NPHP1 – Nephronophthisis 1

NPHP1 encodes nephrocystin-1, a ciliary transition zone protein whose autosomal recessive loss leads to juvenile nephronophthisis type 1, characterised by corticomedullary cysts, tubular basement membrane fibrosis and progression to end-stage renal disease in childhood. NPHP1 is the most frequent genetic cause of this renal ciliopathy, accounting for 6–10% of paediatric ESRD.

Genetic analyses in multiple cohorts have identified homozygous deletions of NPHP1 in 74 families (115 affected individuals) and compound heterozygous deletions with point mutations in 5 additional families ([PMID:8995741]). Linkage and haplotype studies demonstrated segregation in 10 of 16 families, and 61 multiplex kindreds showed consistent co-segregation of NPHP1 loss with disease ([PMID:8995741], [PMID:11168925]).

Variant spectrum comprises a recurrent ~290 kb whole-gene deletion, splice alterations and missense substitution c.859G>A (p.Gly287Arg) ([PMID:11168925]), as well as rare missense c.1589G>A (p.Arg530Gln) in compound heterozygotes ([PMID:27004562]). No clear founder effect beyond the common deletion has been reported.

Patient-derived and gene-edited hiPSC kidney organoids lacking NPHP1 show defective primary cilia and frequent cyst formation in suspension culture, both rescued by NPHP1 overexpression ([PMID:38989059]). A CRISPR/Cas9 Nphp1 exon 2–20 knockout mouse replicates human renal cystic and extrarenal phenotypes; AAV-mediated Nphp1 re-expression partially rescues both renal and retinal pathology ([PMID:34415307]).

Some juvenile nephronophthisis families lack NPHP1 linkage, reflecting genetic heterogeneity with NPHP3 and other loci ([PMID:7806215], [PMID:11274269]); these findings do not dispute the NPHP1 association but underscore locus diversity.

Collectively, robust segregation in >74 families, concordant functional modelling in organoids and mouse, and a clear loss-of-function mechanism support a definitive gene–disease relationship. Key take-home: NPHP1 molecular testing is essential for early diagnosis, prognosis and genetic counselling in juvenile nephronophthisis.

References

• Genomics • 1994 • Refined mapping of a gene (NPH1) causing familial juvenile nephronophthisis and evidence for genetic heterogeneity. PMID:7806215
• Kidney international • 1997 • Molecular genetic identification of families with juvenile nephronophthisis type 1: rate of progression to renal failure. PMID:8995741
• Kidney international • 2001 • Establishing an algorithm for molecular genetic diagnostics in 127 families with juvenile nephronophthisis. PMID:11168925
• Nephrology, dialysis, transplantation • 2001 • Evidence for further genetic heterogeneity in nephronophthisis. PMID:11274269
• Frontiers in cell and developmental biology • 2024 • Patient-derived and gene-edited pluripotent stem cells lacking NPHP1 recapitulate juvenile nephronophthisis in abnormalities of primary cilia and renal cyst formation. PMID:38989059
• Human molecular genetics • 2021 • An Nphp1 knockout mouse model targeting exon 2-20 demonstrates characteristic phenotypes of human nephronophthisis. PMID:34415307
• Kidney international • 2006 • Nephronophthisis type 1 deletion syndrome with neurological symptoms: prevalence and significance of the association. PMID:16900087

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