Familial Renal Glucosuria

Mendelian MONDO:0009297 Pathograph 6 Show in embeddings browser Renal Tubular Transport Disease Glucose Transport Disorder Inherited Kidney Disorder

Familial renal glucosuria (FRG) is characterized by persistent isolated glucosuria in the absence of hyperglycemia and without a broader Fanconi-type proximal tubulopathy. The great majority of cases are caused by loss-of-function variants in SLC5A2, encoding the renal sodium-glucose cotransporter SGLT2, which mediates the bulk of proximal tubular glucose reabsorption. A minority of cases are caused by biallelic loss-of-function variants in PDZK1IP1, encoding MAP17, an obligate accessory protein required for SGLT2 transport activity; MAP17 deficiency produces a clinically indistinguishable glucosuric phenotype by impairing the SGLT2 complex rather than the transporter itself. FRG is usually benign and frequently an incidental finding; the main documented risks are osmotic polyuria and, in patients with more massive glucosuria, mild volume depletion with secondary renin-angiotensin-aldosterone activation. The pharmacological SGLT2 inhibitors ("gliflozins") used to treat type 2 diabetes and heart failure deliberately reproduce this same reduced proximal tubular glucose reabsorption mechanism, though that drug class is curated separately and is only noted here for mechanistic context.

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1
Inheritance
3
Pathophys.
2
Phenotypes
6
Pathograph
2
Genes
1
Medical Actions
2
Subtypes
2
Differentials
5
References
👪

Inheritance

1
Semidominant with incomplete penetrance HP:0032113
SLC5A2-related FRG behaves as a semidominant (codominant) trait: a single SLC5A2 variant is frequently sufficient to cause detectable, usually mild, glucosuria, but two variants (homozygous or compound heterozygous) are associated with earlier diagnosis and substantially higher urinary glucose excretion. Penetrance in heterozygotes is incomplete and variable - some heterozygous relatives of affected probands have normal urinary glucose. PDZK1IP1-related FRG has been described only in the biallelic (homozygous) state to date; monoallelic PDZK1IP1 penetrance has not been established.
Semidominant inheritance Penetrance: INCOMPLETE
Show evidence (1 reference)
PMID:22314875 SUPPORT Human Clinical
"Patients with two mutations were diagnosed earlier with larger amounts of urinary glucose excretion than patients with single mutations. Pedigree analysis data were consistent with the inheritance of a codominant trait with incomplete penetrance."
Directly documents the gene-dosage effect (biallelic vs. monoallelic) and incomplete penetrance underlying the semidominant inheritance model.
◆

Subtypes

2
⚙

Pathophysiology

3
Reduced Proximal Tubular Glucose Reabsorption
The shared convergent mechanism across both genetic causes: failure of the SGLT2 transport complex in the S1/S2 segment of the proximal tubule lowers the renal threshold for glucose, so glucose that would normally be almost completely reabsorbed is excreted in the urine despite normal plasma glucose concentrations.
Proximal tubule epithelial cell CL:1000838 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Proximal tubule epithelial cell, annotated with kidney proximal convoluted tubule epithelial cell (CL:1000838). CL:1000838 is a cell type from the Cell Ontology.
Renal D-glucose absorption GO:0035623 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Renal D-glucose absorption (GO:0035623). GO:0035623 is a biological process from the Gene Ontology. ↓ DECREASED
proximal convoluted tubule UBERON:0001287 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in proximal convoluted tubule (UBERON:0001287). UBERON:0001287 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Isolated Renal Glucosuria Reduced SGLT2-mediated glucose reabsorption lowers the renal glucose threshold, so glucose appears in the urine at normal (non-diabetic) blood glucose concentrations.
Show evidence (1 reference)
PMID:14569097 SUPPORT Human Clinical
"The role of SGLT2 (the gene for a renal sodium-dependent glucose transporter) in renal glucosuria was evaluated."
Establishes SGLT2-mediated proximal tubular glucose reabsorption as the central mechanism disrupted in FRG.
SLC5A2 Loss-of-Function
Biallelic or (more mildly) monoallelic loss-of-function variants in SLC5A2 directly reduce or abolish SGLT2 transporter activity at the apical membrane of proximal tubule cells.
SLC5A2 hgnc:11037 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SLC5A2 (hgnc:11037). hgnc:11037 is a gene from the HUGO Gene Nomenclature Committee.
low-affinity D-glucose:sodium symporter activity GO:0005362 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased low-affinity D-glucose:sodium symporter activity (GO:0005362). GO:0005362 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Reduced Proximal Tubular Glucose Reabsorption Loss-of-function SLC5A2 variants directly impair the SGLT2 transporter itself, reducing proximal tubular glucose reabsorption.
Show evidence (1 reference)
PMID:14569097 SUPPORT Human Clinical
"In 21 families, 21 different SGLT2 mutations were detected."
Documents allelic heterogeneity of SLC5A2 loss-of-function variants causing FRG.
PDZK1IP1/MAP17 Loss-of-Function Impairing SGLT2 Complex Function
Biallelic loss-of-function variants in PDZK1IP1 abolish production or function of MAP17, the obligate accessory protein that activates SGLT2. MAP17 does not alter the amount of SGLT2 protein trafficked to the cell surface but is nonetheless required for its transport activity, so its loss produces a functional SGLT2 complex deficiency phenotypically equivalent to a direct SLC5A2 lesion.
PDZK1IP1 hgnc:16887 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PDZK1IP1 (hgnc:16887). hgnc:16887 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Reduced Proximal Tubular Glucose Reabsorption Loss of MAP17-mediated activation of SGLT2 reduces net SGLT2 transport activity, lowering proximal tubular glucose reabsorption to the same degree seen with direct SLC5A2 lesions.
Show evidence (1 reference)
PMID:27288013 SUPPORT In Vitro
"Notably, transfection with MAP17 did not change the quantity of SGLT2 protein at the cell surface in either cell type."
Shows MAP17 loss impairs SGLT2 function without altering its surface abundance, i.e. a functional (not trafficking-quantity) complex defect.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Familial Renal Glucosuria Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

2
Genitourinary 1
Isolated Renal Glucosuria Glycosuria HP:0003076 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Glucosuria, annotated with Glycosuria (HP:0003076). HP:0003076 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:14569097 SUPPORT Human Clinical
"The role of SGLT2 (the gene for a renal sodium-dependent glucose transporter) in renal glucosuria was evaluated."
Establishes glucosuria as the defining phenotype of FRG.
Metabolism 1
Mild Volume Depletion with Renin-Angiotensin-Aldosterone Activation OCCASIONAL Dehydration HP:0001944 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dehydration (HP:0001944). HP:0001944 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16518345 SUPPORT Human Clinical
"The patient homozygous for the p.A102V mutation had glucosuria of 65.6 g/1.73 m(2)/24 h, evidence of renal sodium wasting, mild volume depletion, and raised basal plasma renin and serum aldosterone levels."
Documents mild volume depletion and secondary RAAS activation in a patient with massive glucosuria, supporting dehydration risk as an occasional but real complication of severe FRG.
🧬

Genetic Associations

2
SLC5A2 (CAUSATIVE)
Gene: SLC5A2 hgnc:11037 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SLC5A2 (hgnc:11037). hgnc:11037 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:14569097 SUPPORT Human Clinical
"In 21 families, 21 different SGLT2 mutations were detected."
Establishes SLC5A2 as the major causative gene for FRG.
PDZK1IP1 (CAUSATIVE)
Gene: PDZK1IP1 hgnc:16887 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PDZK1IP1 (hgnc:16887). hgnc:16887 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:27288013 SUPPORT Human Clinical
"One patient without any identifiable mutation in the SGLT2 coding gene (SLC5A2) displayed homozygosity for a splicing mutation (c.176+1G>A) in the MAP17 coding gene (PDZK1IP1)."
Direct evidence for PDZK1IP1 as a second, rarer causative gene for FRG.
💊

Medical Actions

1
Hydration Counseling and Monitoring
Action: Supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
FRG generally requires no specific treatment. Management is limited to reassurance (most patients are asymptomatic and the condition is benign), maintaining adequate fluid intake to offset osmotic diuresis, and monitoring during catabolic or volume-depleting stress (illness, fasting, pregnancy) when dehydration risk is increased. Because the mechanism (reduced SGLT2-mediated proximal tubular glucose reabsorption) is the same one deliberately induced pharmacologically by SGLT2 inhibitors (gliflozins) in diabetes/heart failure/CKD, clinicians should be aware of the mechanistic parallel, though gliflozin pharmacology itself is out of scope for this entry.
Show evidence (1 reference)
PMID:16518345 SUPPORT Human Clinical
"Familial renal glucosuria (FRG) is an inherited renal tubular disorder characterized by persistent isolated glucosuria in the absence of hyperglycemia."
Supports a supportive-care/monitoring approach, since FRG is a persistent but generally uncomplicated tubular transport trait rather than a disease requiring targeted therapy.
🔬

Diagnosis

1
Renal Threshold of Glucose / Kidney Function Testing
Diagnosis rests on demonstrating persistent glucosuria with normal fasting and post-prandial blood glucose (excluding diabetes mellitus), quantifying the renal threshold of glucose (RTG), and, critically, excluding other proximal tubular solute losses (generalized aminoaciduria, phosphaturia, bicarbonaturia/renal tubular acidosis, or low-molecular-weight proteinuria). This negative Fanconi workup is diagnostically important: it distinguishes isolated FRG from generalized proximal tubulopathies such as Fanconi-Bickel syndrome (SLC2A2-related) and other renal Fanconi syndromes, in which glucosuria accompanies multiple other tubular transport defects rather than occurring in isolation.
kidney function testing NCIT:C74972 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:38344682 SUPPORT Human Clinical
"We sequenced SLC5A2 and PDZK1IP1 in 21 FRG patients and measured the renal threshold of glucose (RTG) in 15 patients."
Demonstrates the diagnostic workup (renal threshold of glucose quantification plus SLC5A2/PDZK1IP1 sequencing) used to characterize and confirm FRG.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Familial Renal Glucosuria:

Fanconi-Bickel Syndrome / Renal Fanconi Syndrome
Overlapping Features Generalized proximal tubulopathies (e.g. SLC2A2-related Fanconi-Bickel syndrome) present with glucosuria as one of several concurrent proximal tubular solute losses (generalized aminoaciduria, phosphaturia, bicarbonaturia), in contrast to the isolated glucosuria with otherwise normal tubular function that defines FRG. Curated as a separate dismech entry (SLC2A2-related Fanconi-Bickel syndrome).
Distinguishing Features
  • Concurrent generalized aminoaciduria, phosphaturia, and bicarbonaturia (absent in isolated FRG)
  • Hepatomegaly and growth failure from glycogen storage (Fanconi-Bickel), absent in FRG
  • Different causative gene (SLC2A2/GLUT2) and cell-type localization (basolateral rather than apical transporter)
Diabetes Mellitus
Overlapping Features Diabetic glucosuria occurs secondary to hyperglycemia exceeding the normal renal glucose threshold, whereas FRG glucosuria occurs despite normal blood glucose concentrations.
Distinguishing Features
  • Elevated fasting/postprandial blood glucose and abnormal HbA1c in diabetes, both normal in FRG
{ }

Source YAML

click to show 
name: Familial Renal Glucosuria
creation_date: "2026-07-06T00:00:00Z"
category: Mendelian
synonyms:
- Renal Glycosuria
- SGLT2 Deficiency
- Isolated Renal Glucosuria
description: >
  Familial renal glucosuria (FRG) is characterized by persistent isolated
  glucosuria in the absence of hyperglycemia and without a broader
  Fanconi-type proximal tubulopathy. The great majority of cases are caused
  by loss-of-function variants in SLC5A2, encoding the renal sodium-glucose
  cotransporter SGLT2, which mediates the bulk of proximal tubular glucose
  reabsorption. A minority of cases are caused by biallelic loss-of-function
  variants in PDZK1IP1, encoding MAP17, an obligate accessory protein
  required for SGLT2 transport activity; MAP17 deficiency produces a
  clinically indistinguishable glucosuric phenotype by impairing the SGLT2
  complex rather than the transporter itself. FRG is usually benign and
  frequently an incidental finding; the main documented risks are osmotic
  polyuria and, in patients with more massive glucosuria, mild volume
  depletion with secondary renin-angiotensin-aldosterone activation. The
  pharmacological SGLT2 inhibitors ("gliflozins") used to treat type 2
  diabetes and heart failure deliberately reproduce this same reduced
  proximal tubular glucose reabsorption mechanism, though that drug class is
  curated separately and is only noted here for mechanistic context.
disease_term:
  preferred_term: familial renal glucosuria
  term:
    id: MONDO:0009297
    label: familial renal glucosuria
parents:
- Renal Tubular Transport Disease
- Glucose Transport Disorder
- Inherited Kidney Disorder
has_subtypes:
- name: SLC5A2-Related
  display_name: SLC5A2-Related Familial Renal Glucosuria (SGLT2 Deficiency)
  subtype_term:
    preferred_term: familial renal glucosuria
    term:
      id: MONDO:0009297
      label: familial renal glucosuria
  description: >
    The classic and common form of FRG, caused by loss-of-function variants
    in SLC5A2. Inheritance behaves as a semidominant/codominant trait with
    variable, incomplete penetrance: heterozygous carriers frequently show
    mild glucosuria, while individuals with two SLC5A2 variants (homozygous
    or compound heterozygous) present earlier and with substantially greater
    urinary glucose excretion.
  genes:
  - preferred_term: SLC5A2
    term:
      id: hgnc:11037
      label: SLC5A2
  evidence:
  - reference: PMID:14569097
    reference_title: Molecular analysis of the SGLT2 gene in patients with renal glucosuria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that SGLT2 plays an important role in renal tubular glucose reabsorption. Inheritance of renal glucosuria shows characteristics of a codominant trait with variable penetrance."
    explanation: >-
      Founding molecular-genetic study establishing SLC5A2 as the cause of
      FRG and characterizing the codominant, variably penetrant inheritance
      pattern.
  - reference: PMID:22314875
    reference_title: "Familial renal glucosuria: a clinicogenetic study of 23 additional cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pedigree analysis data were consistent with the inheritance of a codominant trait with incomplete penetrance."
    explanation: >-
      Independent Korean pediatric cohort confirms codominant inheritance
      with incomplete penetrance and a genotype-phenotype gradient between
      single- and double-variant carriers.
- name: PDZK1IP1-Related
  display_name: PDZK1IP1-Related Familial Renal Glucosuria (MAP17 Deficiency)
  subtype_term:
    preferred_term: familial renal glucosuria
    term:
      id: MONDO:0009297
      label: familial renal glucosuria
  description: >
    A rare genocopy of SLC5A2-related FRG caused by biallelic loss-of-function
    variants in PDZK1IP1, encoding MAP17, an accessory protein required for
    SGLT2 transport activity in the proximal tubule. Identified in a patient
    with a homozygous splicing variant (c.176+1G>A) and no identifiable
    SLC5A2 mutation, within a cohort of 60 individuals with FRG, and confirmed
    functionally: co-expression of SGLT2 with wild-type MAP17 stimulated
    glucose uptake far above SGLT2 alone, whereas co-expression with the
    mutant MAP17 did not. OMIM 607178 is the PDZK1IP1 gene locus record (no
    separate phenotype MIM has been assigned for this genocopy).
  genes:
  - preferred_term: PDZK1IP1
    term:
      id: hgnc:16887
      label: PDZK1IP1
  evidence:
  - reference: PMID:27288013
    reference_title: MAP17 Is a Necessary Activator of Renal Na+/Glucose Cotransporter SGLT2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To confirm the physiologic relevance of the MAP17-SGLT2 interaction, we studied a cohort of 60 individuals with familial renal glucosuria. One patient without any identifiable mutation in the SGLT2 coding gene (SLC5A2) displayed homozygosity for a splicing mutation (c.176+1G>A) in the MAP17 coding gene (PDZK1IP1)."
    explanation: >-
      Direct clinical-genetic evidence that biallelic PDZK1IP1 loss-of-function
      causes an SLC5A2-negative case of familial renal glucosuria.
  - reference: PMID:27288013
    reference_title: MAP17 Is a Necessary Activator of Renal Na+/Glucose Cotransporter SGLT2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Using expression cloning, we identified an accessory protein, 17 kDa membrane-associated protein (MAP17), that increased SGLT2 activity in RNA-injected Xenopus oocytes by two orders of magnitude. Significant stimulation of SGLT2 activity also occurred in opossum kidney cells cotransfected with SGLT2 and MAP17."
    explanation: >-
      Functional evidence that MAP17 is required to activate SGLT2 transport
      activity, establishing the mechanistic basis for PDZK1IP1-related FRG.
  - reference: PMID:38344682
    reference_title: Genetic and clinical characterization of familial renal glucosuria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We sequenced SLC5A2 and PDZK1IP1 in 21 FRG patients and measured the renal threshold of glucose (RTG) in 15 patients."
    explanation: >-
      Contemporary clinical-genetics cohort study that routinely sequences
      PDZK1IP1 alongside SLC5A2 in the diagnostic workup of FRG, confirming
      PDZK1IP1 as an accepted second causative gene for the same phenotype.
inheritance:
- name: Semidominant with incomplete penetrance
  inheritance_term:
    preferred_term: Semidominant inheritance
    term:
      id: HP:0032113
      label: Semidominant inheritance
  penetrance: INCOMPLETE
  description: >
    SLC5A2-related FRG behaves as a semidominant (codominant) trait: a single
    SLC5A2 variant is frequently sufficient to cause detectable, usually mild,
    glucosuria, but two variants (homozygous or compound heterozygous) are
    associated with earlier diagnosis and substantially higher urinary
    glucose excretion. Penetrance in heterozygotes is incomplete and variable
    - some heterozygous relatives of affected probands have normal urinary
    glucose. PDZK1IP1-related FRG has been described only in the biallelic
    (homozygous) state to date; monoallelic PDZK1IP1 penetrance has not been
    established.
  evidence:
  - reference: PMID:22314875
    reference_title: "Familial renal glucosuria: a clinicogenetic study of 23 additional cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with two mutations were diagnosed earlier with larger amounts of urinary glucose excretion than patients with single mutations. Pedigree analysis data were consistent with the inheritance of a codominant trait with incomplete penetrance."
    explanation: >-
      Directly documents the gene-dosage effect (biallelic vs. monoallelic)
      and incomplete penetrance underlying the semidominant inheritance model.
pathophysiology:
- name: Reduced Proximal Tubular Glucose Reabsorption
  description: >
    The shared convergent mechanism across both genetic causes: failure of
    the SGLT2 transport complex in the S1/S2 segment of the proximal tubule
    lowers the renal threshold for glucose, so glucose that would normally be
    almost completely reabsorbed is excreted in the urine despite normal
    plasma glucose concentrations.
  cell_types:
  - preferred_term: Proximal tubule epithelial cell
    term:
      id: CL:1000838
      label: kidney proximal convoluted tubule epithelial cell
  biological_processes:
  - preferred_term: Renal D-glucose absorption
    term:
      id: GO:0035623
      label: renal D-glucose absorption
    modifier: DECREASED
  locations:
  - preferred_term: proximal convoluted tubule
    term:
      id: UBERON:0001287
      label: proximal convoluted tubule
  evidence:
  - reference: PMID:14569097
    reference_title: Molecular analysis of the SGLT2 gene in patients with renal glucosuria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The role of SGLT2 (the gene for a renal sodium-dependent glucose transporter) in renal glucosuria was evaluated."
    explanation: >-
      Establishes SGLT2-mediated proximal tubular glucose reabsorption as the
      central mechanism disrupted in FRG.
  downstream:
  - target: Isolated Renal Glucosuria
    description: >
      Reduced SGLT2-mediated glucose reabsorption lowers the renal glucose
      threshold, so glucose appears in the urine at normal (non-diabetic)
      blood glucose concentrations.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38344682
      reference_title: Genetic and clinical characterization of familial renal glucosuria.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "RTG in our cohort ranged from 1.0 to 9.2 mmol/L."
      explanation: >-
        Quantifies the lowered renal threshold of glucose (RTG) directly
        produced by impaired SGLT2-mediated reabsorption.
- name: SLC5A2 Loss-of-Function
  subtypes:
  - SLC5A2-Related
  description: >
    Biallelic or (more mildly) monoallelic loss-of-function variants in
    SLC5A2 directly reduce or abolish SGLT2 transporter activity at the
    apical membrane of proximal tubule cells.
  genes:
  - preferred_term: SLC5A2
    term:
      id: hgnc:11037
      label: SLC5A2
  molecular_functions:
  - preferred_term: low-affinity D-glucose:sodium symporter activity
    term:
      id: GO:0005362
      label: low-affinity D-glucose:sodium symporter activity
    modifier: DECREASED
  evidence:
  - reference: PMID:14569097
    reference_title: Molecular analysis of the SGLT2 gene in patients with renal glucosuria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 21 families, 21 different SGLT2 mutations were detected."
    explanation: >-
      Documents allelic heterogeneity of SLC5A2 loss-of-function variants
      causing FRG.
  downstream:
  - target: Reduced Proximal Tubular Glucose Reabsorption
    description: >
      Loss-of-function SLC5A2 variants directly impair the SGLT2 transporter
      itself, reducing proximal tubular glucose reabsorption.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:14569097
      reference_title: Molecular analysis of the SGLT2 gene in patients with renal glucosuria.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Fourteen individuals (including the original patient with 'renal glucosuria type 0') were homozygous or compound heterozygous for an SGLT2 mutation resulting in glucosuria in the range of 14.6 to 202 g/1.73 m(2)/d (81 - 1120 mmol/1.73 m(2)/d)."
      explanation: >-
        Directly links biallelic SLC5A2 loss-of-function genotype to severe
        quantitative glucosuria.
- name: PDZK1IP1/MAP17 Loss-of-Function Impairing SGLT2 Complex Function
  subtypes:
  - PDZK1IP1-Related
  description: >
    Biallelic loss-of-function variants in PDZK1IP1 abolish production or
    function of MAP17, the obligate accessory protein that activates SGLT2.
    MAP17 does not alter the amount of SGLT2 protein trafficked to the cell
    surface but is nonetheless required for its transport activity, so its
    loss produces a functional SGLT2 complex deficiency phenotypically
    equivalent to a direct SLC5A2 lesion.
  genes:
  - preferred_term: PDZK1IP1
    term:
      id: hgnc:16887
      label: PDZK1IP1
  evidence:
  - reference: PMID:27288013
    reference_title: MAP17 Is a Necessary Activator of Renal Na+/Glucose Cotransporter SGLT2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Notably, transfection with MAP17 did not change the quantity of SGLT2 protein at the cell surface in either cell type."
    explanation: >-
      Shows MAP17 loss impairs SGLT2 function without altering its surface
      abundance, i.e. a functional (not trafficking-quantity) complex defect.
  downstream:
  - target: Reduced Proximal Tubular Glucose Reabsorption
    description: >
      Loss of MAP17-mediated activation of SGLT2 reduces net SGLT2 transport
      activity, lowering proximal tubular glucose reabsorption to the same
      degree seen with direct SLC5A2 lesions.
    causal_link_type: DIRECT
    intermediate_mechanisms:
    - MAP17 (PDZK1IP1) forms a complex with SGLT2 in the proximal tubule
      apical membrane and is required to activate its transport activity;
      loss of this interaction reduces SGLT2-mediated glucose transport
      without depleting SGLT2 protein itself.
    evidence:
    - reference: PMID:27288013
      reference_title: MAP17 Is a Necessary Activator of Renal Na+/Glucose Cotransporter SGLT2.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Thus, these results provide the basis for a more thorough characterization of SGLT2 which would include the possible effects of its inhibition on colocalized renal transporters."
      explanation: >-
        Concludes that MAP17 loss-of-function in the patient cohort produces
        the same downstream glucosuric phenotype as direct SGLT2 loss.
phenotypes:
- category: Renal
  name: Isolated Renal Glucosuria
  description: >
    Persistent glucosuria at normal fasting and postprandial blood glucose
    concentrations, without generalized proximal tubular dysfunction. Most
    patients are asymptomatic and the finding is often incidental (e.g. on
    routine urinalysis).
  phenotype_term:
    preferred_term: Glucosuria
    term:
      id: HP:0003076
      label: Glycosuria
  evidence:
  - reference: PMID:14569097
    reference_title: Molecular analysis of the SGLT2 gene in patients with renal glucosuria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The role of SGLT2 (the gene for a renal sodium-dependent glucose transporter) in renal glucosuria was evaluated."
    explanation: Establishes glucosuria as the defining phenotype of FRG.
- category: Renal
  name: Mild Volume Depletion with Renin-Angiotensin-Aldosterone Activation
  description: >
    In patients with more massive glucosuria, osmotic diuresis can produce
    evidence of renal sodium wasting and mild volume depletion, with
    secondary activation of the renin-angiotensin-aldosterone system
    (raised basal plasma renin and serum aldosterone). This is the
    documented mechanistic basis for the dehydration risk described in FRG.
  phenotype_term:
    preferred_term: Dehydration
    term:
      id: HP:0001944
      label: Dehydration
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:16518345
    reference_title: "Familial renal glucosuria: SLC5A2 mutation analysis and evidence of salt-wasting."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient homozygous for the p.A102V mutation had glucosuria of 65.6 g/1.73 m(2)/24 h, evidence of renal sodium wasting, mild volume depletion, and raised basal plasma renin and serum aldosterone levels."
    explanation: >-
      Documents mild volume depletion and secondary RAAS activation in a
      patient with massive glucosuria, supporting dehydration risk as an
      occasional but real complication of severe FRG.
genetic:
- name: SLC5A2
  gene_term:
    preferred_term: SLC5A2
    term:
      id: hgnc:11037
      label: SLC5A2
  subtype: SLC5A2-Related
  association: CAUSATIVE
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:14569097
    reference_title: Molecular analysis of the SGLT2 gene in patients with renal glucosuria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 21 families, 21 different SGLT2 mutations were detected."
    explanation: Establishes SLC5A2 as the major causative gene for FRG.
  notes: >-
    OMIM 233100 is the FRG phenotype MIM associated with SLC5A2 (16p11.2);
    ORPHA:69076 is the corresponding Orphanet entry.
- name: PDZK1IP1
  gene_term:
    preferred_term: PDZK1IP1
    term:
      id: hgnc:16887
      label: PDZK1IP1
  subtype: PDZK1IP1-Related
  association: CAUSATIVE
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:27288013
    reference_title: MAP17 Is a Necessary Activator of Renal Na+/Glucose Cotransporter SGLT2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient without any identifiable mutation in the SGLT2 coding gene (SLC5A2) displayed homozygosity for a splicing mutation (c.176+1G>A) in the MAP17 coding gene (PDZK1IP1)."
    explanation: >-
      Direct evidence for PDZK1IP1 as a second, rarer causative gene for FRG.
  notes: >-
    OMIM 607178 is the PDZK1IP1 GENE locus record, not a distinct FRG
    phenotype MIM; no separate phenotype MIM number has been assigned for the
    PDZK1IP1-related genocopy of FRG. No independent Orphanet entry exists
    for this subtype; it is grouped here under ORPHA:69076/MONDO:0009297.
diagnosis:
- name: Renal Threshold of Glucose / Kidney Function Testing
  diagnosis_term:
    preferred_term: kidney function testing
    term:
      id: NCIT:C74972
      label: Renal Function Test
  description: >
    Diagnosis rests on demonstrating persistent glucosuria with normal
    fasting and post-prandial blood glucose (excluding diabetes mellitus),
    quantifying the renal threshold of glucose (RTG), and, critically,
    excluding other proximal tubular solute losses (generalized
    aminoaciduria, phosphaturia, bicarbonaturia/renal tubular acidosis, or
    low-molecular-weight proteinuria). This negative Fanconi workup is
    diagnostically important: it distinguishes isolated FRG from generalized
    proximal tubulopathies such as Fanconi-Bickel syndrome (SLC2A2-related)
    and other renal Fanconi syndromes, in which glucosuria accompanies
    multiple other tubular transport defects rather than occurring in
    isolation.
  evidence:
  - reference: PMID:38344682
    reference_title: Genetic and clinical characterization of familial renal glucosuria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We sequenced SLC5A2 and PDZK1IP1 in 21 FRG patients and measured the renal threshold of glucose (RTG) in 15 patients."
    explanation: >-
      Demonstrates the diagnostic workup (renal threshold of glucose
      quantification plus SLC5A2/PDZK1IP1 sequencing) used to characterize
      and confirm FRG.
differential_diagnoses:
- name: Fanconi-Bickel Syndrome / Renal Fanconi Syndrome
  description: >
    Generalized proximal tubulopathies (e.g. SLC2A2-related Fanconi-Bickel
    syndrome) present with glucosuria as one of several concurrent proximal
    tubular solute losses (generalized aminoaciduria, phosphaturia,
    bicarbonaturia), in contrast to the isolated glucosuria with otherwise
    normal tubular function that defines FRG. Curated as a separate dismech
    entry (SLC2A2-related Fanconi-Bickel syndrome).
  distinguishing_features:
  - Concurrent generalized aminoaciduria, phosphaturia, and bicarbonaturia (absent in isolated FRG)
  - Hepatomegaly and growth failure from glycogen storage (Fanconi-Bickel), absent in FRG
  - Different causative gene (SLC2A2/GLUT2) and cell-type localization (basolateral rather than apical transporter)
- name: Diabetes Mellitus
  description: >
    Diabetic glucosuria occurs secondary to hyperglycemia exceeding the
    normal renal glucose threshold, whereas FRG glucosuria occurs despite
    normal blood glucose concentrations.
  distinguishing_features:
  - Elevated fasting/postprandial blood glucose and abnormal HbA1c in diabetes, both normal in FRG
treatments:
- name: Hydration Counseling and Monitoring
  description: >
    FRG generally requires no specific treatment. Management is limited to
    reassurance (most patients are asymptomatic and the condition is
    benign), maintaining adequate fluid intake to offset osmotic diuresis,
    and monitoring during catabolic or volume-depleting stress (illness,
    fasting, pregnancy) when dehydration risk is increased. Because the
    mechanism (reduced SGLT2-mediated proximal tubular glucose reabsorption)
    is the same one deliberately induced pharmacologically by SGLT2
    inhibitors (gliflozins) in diabetes/heart failure/CKD, clinicians should
    be aware of the mechanistic parallel, though gliflozin pharmacology
    itself is out of scope for this entry.
  treatment_term:
    preferred_term: Supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:16518345
    reference_title: "Familial renal glucosuria: SLC5A2 mutation analysis and evidence of salt-wasting."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial renal glucosuria (FRG) is an inherited renal tubular disorder characterized by persistent isolated glucosuria in the absence of hyperglycemia."
    explanation: >-
      Supports a supportive-care/monitoring approach, since FRG is a
      persistent but generally uncomplicated tubular transport trait rather
      than a disease requiring targeted therapy.
references:
- reference: PMID:14569097
  title: Molecular analysis of the SGLT2 gene in patients with renal glucosuria.
  findings: []
- reference: PMID:22314875
  title: "Familial renal glucosuria: a clinicogenetic study of 23 additional cases."
  findings: []
- reference: PMID:27288013
  title: MAP17 Is a Necessary Activator of Renal Na+/Glucose Cotransporter SGLT2.
  findings: []
- reference: PMID:38344682
  title: Genetic and clinical characterization of familial renal glucosuria.
  findings: []
- reference: PMID:16518345
  title: "Familial renal glucosuria: SLC5A2 mutation analysis and evidence of salt-wasting."
  findings: []
📚

References & Deep Research

References

5
PMID:14569097
Molecular analysis of the SGLT2 gene in patients with renal glucosuria.
No top-level findings curated for this source.
PMID:22314875
Familial renal glucosuria: a clinicogenetic study of 23 additional cases.
No top-level findings curated for this source.
PMID:27288013
MAP17 Is a Necessary Activator of Renal Na+/Glucose Cotransporter SGLT2.
No top-level findings curated for this source.
PMID:38344682
Genetic and clinical characterization of familial renal glucosuria.
No top-level findings curated for this source.
PMID:16518345
Familial renal glucosuria: SLC5A2 mutation analysis and evidence of salt-wasting.
No top-level findings curated for this source.