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Nephronophthisis is an autosomal recessive ciliopathy characterized by chronic tubulointerstitial nephritis, corticomedullary cysts, and progressive renal failure, often presenting in childhood or adolescence. NPHP3 encodes nephrocystin-3, a 1,330-amino acid ciliary protein that interacts with nephrocystin and inversin to regulate Wnt signaling and planar cell polarity. Disruption of NPHP3 function leads to isolated nephronophthisis or syndromic forms with hepatic fibrosis, retinal degeneration, and skeletal anomalies.
Genetic studies have identified biallelic NPHP3 mutations in over 60 unrelated probands across multiple cohorts worldwide, with inheritance strictly autosomal recessive. Case reports include juvenile and infantile onset with splice-site, missense, and truncating alleles. Notably, a consanguineous family harbored a homozygous splice acceptor deletion c.2694-2_2694-1del segregating with lethal infantile nephronophthisis and thoracic dystrophy (PMID:35987473). Additional cohorts from China and South Africa confirm early onset renal failure often accompanied by hepatic fibrosis and hypertension.
Segregation analysis in multiple families demonstrates co-segregation of NPHP3 variants with disease: at least 8 additional affected relatives across four pedigrees, confirming recessive inheritance. Compound heterozygous and homozygous LoF alleles consistently track with nephronophthisis phenotypes, and no heterozygous carriers manifest clinical disease.
The variant spectrum includes canonical splice-site changes (e.g., c.2694-2_2694-1del), deep intronic mutations disrupting exon inclusion (c.3813-3A>G), missense substitutions, and premature stop codons. Recurrent founder alleles have not been reported, but variants cluster in conserved ciliary interaction domains. The chosen representative mutation is c.2694-2_2694-1del.
Functional assays in animal and cellular models provide strong concordant evidence: the pcy hypomorphic allele in mouse recapitulates cystic kidney disease, while complete knockout results in embryonic lethality with situs inversus and cardiac defects (PMID:18371931). In vitro, nephrocystin-3 interacts with inversin to modulate canonical Wnt signaling, and Xenopus knockdown leads to planar cell polarity defects paralleling human pathology.
No studies have robustly disputed the NPHP3–nephronophthisis association. Large cohorts, cross-species modeling, and in vitro assays uniformly support a loss-of-function mechanism. Deep intronic variants and synonymous changes underscore the need for comprehensive genomic analysis.
Integration of genetic and experimental data establishes a definitive gene–disease relationship: NPHP3 loss-of-function causes autosomal recessive nephronophthisis with or without extrarenal features. Clinical genetic testing for NPHP3 variants informs diagnosis, prognosis, and family counseling, and underscores potential therapeutic avenues targeting ciliary signaling pathways.
Key Take-home: NPHP3 variants underpin a definitive autosomal recessive nephronophthisis syndrome, and comprehensive sequencing including splice-site and deep intronic regions is essential for accurate molecular diagnosis.
Gene–Disease AssociationDefinitiveOver 60 probands across multiple unrelated families, consistent segregation, and extensive functional model concordance Genetic EvidenceStrong62 probands with biallelic NPHP3 variants including homozygous truncating and splice mutations across diverse cohorts, meeting the genetic cap Functional EvidenceStrongMouse and Xenopus models of NPHP3 loss-of-function recapitulate nephronophthisis phenotypes and in vitro assays confirm disrupted Wnt signaling |