birth.
  - reference: PMID:35060086
    reference_title: Homozygous ARHGDIA Gene Mutation in an 11-Month-Old Infant with Steroid-Resistant Nephrotic Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      These cases had infantile-onset; showed diffuse mesangial sclerosis on renal
      biopsy; and rapidly progressed to end-stage renal disease (ESRD) or died
    explanation: >-
      The case report's summary of the earlier ARHGDIA cases, which it cites rather than
      reports.

  - reference: url:https://www.jci.org/articles/view/69134/files/pdf
    reference_title: https://www.jci.org/articles/view/69134/files/pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '-21 2.4 yr -21: SRNS, -21: ID, SNHL ESKD 2.4 yr, ... -23 1 yr -23: SRNS, -23: ID ESKD 3 yr'
    explanation: Gee et al. (2013), PMID:23867502, Table 1 in the full PDF. Age at kidney failure in the G173V family; this is not uniformly an infantile outcome.
- category: Neurological
  name: Intellectual Disability
  description: >-
    Reported for the two genotyped G173V siblings and the R120X infant in Gee Table 1. Neurologic details and age of assessment are limited, particularly for the infant who died at six months. The p.Gly168Arg child was described as developmentally normal at 11 months; normal early development does not exclude later difficulties.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:23867502
    reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      3 of 4 (75%) individuals from 2 independent families had neurological phenotypes
      including intellectual disability (Table 1)
    explanation: Neurological involvement in the original Gee family series; the full PDF table identifies the affected individuals.
  - reference: PMID:35060086
    reference_title: Homozygous ARHGDIA Gene Mutation in an 11-Month-Old Infant with Steroid-Resistant Nephrotic Syndrome.
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An 11-mo-old developmentally normal girl was referred for evaluation of anasarca for the preceding 3 mo.
    explanation: >-
      No developmental abnormality was reported at this early assessment; not evidence against neurologic involvement in the disease generally.

- name: Seizures
  category: Neurological
  description: >-
    Seizures were reported in the R120X infant in Gee Table 1. The small series does not establish prevalence or a seizure syndrome.
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: url:https://www.jci.org/articles/view/69134/files/pdf
    reference_title: https://www.jci.org/articles/view/69134/files/pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 14 d CNS ID, seizures, (DMS; 1 mo), cortical ESKD 6 wk blindness, died at 6 mo
    explanation: Gee et al. (2013), PMID:23867502, Table 1 in the full PDF. Seizures and cortical blindness occur in the same infant; renal and extrarenal columns were checked in the rendered table.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
    reference_title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: ARHGDIA ... AR ... Seizures ... cortical blindness
    explanation: The ARHGDIA row of the syndromic genetic SRNS table lists seizures and cortical blindness.
- name: Sensorineural hearing impairment
  category: Auditory
  description: >-
    Sensorineural hearing loss was reported in individual A1432-21 with homozygous G173V. It is not documented for every affected sibling.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: url:https://www.jci.org/articles/view/69134/files/pdf
    reference_title: https://www.jci.org/articles/view/69134/files/pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '-21: ID, SNHL ... SNHL, sensorineural hearing loss.'
    explanation: Gee et al. (2013), PMID:23867502, Table 1 in the full PDF. The row identifies the affected sibling and the footnote expands SNHL.
- name: Hypercholesterolemia
  category: Metabolic
  description: >-
    Serum cholesterol was 270 mg/dL in the p.Gly168Arg infant, together with hypoalbuminemia and nephrotic-range proteinuria.
  phenotype_term:
    preferred_term: Hypercholesterolemia
    term:
      id: HP:0003124
      label: Hypercholesterolemia
  evidence:
  - reference: PMID:35060086
    reference_title: Homozygous ARHGDIA Gene Mutation in an 11-Month-Old Infant with Steroid-Resistant Nephrotic Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hypoalbuminemia (2.1 g/dL), hyper- cholesterolemia (270 mg/dL), and nephrotic-range proteinu- ria (Up:Uc 5.5) without microscopic hematuria were noted.
    explanation: The published PDF contains line-wrapped hyphenation; the observation is a single-patient laboratory finding.
- name: Cortical blindness
  category: Ophthalmological
  description: >-
    Cortical blindness was reported in the R120X infant, together with seizures and kidney failure. The report does not establish whether the visual deficit is a primary consequence of ARHGDIA deficiency or secondary injury.
  phenotype_term:
    preferred_term: Cortical blindness
    term:
      id: HP:0100704
      label: Cerebral visual impairment
  evidence:
  - reference: url:https://www.jci.org/articles/view/69134/files/pdf
    reference_title: https://www.jci.org/articles/view/69134/files/pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 14 d CNS ID, seizures, (DMS; 1 mo), cortical ESKD 6 wk blindness, died at 6 mo
    explanation: Gee et al. (2013), PMID:23867502, Table 1 in the full PDF. Seizures and cortical blindness occur in the same infant; renal and extrarenal columns were checked in the rendered table.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
    reference_title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: ARHGDIA ... AR ... Seizures ... cortical blindness
    explanation: The ARHGDIA row of the syndromic genetic SRNS table lists seizures and cortical blindness.
genetic:
- name: ARHGDIA
  gene_term:
    preferred_term: ARHGDIA
    term:
      id: hgnc:678
      label: ARHGDIA
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  variants:
  - name: c.553_555del (p.Asp185del)
    description: >-
      In-frame deletion of one of three consecutive aspartate residues (183-185) at the
      GTPase-binding interface; homozygous in two Pakistani sisters with congenital
      nephrotic syndrome. The deleted residue cannot be assigned, so the variant is named
      for position 185.
    evidence:
    - reference: PMID:23434736
      reference_title: "ARHGDIA: a novel gene implicated in nephrotic syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The sisters harbour a homozygous in-frame deletion that is predicted to remove a
        highly conserved aspartic acid residue within the interface where the protein,
        RhoGDIα, interacts with the Rho family of small GTPases (c.553_555del(p.Asp185del)).
      explanation: Identifies the allele and its position.
  - name: c.518G>T (p.Gly173Val)
    description: >-
      Missense, homozygous in two Ashkenazi Jewish siblings; associated with the later
      onset. Retains partial GTPase binding in one study but still fails to restrain RAC1.
    evidence:
    - reference: PMID:23867502
      reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Using WER, we detected in both siblings a homozygous missense mutation
        (c.518G>T;p.G173V) of ARHGDIA (RefSeq accession number NM_001185077.1)
      explanation: Identifies the allele and the reference transcript.
  - name: c.358C>T (p.Arg120Ter)
    description: Nonsense, homozygous in an infant with congenital nephrotic syndrome.
    evidence:
    - reference: PMID:23867502
      reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        we detected a homozygous mutation (c.358C>T;p.R120X) in an infant (A4578-21) with
        congenital NS
      explanation: Identifies the allele.
  - name: p.Gly168Arg
    description: >-
      Homozygous missense in exon 6, reported as likely pathogenic by clinical exome
      sequencing in an 11-month-old South Indian girl; not functionally tested.
    evidence:
    - reference: PMID:35060086
      reference_title: Homozygous ARHGDIA Gene Mutation in an 11-Month-Old Infant with Steroid-Resistant Nephrotic Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        exome sequencing revealed homozygous missense likely-pathogenic variation in exon
        6 of ARHGDIA gene
      explanation: Identifies the allele class and zygosity.
  - name: c.275-1G>A
    description: >-
      Canonical splice-acceptor variant, homozygous and classified likely pathogenic, in a
      child with congenital onset from an Iranian SRNS cohort; not functionally tested.
    evidence:
    - reference: PMID:36245711
      reference_title: High detection rate for disease-causing variants in a cohort of 30 Iranian pediatric steroid resistant nephrotic syndrome cases.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: one allele was a −1 canonical splice site variant in ARHGDIA
      explanation: Identifies the allele class.
    - reference: PMID:36245711
      reference_title: High detection rate for disease-causing variants in a cohort of 30 Iranian pediatric steroid resistant nephrotic syndrome cases.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: ARHGDIA NM_004309.6 | c.275-1G>A; p.(?) | Homo
      explanation: Table 1 identifies the reference transcript and splice allele; the actual splice product was not measured.
  evidence:
  - reference: CGGV:assertion_0e529f2b-21ac-44b2-981e-048e92e377a1-2022-05-24T180000.000Z
    reference_title: "ARHGDIA / nephrotic syndrome, type 8 (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ARHGDIA | HGNC:678 | nephrotic syndrome, type 8 | MONDO:0014099 | AR | Moderate"
    explanation: >-
      ClinGen (Glomerulopathy GCEP, 2022) classifies the gene-disease relationship for
      this MONDO term as Moderate.
  - reference: PMID:36245711
    reference_title: High detection rate for disease-causing variants in a cohort of 30 Iranian pediatric steroid resistant nephrotic syndrome cases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital cases are often caused by disease-causing variants in NPHS1 and we
      identified such variants in two cases as well as disease-causing variants in SGPL1
      or ARHGDIA in one case, respectively.
    explanation: >-
      ARHGDIA accounted for one congenital case among 30 consanguineous Iranian SRNS
      families, consistent with a rare contributor.
  - reference: url:https://www.jci.org/articles/view/69134/files/pdf
    reference_title: https://www.jci.org/articles/view/69134/files/pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A4578 Moroccan Yes ARHGDIA c.358C>T p.R120X 4 (Hom, M, F)
    explanation: Gee et al. (2013), PMID:23867502, Table 1 in the full PDF. The family row reports origin, consanguinity and heterozygous parental segregation; these details were absent from the cached HTML body.
  notes: >-
    The sources describe seven molecularly characterized patients in five families and an additional affected sibling in the G173V family for whom no DNA was available. Gee Table 1 identifies the G173V family as Ashkenazi Jewish and the R120X family as Moroccan and records parental consanguinity in both. Parental consanguinity is also reported in the Pakistani, Iranian and South Indian families. The small, selected series do not estimate population prevalence or penetrance. ClinGen calls the mechanism gain of function; the primary functional studies show impaired RhoGDIalpha regulation with increased downstream GTPase activity, which are distinct levels of description.

inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Molecularly characterized patients in the cited families are homozygous; available parental testing supports recessive segregation. For two heterozygous parents, each pregnancy has a 25% risk of an affected child, 50% probability of a carrier and 25% probability of an unaffected noncarrier. The untested deceased G173V-family sibling should not be counted as molecularly confirmed.
  evidence:
  - reference: PMID:36245711
    reference_title: High detection rate for disease-causing variants in a cohort of 30 Iranian pediatric steroid resistant nephrotic syndrome cases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Parents were heterozygous carriers of the respective variant.
    explanation: Carrier parents of homozygous affected children, including the ARHGDIA family.
  - reference: CGGV:assertion_0e529f2b-21ac-44b2-981e-048e92e377a1-2022-05-24T180000.000Z
    reference_title: "ARHGDIA / nephrotic syndrome, type 8 (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ARHGDIA | HGNC:678 | nephrotic syndrome, type 8 | MONDO:0014099 | AR | Moderate"
    explanation: ClinGen records the mode of inheritance as AR.

  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
    reference_title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic ... carrier ... and a 25% chance of being unaffected and not a carrier.
    explanation: General autosomal recessive SRNS counseling when both parents carry a causative allele.
diagnosis:
- name: Molecular genetic testing
  description: >-
    A nephrotic-syndrome multigene panel including ARHGDIA or exome/genome sequencing can establish the molecular diagnosis, with parental testing to confirm segregation. Panel content varies, so inclusion of this rare gene should be checked. Renal and extrarenal assessment helps interpret candidate variants; diffuse mesangial sclerosis alone does not identify the causal gene.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:23867502
    reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In summary, our findings of ARHGDIA mutation implicate the RHO small GTPase
      RAC1/CDC42 in the pathogenesis of human NS and permit a noninvasive,
      causation-based diagnosis.
    explanation: The founding report's framing of genetic testing as the diagnostic route.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
    reference_title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Molecular genetic testing ... can include a combination of ... targeted testing (single-gene testing or ... ) and comprehensive ... testing
    explanation: GeneReviews describes gene-targeted and comprehensive genomic testing strategies; the relevant linked terms are omitted from this HTML quote.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
    reference_title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Some panels may not include newly discovered and/or rare genes associated with genetic SRNS.
    explanation: Check the actual laboratory panel content rather than assuming ARHGDIA coverage.
- name: Kidney biopsy
  description: >-
    Shows diffuse mesangial sclerosis with foot process effacement. It identifies the
    lesion rather than its cause, and in the fulminant infantile course it may not be
    feasible.
  diagnosis_term:
    preferred_term: kidney biopsy
    term:
      id: NCIT:C51699
      label: Kidney Biopsy
  evidence:
  - reference: PMID:23434736
    reference_title: "ARHGDIA: a novel gene implicated in nephrotic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A renal biopsy was performed at 1 month of age and this showed severe glomerular
      changes consistent with diffuse mesangial sclerosis
    explanation: Biopsy findings in the proband.
  - reference: PMID:35060086
    reference_title: Homozygous ARHGDIA Gene Mutation in an 11-Month-Old Infant with Steroid-Resistant Nephrotic Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Renal biopsy could not be performed.
    explanation: Biopsy was not possible in the later, critically ill case.

treatments:
- name: Corticosteroid Therapy
  description: >-
    Prednisolone failed in the reported p.Gly168Arg case. GeneReviews advises avoiding continued ineffective prednisolone/prednisone after SRNS is established. Decisions about other immunosuppression in genetically diagnosed SRNS require individual assessment.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: prednisolone
      term:
        id: CHEBI:8378
        label: prednisolone
  target_mechanisms:
  - target: Nephrotic Syndrome
    description: No remission after eight weeks of daily prednisolone.
    evidence:
    - reference: PMID:35060086
      reference_title: Homozygous ARHGDIA Gene Mutation in an 11-Month-Old Infant with Steroid-Resistant Nephrotic Syndrome.
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: Despite 8 wk of daily prednisolone, she had not attained remission.
      explanation: Refutes a steroid response in this patient.

  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
    reference_title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Once the diagnosis of SRNS is established, ineffective prednisolone/prednisone treatment should be avoided.
    explanation: General genetic SRNS guidance supports stopping ineffective treatment; not all congenital ARHGDIA patients received a steroid trial.
- name: Dialysis
  description: >-
    Haemodialysis from three months of age in the neonatal proband; peritoneal dialysis in
    the 11-month-old, who remained anuric and died 18 days later.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: renal dialysis
    term:
      id: NCIT:C15221
      label: Dialysis
  target_mechanisms:
  - target: Kidney Failure
    treatment_effect: BYPASSES
    description: Replaces excretory function without altering the podocyte lesion.
  evidence:
  - reference: PMID:23434736
    reference_title: "ARHGDIA: a novel gene implicated in nephrotic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient rapidly deteriorated and developed end stage renal failure at 3 months
      of age that was treated by haemodialysis.
    explanation: Dialysis in early infancy.
  - reference: PMID:35060086
    reference_title: Homozygous ARHGDIA Gene Mutation in an 11-Month-Old Infant with Steroid-Resistant Nephrotic Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We initiated peritoneal dialysis, but she remained anuric and eventually died 18 d
      later
    explanation: Peritoneal dialysis, with a fatal outcome.

- name: Kidney Transplantation
  description: >-
    Kidney transplantation is part of the management of genetic SRNS. In the reported p.Asp185del proband, a deceased-donor graft at age two never functioned because of venous thrombosis. This event does not establish recurrent ARHGDIA nephropathy, and the cited cases do not provide a genotype-specific recurrence estimate.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: kidney transplantation
    term:
      id: NCIT:C15265
      label: Kidney Transplantation
  target_mechanisms:
  - target: Kidney Failure
    treatment_effect: BYPASSES
    description: Would replace the kidney carrying the podocyte lesion.
  evidence:
  - reference: PMID:23434736
    reference_title: "ARHGDIA: a novel gene implicated in nephrotic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She received a cadaveric renal transplant at the age of 2 years, but the graft
      never functioned due to venous thrombosis in the transplant, and so the patient
      remains on dialysis.
    explanation: The only reported transplant, a technical graft loss.

  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
    reference_title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: All genetic SRNS can be corrected with kidney transplantation.
    explanation: General genetic SRNS guidance; ARHGDIA-specific transplant outcome evidence remains limited.
- name: Renin-angiotensin-aldosterone system inhibition
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    GeneReviews recommends renin-angiotensin-aldosterone system inhibitors to reduce proteinuria in established SRNS. Treatment requires specialist assessment of blood pressure, kidney function and volume status; this is general genetic SRNS care, not an ARHGDIA-specific clinical efficacy estimate.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
    reference_title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Instead affected individuals should be treated with renin-angiotensin-aldosterone system inhibitors (RAASi) to reduce proteinuria.
    explanation: General SRNS management baseline.
  target_mechanisms:
  - target: Nephrotic-Range Proteinuria
- name: Supportive renal care
  therapeutic_modality: OTHER
  description: >-
    General genetic SRNS management includes prompt hypertension treatment, cautious diuretic use and management of chronic kidney disease. Vitamin D and thyroid hormone replacement are considered according to clinical need. Renal replacement is required when kidney failure develops.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
    reference_title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Prompt detection and treatment of hypertension
    explanation: GeneReviews management section.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
    reference_title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Cautious use of diuretics, vitamin D, and thyroid hormone substitution
    explanation: General management guidance; not a claim that every ARHGDIA patient needs each replacement.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Family screening and genetic counseling
  therapeutic_modality: OTHER
  description: >-
    Offer at-risk first-degree relatives urine testing for proteinuria and targeted testing once familial variants are identified. Counsel on autosomal recessive recurrence and reproductive options. Potential related kidney donors require genetic and clinical evaluation; heterozygous carriers of recessive SRNS alleles may be assessed as possible donors.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
    reference_title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: First degree relatives, including sibs, should be offered urine analysis for proteinuria.
    explanation: Early family assessment baseline.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/
    reference_title: Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Carrier testing for at-risk relatives requires prior identification of the ... SRNS-causing pathogenic variants in the family.
    explanation: GeneReviews requires identification of familial variants to guide carrier testing.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
- name: Experimental RAC1 inhibition
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    RAC1 inhibitors reversed enhanced migration of ARHGDIA-knockdown human podocytes and partially reduced edema and proteinuria in zebrafish morphants. Rac inhibition also reduced renal injury in knockout mice. These are preclinical interventions, with no established ARHGDIA-specific clinical efficacy.
  evidence:
  - reference: PMID:23867502
    reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We found that RAC1 inhibitors were partially effective in our zebrafish model in reducing edema from 70% in untreated arhgdia knockdown zebrafish to 47% for the RAC1 inhibitor-treated fish
    explanation: Partial edema rescue in morphants; no human efficacy inferred.
  - reference: PMID:23867502
    reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the addition to podocyte cultures of either one of the RAC1 inhibitors reversed the migratory phenotype
    explanation: Pharmacological reversal of the human podocyte knockdown phenotype.
  target_mechanisms:
  - target: RAC1 Hyperactivation in Podocytes
    description: Pharmacological inhibition of the implicated GTPase pathway.
- name: Experimental eplerenone treatment
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    The mineralocorticoid-receptor antagonist eplerenone partially reduced edema in arhgdia morphant zebrafish, from 70% to 54% in the reported experiment. Mineralocorticoid-receptor blockade also reduced albuminuria and histological injury in Arhgdia-null mice. No ARHGDIA-specific patient response is established.
  treatment_term:
    preferred_term: eplerenone therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: eplerenone
      term:
        id: NCIT:C47513
        label: Eplerenone
  evidence:
  - reference: PMID:23867502
    reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: 54% for eplerenone-treated fish, whereas RHO inhibitors (RHO inhibitor 1, Y-27632, and fasudil) showed no effect
    explanation: Partial morphant rescue; the untreated edema proportion was 70%.
  - reference: PMID:19029984
    reference_title: "Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: albuminuria and histological changes in Arhgdia(-/-) mice were suppressed by mineralocorticoid receptor blockade
    explanation: Mouse evidence for blockade of this pathway.
  target_mechanisms:
  - target: Renal Mineralocorticoid Receptor Overactivation
animal_models:
- name: Arhgdia knockout mouse
  species: Mouse
  genotype: Arhgdia-/- (constitutive)
  publication: PMID:10498891
  description: >-
    The constitutive null developed massive proteinuria and died of renal failure within
    a year, with tubular degeneration and dilatation; males were infertile. A later study
    in the same line showed increased renal Rac1 (not RhoA) and mineralocorticoid receptor
    signalling, reduced by a Rac inhibitor, and suppression of albuminuria by
    mineralocorticoid receptor blockade.
  modeled_mechanisms:
  - target: Glomerular Filtration Barrier Failure
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Heavy proteinuria and fatal renal failure after initial viability.
    limitations: >-
      Renal injury develops over months in this constitutive model. The 1999 abstract emphasizes tubular degeneration, while the 2013 human paper summarizes mouse glomerulosclerosis and foot-process injury from earlier work. This does not establish identity with the diffuse mesangial sclerosis of human biopsies. The reproductive phenotype has no established human counterpart in these case reports.
    evidence:
    - reference: PMID:10498891
      reference_title: Progressive impairment of kidneys and reproductive organs in mice lacking Rho GDIalpha.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Rho GDIalpha -/- mice were initially viable but developed massive proteinuria
        mimicking nephrotic syndrome, leading to death due to renal failure within a year.
      explanation: Establishes the renal phenotype of the null.
  - target: Renal Mineralocorticoid Receptor Overactivation
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      A Rac-specific inhibitor and mineralocorticoid receptor blockade each reduced renal
      damage in the knockout.
    limitations: >-
      Preclinical only. No Rac1 inhibitor or mineralocorticoid receptor antagonist has
      been reported in a patient with ARHGDIA disease, and the rescue was in a model with
      a slower course than the human disease.
    evidence:
    - reference: PMID:19029984
      reference_title: "Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Furthermore, albuminuria and histological changes in Arhgdia(-/-) mice were
        suppressed by mineralocorticoid receptor blockade, confirming the pathological
        role of Rac1-mineralocorticoid receptor interaction.
      explanation: The in vivo rescue.
- name: arhgdia morphant zebrafish
  species: Zebrafish
  genotype: arhgdia morpholino knockdown (translation-blocking and splice-blocking)
  publication: PMID:23867502
  description: >-
    Knockdown produced periorbital and whole-body edema in 70% of embryos at 120 hours
    post-fertilization, with proteinuria; RAC1 inhibitors and eplerenone partly reduced
    the edema, while RHO inhibitors did not.
  modeled_mechanisms:
  - target: Glomerular Filtration Barrier Failure
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Edema and measured proteinuria in larvae.
    limitations: >-
      Transient morpholino knockdown in a pronephros; glomerular histology and podocyte
      ultrastructure are not reported in the cached text.
    evidence:
    - reference: PMID:23867502
      reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Coinjection of the p53 control MO with an MO targeting the translation initiation
        site of zebrafish arhgdia caused the nephrosis phenotype of periorbital and total
        body edema in 70% of embryos at 120 hpf
      explanation: Establishes the phenotype and its penetrance.
  - target: RAC1 Hyperactivation in Podocytes
    relationship: RESCUES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      RAC1 inhibition partly reduced edema; RHO inhibitors had no effect, supporting RAC1
      over RHOA as the effector.
    limitations: >-
      Partial effect only (70% to 47% of embryos with edema), and RAC1 activity was not
      measured in the fish. Preclinical only.
    evidence:
    - reference: PMID:23867502
      reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We found that RAC1 inhibitors were partially effective in our zebrafish model in
        reducing edema from 70% in untreated arhgdia knockdown zebrafish to 47% for the
        RAC1 inhibitor-treated fish
      explanation: Quantifies the partial rescue.
    - reference: PMID:23867502
      reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: whereas RHO inhibitors (RHO inhibitor 1, Y-27632, and fasudil) showed no effect
      explanation: The negative control that points to RAC1 rather than RHOA.

- name: Drosophila nephrocyte RhoGDI knockdown
  species: Drosophila
  genotype: Nephrocyte knockdown of RhoGDI (CG7823)
  publication: PMID:23867502
  description: >-
    Reduced uptake of a secreted ANF-GFP fusion protein in pericardial nephrocytes after RhoGDI knockdown. This supports a role in nephrocyte function but does not directly measure mammalian glomerular filtration or recapitulate the clinical syndrome.
  modeled_mechanisms:
  - target: Glomerular Filtration Barrier Failure
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: Altered nephrocyte handling of a secreted protein provides a functional analog rather than a direct filtration-barrier assay.
    evidence:
    - reference: PMID:23867502
      reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: knockdown of Drosophila RhoGDI (CG7823) in nephrocytes reduced the uptake ability of the secreted fusion protein of rat atrial natriuretic factor (ANF) and GFP
      explanation: Primary functional assay in fly nephrocytes.
experimental_models:
- name: ARHGDIA-depleted or mutant-reconstituted podocyte lines
  experimental_model_type: CELL_LINE
  description: >-
    Cultured human podocytes with ARHGDIA siRNA or mutant overexpression (Gee), and mouse
    podocytes with shRNA knockdown alone or reconstituted with each patient allele
    (Gupta; Auguste).
  publication: PMID:26726844
  modeled_mechanisms:
  - target: RAC1 Hyperactivation in Podocytes
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: RAC1 activation is reproduced with all three characterized alleles.
    limitations: >-
      Immortalized podocytes in two dimensions; the direction of the motility phenotype
      differs between the human-overexpression and mouse-replacement designs.
    evidence:
    - reference: PMID:26726844
      reference_title: Disease-causing mutations of RhoGDIα induce Rac1 hyperactivation in podocytes.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Among the 3 prototypical Rho-GTPases, Rac1 was markedly hyperactivated in
        podocytes with any of the 3 mutant forms of GDIα while the activation of RhoA and
        Cdc42 was modest and variable.
      explanation: Allele-by-allele reproduction of the effector step.
- name: Patient-derived fibroblasts (p.Asp185del)
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: Skin fibroblasts from the homozygous p.Asp185del proband.
  publication: PMID:23434736
  modeled_mechanisms:
  - target: Biallelic ARHGDIA Loss of Function
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Endogenous mutant protein, mislocalized, with Rho-GTPase hyperactivation.
    limitations: >-
      Fibroblasts are not podocytes, and the actin response to RhoGDIalpha loss is
      reported to differ between the two cell types.
    evidence:
    - reference: PMID:23434736
      reference_title: "ARHGDIA: a novel gene implicated in nephrotic syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The proband's fibroblasts demonstrated mislocalisation of RhoGDIα to the nucleus,
        hyperactivation of the three Rho-GTPases, and impaired cell motility, suggesting
        that the in-frame deletion leads to a loss of function.
      explanation: The patient-cell readout.

discussions:
- discussion_id: arhgdia_motility_direction
  kind: CONTROVERSY
  prompt: >-
    Does RhoGDIalpha loss make podocytes more migratory or less?
  attaches_to:
  - pathophysiology#Dysregulated Podocyte Motility
  rationale: >-
    The Gee group found enhanced migration of human podocytes after ARHGDIA knockdown or mutant overexpression, reversible with RAC1 inhibitors. The Gupta and Auguste studies found impaired motility in mouse podocytes and in patient fibroblasts. Auguste et al. attribute the difference to design: Gee overexpressed mutants on a background of endogenous wild-type RhoGDIalpha, whereas they knocked down the endogenous protein and re-expressed the mutant. Both groups agree that RAC1 is hyperactivated and that podocyte motility is abnormal; the entry therefore records the process as dysregulated rather than increased or decreased. The design explanation remains incomplete because Gee also observed enhanced migration after siRNA knockdown. Species, assay and expression differences may contribute.
  evidence:
  - reference: PMID:26726844
    reference_title: Disease-causing mutations of RhoGDIα induce Rac1 hyperactivation in podocytes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These differences may be explained by the WT GDIα present in the human podocytes
      used by Gee et al. since they overexpressed the mutants without knocking down the
      endogenous GDIα
    explanation: The authors' explanation for the discrepancy.
- discussion_id: arhgdia_rhoa_role
  kind: CONTROVERSY
  prompt: Is RHOA activation part of the mechanism, or is the disease RAC1 (and CDC42) driven?
  attaches_to:
  - pathophysiology#Variable RHOA Activation
  - pathophysiology#Variable CDC42 Activation
  - pathophysiology#RAC1 Hyperactivation in Podocytes
  rationale: >-
    RhoA was hyperactivated in the Gupta knockdown podocytes and patient fibroblasts, but
    not in the Gee human podocyte assays, not in the Arhgdia-null mouse kidney, and only
    modestly and inconsistently in the Auguste allele panel. RHO inhibitors had no effect
    in the zebrafish model, where RAC1 inhibitors did. The weight of evidence favors
    RAC1, but no study has measured RHOA activation in patient podocytes.
- discussion_id: arhgdia_transplant_recurrence
  kind: KNOWLEDGE_GAP
  prompt: >-
    What is the outcome of kidney transplantation, including post-transplant recurrence,
    in ARHGDIA disease?
  attaches_to:
  - treatments#Kidney Transplantation
  rationale: >-
    The single reported graft failed from venous thrombosis and never functioned. A
    podocyte-intrinsic genetic lesion would predict that the donor kidney is unaffected,
    but no ARHGDIA-specific post-transplant data exist in the sources used here, and the
    entry does not infer a recurrence rate from other forms of monogenic SRNS.
- discussion_id: arhgdia_extrarenal_phenotype
  kind: KNOWLEDGE_GAP
  prompt: >-
    What causes the variable neurologic phenotype, and is there reproductive involvement in humans?
  attaches_to:
  - phenotypes#Intellectual Disability
  - animal_models#Arhgdia knockout mouse
  rationale: >-
    Gee Table 1 documents intellectual disability in the two genotyped G173V siblings and the R120X infant, with hearing loss in one G173V sibling and seizures and cortical blindness in the R120X infant. The p.Gly168Arg child was described as developmentally normal at 11 months. Few patients and early deaths limit assessment of neurologic and reproductive outcomes. Infertility in male knockout mice has not been established as a human phenotype in these reports.
  evidence:
  - reference: PMID:23867502
    reference_title: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is not clear whether individuals with ARHGDIA mutations also have abnormal
      reproductive phenotypes
    explanation: The founding authors state the reproductive question as open.
  - reference: PMID:10498891
    reference_title: Progressive impairment of kidneys and reproductive organs in mice lacking Rho GDIalpha.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Rho GDIalpha -/- male mice were infertile and showed impaired spermatogenesis with
      vacuolar degeneration of seminiferous tubules in their testes.
    explanation: The mouse phenotype that raises the question.
- discussion_id: arhgdia_mechanism_wording
  kind: INTERPRETATION
  prompt: Is ARHGDIA disease loss of function or gain of function?
  attaches_to:
  - pathophysiology#Biallelic ARHGDIA Loss of Function
  rationale: >-
    ClinGen's evidence summary states the mechanism of pathogenicity as gain of function.
    The primary studies it cites show loss of RhoGDIalpha function (recessive, including a
    nonsense allele, with loss of GTPase binding) whose consequence is gain of RAC1
    activity. The entry records loss of function on the variant and increased activity
    on the RAC1 node, which is what the functional data show; the ClinGen wording is best
    read as describing the downstream GTPase state.
  evidence:
  - reference: CGGV:assertion_0e529f2b-21ac-44b2-981e-048e92e377a1-2022-05-24T180000.000Z
    reference_title: "ARHGDIA / nephrotic syndrome, type 8 (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The mechanism of pathogenicity is Gain of Function.
    explanation: The ClinGen statement discussed here.

notes: >-
  ARHGDIA-related nephrotic syndrome is modeled as one recessive gene-defined disease, including congenital and early-childhood presentations. OMIM:615244 maps to the broader Orphanet hereditary SRNS record ORPHA:656. The steroid-resistant label follows the disease grouping; some congenital patients were not documented to have received a steroid trial. The genetic SRNS GeneReviews chapter supplies the general clinical, diagnostic, management and counseling baseline; rates or therapies for unrelated genetic syndromes are not transferred to ARHGDIA. The clinical series includes seven molecularly characterized patients and one additional affected sibling without available DNA in Gee Table 1.
mechanistic_hypotheses:
- hypothesis_group_id: arhgdia_cellular_glomerular_injury
  hypothesis_label: Cellular actin and motility changes produce glomerular lesions
  status: EMERGING
  description: The studies propose that disturbed actin organization and podocyte migration produce foot-process injury and developmental glomerular disease; the specific intervening steps are incompletely established.

📚

References & Deep Research

References

3

PMID:34436835

Genetic Steroid-Resistant Nephrotic Syndrome Overview.

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK573219/

Genetic Steroid-Resistant Nephrotic Syndrome Overview - GeneReviews® - NCBI Bookshelf

No top-level findings curated for this source.

url:https://www.jci.org/articles/view/69134/files/pdf

https://www.jci.org/articles/view/69134/files/pdf

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Review ARHGDIA nephrotic syndrome against cached full texts and GeneReviews · 2026-09-26T22:52:55Z · View source

Reviewed the existing entry and deep-research report against the Gupta, Gee, Auguste, Indian case and Iranian cohort full texts, and the remaining mechanistic abstracts. Recovered and visually checked Gee Table 1 from the publisher PDF: seven molecularly characterized patients across the cited sources and one additional affected sibling without available DNA; added seizures, cortical blindness, sensorineural hearing loss, precise onset and renal outcomes. Added the case-specific hypercholesterolemia and splice-allele table evidence. Mined the actual genetic SRNS GeneReviews chapter for clinical characteristics, diagnosis, management and counseling, distinguishing general SRNS recommendations from ARHGDIA patient evidence. Split protein abundance, GTPase activation, actin structure and migration; preserved conflicting experimental results and identified proposed cellular-to-glomerular steps as emerging hypotheses. Added experimental RAC1 inhibition, eplerenone and the fly nephrocyte assay with model limitations. Corrected research-report overstatements about extrarenal disease, zygosity and transplant recurrence rather than propagating them. Publisher attempts for the 1999 and 2008 mouse papers yielded subscription pages, and the LPS paper returned HTTP 403; their claims remain limited to available abstracts. No ARHGDIA-specific clinical trial or public dataset accession was surfaced. All eight research-completeness dimensions were assessed; major supported clinical and mechanistic themes are represented. Validation passed with 106 snippets and 109 titles, zero skipped or unavailable snippets; two scoped data tests, ontology, entity references, causal targets, snippet boundaries, title and grading checks passed.

Create: ARHGDIA-Related_Steroid-Resistant_Nephrotic_Syndrome · 2026-09-23T15:49:56Z · View source

New entry for nephrotic syndrome, type 8 (MONDO:0014099; ARHGDIA, hgnc:678), replacing stub stubs/Nephrotic_Syndrome_Type_8.yaml (deleted). Named ARHGDIA-Related Steroid-Resistant Nephrotic Syndrome to match COQ6-Related_Steroid-Resistant_Nephrotic_Syndrome; disease_term keeps the exact MONDO label. Lump/split: single Disease entry (one gene, one mechanism, one MONDO term); no subtypes. Deep research: one run, falcon requested with claude_code fallback. Falcon returned HTTP 402 (out of credits); claude_code produced research/ARHGDIA-Related_Steroid-Resistant_Nephrotic_Syndrome-deep-research-claude_code.md (frontmatter records fell_back, requested_provider: falcon, provider_attempts). Reference validation 6/6 resolved, 0 off topic; term validation needs_review true (2 label variants: HP:0410280 is Pediatric onset, not Infantile onset; neither was used). just preflight-dr returned WARN only because RAC1, the downstream effector, is mentioned often; the report's gene (ARHGDIA) and OMIM (615244) match MONDO, so it was used. The report was treated as leads: it misattributes PMC4905261 (PMID:26726844, Auguste et al.) to Gupta, and its Iranian-cohort and Indian-case details were paraphrase; all claims in the entry were re-derived from cached primary text. Structured sources: ClinGen CGGV assertion (Moderate, Glomerulopathy GCEP 2022-05-24) cached with --cache-dir references_cache from a fresh download of the ClinGen CSV whose sha256 differs from the pin in data/clingen/MANIFEST.yaml (upstream drift); the manifest was not repinned and the cache file therefore states the pinned snapshot date. ORPHA:656 (hereditary SRNS) cached from the main-checkout Orphadata XML; Orphanet maps OMIM:615244 to it as broader, with no ARHGDIA-specific code. GeneReviews: no ARHGDIA chapter; the genetic SRNS overview PMID:34436835 is tagged and cited for the evaluation-strategy statement only, since its cached record is the purpose statement. Dropped for lack of a quotable source: hypercholesterolemia/hyperlipidemia (the only case-level value sits inside a parenthetical that the validator strips), per-patient neurological features beyond intellectual disability (Gee Table 1 not in cache), post-transplant recurrence (no ARHGDIA data), prevalence. The claim-issue comment suggested PMID:23934128 for Gee et al.; the correct PMID is 23867502. Validation: just validate, count-verified-snippets (76/76), validate-terms, check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, list-gene-term-mismatches, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens, check-environmental-evidence, check-coarse-phenotypes, check-reference-titles, check-genereviews --online; validate-disorders run before push.

Claude Code ▸

ARHGDIA-Related Steroid-Resistant Nephrotic Syndrome (Nephrotic Syndrome, Type 8 / NPHS8) — Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 17 citations 2026-09-23T15:25:22.923931

ARHGDIA-Related Steroid-Resistant Nephrotic Syndrome (Nephrotic Syndrome, Type 8 / NPHS8) — Research Report

Identifiers: OMIM #615244 (NPHS8); Gene: ARHGDIA, OMIM *601925, HGNC:678, UniProt P52565, chr17q25.3, GRCh38 ENSG00000141522; MONDO:0014099; Orphanet ORPHA:656 (Hereditary steroid-resistant nephrotic syndrome, parent grouping — no disease-specific ORPHA code was found for the ARHGDIA subtype specifically; it is cataloged under this broader hereditary SRNS entry and via GeneCC gene-disease submissions at thegencc.org/genes/HGNC:678); Inheritance: autosomal recessive.

1. Disease Overview

ARHGDIA-related nephrotic syndrome (NPHS8) is a genetically defined, autosomal recessive form of steroid-resistant nephrotic syndrome (SRNS) caused by biallelic loss-of-function variants in ARHGDIA, which encodes Rho GDP-dissociation inhibitor alpha (RhoGDIα/GDIα). It was established as a monogenic SRNS cause simultaneously by two independent groups in 2013: Gee et al. (PMID:23867502, J Clin Invest 123(8):3243-3253) via homozygosity mapping/whole-exome sequencing in a consanguineous family, and Gupta et al. (PMID:23434736, J Med Genet 50(5):330-338) via whole-exome sequencing of two affected sisters. Both groups independently converged on the same gene and the same podocyte cytoskeletal mechanism, which is unusually strong corroboration for a single-gene SRNS discovery.

Direct quote (Gee et al., abstract): "We combined homozygosity mapping with whole-exome resequencing and identified an ARHGDIA mutation that causes SRNS... These findings identify a single-gene cause of NS and reveal that RHO GTPase signaling is a pathogenic mediator of SRNS."

Direct quote (Gupta et al., conclusions): "Mutations in ARHGDIA need to be considered in the aetiology of heritable forms of nephrotic syndrome."

2. Etiology / Genetic Basis

Gene function. ARHGDIA's product sequesters RHOA, RAC1, and CDC42 in their inactive, GDP-bound, cytosolic form and protects them from proteasomal degradation. Gee et al.: "ARHGDIA is in a complex with RHO GTPases and is prominently expressed in podocytes of rat glomeruli."

Reported pathogenic variants (all biallelic, AR): | Variant | Type | Source | |---|---|---| | c.553_555del, p.Asp185del (ΔD185) | In-frame deletion, homozygous, two affected sisters | Gupta et al. 2013, PMID:23434736 | | p.Arg120Ter (R120X) | Nonsense | Gee et al. 2013, PMID:23867502 | | p.Gly173Val (G173V) | Missense | Gee et al. 2013, PMID:23867502 | | Additional novel variant, single case | Iranian consanguineous SRNS cohort (n=30 families) | Estiar-Nejad/colleagues cohort, PMC9555279 — reports ARHGDIA among single-case genetic causes alongside NUP205, COQ6, SGPL1, NPHP1; states one ARHGDIA variant "had not previously been reported as disease-causing" (paraphrase from search synthesis — exact primary-text confirmation of this ARHGDIA-specific detail was not independently verified by direct fetch; treat as a lead pending confirmation of full text) | | Homozygous ARHGDIA mutation, 11-month-old infant | Case report | PMID:35060086, Indian J Pediatr — abstract text could not be retrieved directly; title and indexing confirm a third clinical report of infantile-onset SRNS with a homozygous ARHGDIA variant |

Zygosity/origin: all reported cases are homozygous or compound-heterozygous germline variants, consistent with autosomal recessive, loss-of-function disease mechanism. No modifier genes, digenic interactions, or protective alleles have been reported in the literature retrieved.

Frequency among SRNS cohorts: ARHGDIA is a rare cause. In the largest reported consanguineous SRNS cohort search returned (30 Iranian families, PMC9555279), the dominant genes were NPHS1 (~30%), NPHS2 (~20%), and WT1 (~7%), with ARHGDIA appearing only in a single case — consistent with it being a minor contributor genome-wide, as expected for a gene identified from single/small pedigrees rather than large cohort screens.

3. Phenotypes

Onset: neonatal to early infancy in the founding reports — Gupta et al.'s sisters had congenital nephrotic syndrome; the case report literature includes an 11-month-old infant (PMID:35060086). OMIM's synopsis (per search-engine synthesis of the omim.org entry, direct fetch blocked by a bot-verification wall) describes "neonatal or early childhood onset steroid resistant renal disease."

Core renal phenotype: - Severe proteinuria, nephrotic-range - Hypoalbuminemia - Generalized edema - Hyperlipidemia - Progressive renal failure to end-stage kidney disease (steroid-resistant by definition — unresponsive to corticosteroid therapy)

Suggested HPO terms: HP:0000100 (Nephrotic syndrome), HP:0003155 (Elevated urine protein/proteinuria — or HP:0000093 Proteinuria), HP:0003073 (Hypoalbuminemia), HP:0003077 (Hyperlipidemia), HP:0000969 (Edema), HP:0000083 (Renal insufficiency)/HP:0000822 progression to HP:0003774 (Stage 5 chronic kidney disease), HP:0012622 (Chronic kidney disease). Onset: HP:0003623 (Neonatal onset) or HP:0410280 (Infantile onset) depending on the individual case.

Histopathology (kidney biopsy): diffuse mesangial sclerosis — small glomeruli, hypercellularity, increased extracellular matrix, contracted/collapsed glomerular tufts surrounded by immature/abnormal podocytes. Electron microscopy: diffuse foot process effacement and thinning of the glomerular basement membrane (per search synthesis of case-report content; this histologic description should be re-verified against primary-text access to the case report(s) before use as a direct quote in curation — flagged as a lead, not independently confirmed by direct source fetch).

Extrarenal involvement: None consistently reported in the human literature retrieved. Note that the mouse knockout (Togawa et al. 1999, below) additionally shows reproductive organ impairment and lymphocyte trafficking defects (Ishizaki et al. 2006, J Immunol, GDIα/GDIβ double knockout) — these are model-organism findings and have not been reported as part of the human phenotype in the literature surveyed; this is a candidate HUMAN_MODEL_MISMATCH/undetermined-translatability point rather than an established pediatric extrarenal manifestation.

4. Molecular Mechanism / Pathophysiology

Causal chain (as established by the founding papers and mechanistic follow-up):

Biallelic loss-of-function ARHGDIA variant (R120X, G173V, ΔD185, or other) →
Mutant RhoGDIα protein fails to bind RHO-family GTPases (RHOA, RAC1, CDC42) — demonstrated directly by co-immunoprecipitation/binding assays in HEK293T cells (Gupta et al.) and by loss of GTPase interaction for R120X/G173V (Gee et al.) →
Loss of GDIα-mediated cytosolic sequestration and protection from proteasomal degradation of RHO-GTPases →
Hyperactivation of GTP-bound RAC1 (most consistently and prominently implicated) and CDC42, but not RHOA — Gee et al.: "ARHGDIA mutations (R120X and G173V) ... increased active GTP-bound RAC1 and CDC42, but not RHOA, indicating that RAC1 and CDC42 are more relevant to the pathogenesis of this SRNS variant than RHOA." The follow-up mechanistic paper (Gupta, Small GTPases 2016, PMC4905261) sharpens this further: "Rac1 activity was markedly increased in GDIα KD podocytes" and Rac1 showed the most pronounced, consistent hyperactivation of the three GTPases tested across all three disease mutations. Gupta et al. 2013 additionally showed hyperactivation of all three GTPases (RhoA, Rac1, Cdc42) in patient fibroblasts and GDIα-knockdown podocytes, with GDIα mislocalized to the nucleus in the ΔD185 proband's fibroblasts.
Rho-GTPase (chiefly RAC1) dysregulation causes derangement of the podocyte actin cytoskeleton →
Altered podocyte motility — mutant GDIα enhanced migration of cultured human podocytes, an effect reversible with RAC1 inhibitors (Gee et al.) — and impaired podocyte morphology/adhesion →
Foot process effacement / podocyte injury and glomerular filtration barrier breakdown →
Proteinuria, hypoalbuminemia, edema, hyperlipidemia (nephrotic syndrome) →
Progressive glomerulosclerosis (diffuse mesangial sclerosis pattern) → chronic/end-stage renal failure.

Model-organism confirmation of the chain: Gee et al. recapitulated the nephrotic phenotype in arhgdia-deficient zebrafish, and RAC1 inhibitors were "partially effective in ameliorating arhgdia-associated defects" — direct evidence that step 4→6 is causally load-bearing and pharmacologically targetable, at least in the fish model. The original constitutive mouse knockout (Togawa et al. 1999, Oncogene 18:5373-5380, PMID:10498891) independently established, well before the human disease-gene discovery, that Arhgdia−/− mice "developed massive proteinuria mimicking nephrotic syndrome, leading to death due to renal failure within a year," with additional degeneration of tubular epithelial cells and progressive reproductive-organ impairment — the mouse model that first flagged this gene as renally relevant, later mined by Gupta et al. as translational justification for pursuing ARHGDIA as a human candidate gene ("Mice with targeted inactivation of ARHGDIA are known to develop severe proteinuria and nephrotic syndrome, therefore this gene was pursued in functional studies").

Molecular pathway/GO/CL suggestions: - GO:0005094 (Rho GDP-dissociation inhibitor activity) — ARHGDIA's own molecular function - GO:0007266 (Rho protein signal transduction); GO:0030036 (actin cytoskeleton organization); GO:0030334 (regulation of cell migration) - CL:0000653 (podocyte) — the principal disease-relevant cell type - Relevant downstream GTPases as distinct entities: RAC1 (HGNC:9801), CDC42 (HGNC:1736); note RHOA (HGNC:667) is implicated in in-vitro/fibroblast assays but was explicitly not hyperactivated in the podocyte/patient-derived Rho-GTPase activity assays in Gee et al., a distinction worth preserving rather than lumping all three GTPases together in a pathophysiology node.

5. Anatomical/Cellular Localization

Organ: kidney (glomerulus) — primary and essentially sole clinically established site of disease.
Tissue: glomerular filtration barrier / mesangium.
Cell type: podocyte (CL:0000653), the cell type in which ARHGDIA is "prominently expressed" per both founding papers, in rat and mouse glomeruli.
Subcellular: cytoplasm (GDIα's normal sequestering compartment for inactive GTPases) vs. pathological nuclear mislocalization of mutant GDIα reported in ΔD185 patient fibroblasts (Gupta et al.) — a notable subcellular mislocalization finding suggesting disruption of normal cytoplasmic tethering as part of the loss-of-function mechanism.

6. Diagnostics

Clinical presentation: infantile/early-childhood nephrotic syndrome that fails to respond to corticosteroid therapy (defining "steroid-resistant" status), prompting genetic workup.
Genetic testing: targeted single-gene sequencing or inclusion in SRNS/congenital nephrotic syndrome gene panels (alongside NPHS1, NPHS2, WT1, PLCE1, LAMB2, and others); whole-exome sequencing was the discovery method in both founding cohorts and remains the practical diagnostic route for a gene this rare (not typically first-tier on narrow panels given its low prevalence in cohorts).
Renal biopsy: diffuse mesangial sclerosis pattern; EM shows foot process effacement — supportive but non-specific; overlaps histologically with WT1- and PLCE1-related DMS, so histology alone cannot discriminate genotype.
No specific biomarker or functional assay for ARHGDIA deficiency is reported in a clinically validated form; functional confirmation (GTPase activity assays, fibroblast Rho-GTPase pulldown) has so far been used only in the research setting (Gupta et al.'s proband fibroblast studies), not as a routine diagnostic.

7. Treatment / Prognosis

No disease-specific approved therapy exists. Standard nephrotic-syndrome supportive management applies (ACE inhibitor/ARB for proteinuria reduction, management of edema/hyperlipidemia, and ultimately renal replacement therapy/transplantation for progression to ESKD), consistent with general SRNS management principles; the literature retrieved contains no ARHGDIA-specific clinical trial or approved pharmacotherapy.
Experimental/mechanistic therapeutic signal: RAC1 inhibition. Gee et al. showed pharmacological RAC1 inhibition reversed the enhanced podocyte migration phenotype in vitro and was "partially effective in ameliorating arhgdia-associated defects" in the zebrafish model — this is model-system evidence for a targeted mechanism-based therapeutic strategy, not a clinically validated treatment; would map to a HUMAN_MODEL_MISMATCH/emerging hypothesis framing rather than an established treatment entry.
Renal transplantation: general literature confirms recurrent nephrotic syndrome/FSGS after transplant is a recognized risk in genetic SRNS broadly (~30–40% depending on native histology), but no ARHGDIA-specific post-transplant recurrence case was identified in the searches performed; this should be recorded as a gap rather than inferred from the general SRNS transplant-recurrence literature.

8. Animal/Model Organism Summary

Model	Genotype	Phenotype	Source
Mouse	Arhgdia−/− (constitutive KO)	Massive proteinuria mimicking nephrotic syndrome, death from renal failure within ~1 year; tubular epithelial degeneration; progressive reproductive organ impairment	Togawa et al. 1999, Oncogene 18:5373-5380, PMID:10498891
Mouse	Arhgdia/Arhgdib double KO	Defective chemokine-directed lymphocyte migration/development	Ishizaki et al. 2006, J Immunol (lymphocyte/immune phenotype, not renal-focused; relevance to the human kidney disease is indirect)
Zebrafish	arhgdia-deficient (morpholino/genetic)	Recapitulated nephrotic phenotype; partially rescued by RAC1 inhibitor	Gee et al. 2013, PMID:23867502
Cultured human podocytes	GDIα knockdown ± reconstitution with R120X/G173V/ΔD185 mutant constructs	RAC1 (and CDC42/RHOA in some assays) hyperactivation, impaired/enhanced motility phenotypes reversible by RAC1 inhibition, impaired actin polymerization	Gee et al. 2013; Gupta et al. Small GTPases 2016 (PMC4905261)
HEK293T cells	Transfected WT vs. mutant RhoGDIα	Mutant protein fails to bind RhoA/Rac1/Cdc42	Gupta et al. 2013, PMID:23434736

The mouse constitutive knockout is notably the oldest piece of evidence in this entire causal chain (1999) — it identified the renal phenotype 14 years before the gene was linked to human disease, making it an unusually direct instance of animal-model-first gene discovery being retrospectively validated in humans. Model fidelity is high for the core proteinuria/glomerular phenotype but the mouse model's additional reproductive and immune phenotypes have no reported human correlate and should not be imported into the human pathograph without qualification.

9. Notable Gaps / Items Requiring Further Verification Before KB Entry

Full-text confirmation of the Iranian cohort paper's (PMC9555279) specific ARHGDIA variant, zygosity, and patient-level clinical detail — direct fetch was blocked (reCAPTCHA); only search-engine synthesis was obtained, which per this repository's evidence standards is not an exact quotable snippet and must be re-fetched (e.g., via just fetch-reference) before citation.
PMID:35060086 (Indian J Pediatr case report) abstract text could not be retrieved directly (fetch attempts returned only citation metadata or server errors); title/indexing confirm its existence and relevance but no quotable snippet was obtained.
OMIM #615244's full clinical synopsis could not be directly fetched (bot-verification wall on omim.org); the clinical description used above is a search-engine paraphrase of the OMIM entry and should be re-verified against the primary OMIM text (or GeneReviews, if one exists — none was identified in these searches) before use as a cited snippet.
No dedicated Orphanet disease-specific code (distinct from the broader ORPHA:656 "Hereditary steroid-resistant nephrotic syndrome" grouping) was confirmed for the ARHGDIA subtype specifically.
Prevalence/incidence figures specific to NPHS8 were not found in any source; it appears only as single-case/single-family reports (three independent pedigrees/cases identified: the original consanguineous family, two sisters, the Iranian single case, and the Indian infant case report), consistent with an ultra-rare designation, but no formal prevalence class (Orphanet-style) was located.

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	6
Resolved	6
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	6
On topic	5
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	26
Resolved	18
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	8
Terms whose name was checked	14
Terms named correctly	12
Terms named as a different term	0
Terms whose name is worth a second look	2

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0410280 (1 mention) - the report calls it "Infantile onset"; HP calls it Pediatric onset
CL:0000653 (2 mentions) - the report calls it "podocyte", "Cell type: podocyte"; CL calls it podocyte, and lists "renal podocyte" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

CL:0000653 - called "podocyte", "Cell type: podocyte"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, EXT_ID, MIM.

18 of 26 terms resolved to a current term; the rest could not be looked up either way.

ARHGDIA-Related Steroid-Resistant Nephrotic Syndrome

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ARHGDIA-Related Steroid-Resistant Nephrotic Syndrome (Nephrotic Syndrome, Type 8 / NPHS8) — Research Report

1. Disease Overview

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