NPHS1 – Nephrotic Syndrome

NPHS1 encodes nephrin, a key transmembrane component of the podocyte slit diaphragm essential for glomerular filtration. Biallelic NPHS1 variants cause autosomal recessive nephrotic syndrome characterized by heavy proteinuria, hypoalbuminemia, and edema. Nephrotic syndrome (MONDO:0005377) presents as congenital nephrotic syndrome of the Finnish type or later‐onset steroid-resistant forms.

Genetic studies across diverse cohorts have demonstrated autosomal recessive inheritance with compound heterozygous or homozygous NPHS1 variants. In a European cohort of 80 families with nephrotic syndrome manifesting in the first year of life, disease-causing NPHS1 variants were identified in 53 families (66% of cases) (53 probands) with segregation of homozygous or compound heterozygous alleles (PMID:17371932). Similarly, screening of 160 patients from 142 unrelated families with childhood-onset steroid-resistant nephrotic syndrome revealed NPHS1 mutations in 10 probands, including truncating, splice-site, and missense variants correlating with later onset and milder disease when at least one “mild” allele was present (PMID:18614772).

The variant spectrum comprises protein-truncating nonsense and frameshift mutations as well as missense substitutions predominantly affecting extracellular Ig-like domains. A recurrent allele, c.2479C>T (p.Arg827Ter), truncates the cytoplasmic tail and abolishes nephrin function (PMID:18614772). Other notable variants include c.3720_*9del (p.Val1241fs) and c.286C>G (p.Leu96Val), reflecting broad allelic heterogeneity. No founder mutations have been universally observed, though population-specific recurrence of certain missense changes has been reported.

Functional assays confirm pathogenicity through impaired nephrin trafficking and signaling. Most missense mutants are retained in the endoplasmic reticulum, failing to reach the cell surface (PMID:11726550). Chemical chaperone treatment with sodium 4-phenylbutyrate rescued several misfolded forms to the plasma membrane, restoring Neph1 interaction and tyrosine phosphorylation (PMID:15213260). A zebrafish nphs1 knockout recapitulates edema, proteinuria, and foot process effacement, further supporting loss-of-function as the disease mechanism (PMID:36187478).

No studies to date have refuted the causal role of NPHS1 in nephrotic syndrome. Alternative etiologies such as WT1 or NPHS2 defects apply to non-NEPHRIN presentations, but do not dispute NPHS1’s definitive association.

In summary, biallelic NPHS1 variants cause autosomal recessive nephrotic syndrome with genotype-phenotype correlations driven by variant severity. Functional concordance across cellular and animal models underpins a definitive gene–disease relationship. Genetic testing of NPHS1 is critical for early diagnosis, prognosis, and guiding immunosuppressive or transplantation decisions.

Key take-home: NPHS1 sequencing is essential in congenital and early-onset nephrotic syndrome to direct management and inform family counseling.

References

• Pediatrics • 2007 • Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2) PMID:17371932
• Journal of the American Society of Nephrology • 2008 • Nephrin mutations can cause childhood-onset steroid-resistant nephrotic syndrome PMID:18614772
• 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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