NPHS1 – congenital nephrotic syndrome, Finnish type

Congenital nephrotic syndrome of the Finnish type is an autosomal recessive disorder characterized by massive proteinuria, hypoalbuminemia, and early-onset renal failure. The disease is caused by biallelic pathogenic variants in NPHS1 (nephrin), which encodes a critical slit diaphragm component of podocyte foot processes ([HGNC:7908], [MONDO:0009732]). Initial identification of NPHS1 in Finnish patients highlighted early truncating and missense variants as underlying causes of severe nephrotic syndrome (PMID:11726550).

Genetic studies in diverse populations have expanded the variant spectrum to over 61 distinct NPHS1 alleles observed in 30 Chinese patients, including 25 novel changes, and an additional three unrelated Vietnamese patients (PMID:34859019; PMID:28392951). These variants encompass predominantly missense substitutions along with nonsense, frameshift, and splice-site mutations under an autosomal recessive inheritance model. A recurrent founder variant, c.928G>A (p.Asp310Asn), was seen in eight Chinese patients (PMID:34859019). Selected probands in multiple families demonstrate compound heterozygosity or homozygosity with co-segregation of NPHS1 alleles and disease phenotype.

The variant spectrum includes c.2404C>T (p.Arg802Trp), which impairs nephrin folding and transport, as well as truncating alleles such as c.2479C>T (p.Arg827Ter) that abolish slit diaphragm assembly (PMID:11726550). Segregation analyses in these cohorts confirm that affected individuals inherit two pathogenic NPHS1 alleles, while heterozygous carriers remain asymptomatic.

Functional assays across independent studies demonstrate that most missense nephrin mutants are retained in the endoplasmic reticulum, abolishing cell-surface localization and slit diaphragm integration. Rescue experiments with the chemical chaperone sodium 4-phenylbutyrate restored membrane targeting and tyrosine phosphorylation of selected mutants (PMID:15213260). Complementary in vitro analyses of p.Asp819Val and p.Glu447Lys variants corroborate defective trafficking in HEK293 cells (PMID:12324903).

No significant conflicting evidence has been reported that refutes the NPHS1–congenital nephrotic syndrome association. The cumulative genetic and experimental data satisfy ClinGen criteria for a definitive gene–disease relationship. Future screening of NPHS1 variants informs early diagnosis, genetic counseling, and exploration of targeted therapies to correct protein misfolding.

Key Take-home: Biallelic NPHS1 variants cause congenital nephrotic syndrome, Finnish type, through misfolding-induced nephrin trafficking defects, underscoring the utility of genetic testing and chaperone-based therapeutic strategies.

References

• 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
• Frontiers in medicine • 2021 • Genetic Variations and Clinical Features of NPHS1-Related Nephrotic Syndrome in Chinese Children: A Multicenter, Retrospective Study. PMID:34859019
• Case reports in genetics • 2017 • Three Novel Mutations in the NPHS1 Gene in Vietnamese Patients with Congenital Nephrotic Syndrome. PMID:28392951
• American journal of kidney diseases • 2002 • A missense mutation in the nephrin gene impairs membrane targeting. PMID:12324903
• Journal of the American Society of Nephrology : JASN • 2004 • Defective trafficking of nephrin missense mutants rescued by a chemical chaperone. PMID:15213260

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