NPHP1 – Nephronophthisis

Nephronophthisis is an autosomal recessive cystic kidney disease characterized by progressive tubulointerstitial nephritis, tubular basement membrane disruption, interstitial fibrosis, tubular cysts, and eventual end-stage renal disease ([PMID:18076122]). Homozygous deletions of the NPHP1 gene account for the majority of juvenile nephronophthisis cases. Large cohorts have confirmed biallelic NPHP1 variants in approximately 440 patients from 365 families, with consistent cosegregation in autosomal recessive pedigrees and extrarenal features in subsets ([PMID:21866095]). Adult-onset nephronophthisis due to NPHP1 deletion was detected in 26 of 5 606 ESRD transplant recipients (0.5%), many of whom were not clinically recognized as nephronophthisis before genetic testing ([PMID:29654215]).

Genetic evidence has defined a broad spectrum of NPHP1 pathogenic variants, including homozygous full-gene deletions, nonsense, frameshift, missense, and splice-site mutations. Ninety-seven homozygous deletions were identified among 470 unrelated patients by multiplex PCR and homozygosity mapping ([PMID:18076122]), and additional point mutations such as c.859G>A (p.Gly287Arg) have been reported in families with typical juvenile nephronophthisis ([PMID:18076122]). The inheritance is strictly autosomal recessive, with segregation of biallelic loss-of-function alleles in affected sibships.

Functional studies demonstrate that NPHP1 loss disrupts ciliary signaling and promotes renal epithelial apoptosis. Nphp1del2-20/del2-20 knockout mice faithfully reproduce human nephronophthisis phenotypes—including renal cyst formation, tubular basement membrane thickening, retinal degeneration, and defective spermatogenesis—and are partially rescued by AAV9-mediated Nphp1 re-expression ([PMID:34415307]). Biochemical assays show that the SH3 domain of nephrocystin-1 binds a polyproline motif in the C-terminus of polycystin-1, linking two ciliopathy proteins and regulating apoptosis ([PMID:20856870]).

No substantive studies have refuted the causative role of NPHP1 in nephronophthisis, and conflicting reports largely reflect phenotypic overlap with related ciliopathies rather than true discordance. The genetic and experimental concordance across human cohorts and animal models supports a Definitive gene-disease association.

Key Take-home: Biallelic loss-of-function variants in NPHP1 cause autosomal recessive nephronophthisis; genetic testing for NPHP1 deletions and point mutations is critical for diagnosis, prognostication, and family counseling.

References

• PloS One • 2010 • Nephrocystin-1 forms a complex with polycystin-1 via a polyproline motif/SH3 domain interaction and regulates the apoptotic response in mammals PMID:20856870
• Kidney international • 2011 • Genotype-phenotype correlation in 440 patients with NPHP-related ciliopathies PMID:21866095
• Journal of the American Society of Nephrology • 2018 • NPHP1 (Nephrocystin-1) Gene Deletions Cause Adult-Onset ESRD. PMID:29654215
• Human mutation • 2008 • Mutation analysis in nephronophthisis using a combined approach of homozygosity mapping, CEL I endonuclease cleavage, and direct sequencing. PMID:18076122
• Human molecular genetics • 2021 • An Nphp1 knockout mouse model targeting exon 2-20 demonstrates characteristic phenotypes of human nephronophthisis. PMID:34415307

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