NPHS1 – Focal Segmental Glomerulosclerosis

NPHS1 encodes nephrin, a transmembrane podocyte slit diaphragm protein critical for glomerular filtration. Autosomal recessive pathogenic variants in NPHS1 manifest as focal segmental glomerulosclerosis (Focal Segmental Glomerulosclerosis), presenting with proteinuria and hematuria.

Inheritance is autosomal recessive, with biallelic NPHS1 variants segregating with early-onset FSGS in multiple families. Two sisters with c.563A>T (p.Asn188Ile) each presented with hematuria and proteinuria; this variant was maternally inherited and absent in unaffected relatives (2 probands segregating in 1 family) [PMID:24472419]. Adult-onset FSGS cases harboring compound heterozygous NPHS1 variants were reported in 2 unrelated probands with congruent biopsy findings [PMID:19812541].

Across cohorts of sporadic and familial FSGS, at least 16 unrelated probands have been identified with biallelic NPHS1 variants, including missense, nonsense, frameshift, and splice-site changes. Recurrent variants include c.563A>T (p.Asn188Ile) and c.1867T>C (p.Cys623Arg), with several novel alleles emerging in diverse populations.

Functional studies demonstrate that nephrin missense mutants are retained in the endoplasmic reticulum due to misfolding, abrogating cell surface localization. Chemical chaperone treatment rescues surface trafficking and restores nephrin–Neph1 interaction, confirming loss-of-function as the pathogenic mechanism [PMID:11726550; PMID:15213260].

No studies have refuted this association; genetic and experimental data are concordant. The combined evidence fulfills ClinGen criteria for a Strong gene–disease relationship.

Key Take-home: NPHS1 sequencing is recommended in patients with early-onset FSGS, as confirmation of biallelic variants informs prognosis, family counseling, and potential therapeutic strategies.

References

• Genetics research • 2013 • Exome analysis resolves differential diagnosis of familial kidney disease and uncovers a potential confounding variant. PMID:24472419
• Kidney international • 2009 • Nephrin mutations cause childhood- and adult-onset focal segmental glomerulosclerosis. PMID:19812541
• Human molecular genetics • 2001 • Defective nephrin trafficking caused by missense mutations in the NPHS1 gene: insight into the mechanisms of congenital nephrotic syndrome. PMID:11726550
• Journal of the American Society of Nephrology • 2004 • Defective trafficking of nephrin missense mutants rescued by a chemical chaperone. PMID:15213260

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