NPHP3 – Nephronophthisis Type 3

NPHP3 has been implicated in adolescent nephronophthisis type 3 (MONDO:0011456), an autosomal recessive cystic kidney disease characterized by progressive tubulointerstitial nephropathy leading to end-stage renal disease (ESRD) in late adolescence. Initial linkage analysis in a large Venezuelan kindred demonstrated NPH3 mapping to chromosome 3q21–q22 with ESRD at a median age of 19 years, segregating in four families and identity by descent in one (PMID:11274269).

Molecular genetic studies across eight unrelated families identified homozygous or compound heterozygous truncating and splice-site variants in NPHP3 in 11 unrelated probands (PMID:11274269; PMID:30002499; PMID:34212438; PMID:36878198; PMID:33024573). Reported variants include c.2214T>A (p.Cys738Ter), c.2694-2_2694-1del, and c.3813-3A>G, with segregation confirmed in five additional affected relatives (PMID:30002499; PMID:34212438).

Functional studies in mouse models demonstrate that complete loss of Nphp3 function causes embryonic lethality, situs inversus, and cardiac anomalies, whereas hypomorphic alleles recapitulate the cystic kidney phenotype (PMID:18371931). Mechanistically, nephrocystin-3 interacts with inversin to inhibit canonical Wnt signaling and its deficiency in Xenopus laevis leads to planar cell polarity defects, mirroring human ciliary dysfunction (PMID:18371931).

Human urine-derived renal epithelial cell (hUREC) studies confirmed kidney-specific retention of exon 15 and aberrant splicing caused by the synonymous variant c.2154C>T (p.Phe718=), highlighting the necessity of tissue-specific transcript assessment for splice-site variants (PMID:30002499).

Clinical reanalysis of whole-exome sequencing in a 4-year-old Chinese boy with ESRD identified a homozygous intronic splice variant c.3813-3A>G, with in vitro minigene assays validating its deleterious effect on normal splicing and underpinning its diagnostic significance (PMID:36878198).

Collectively, robust linkage, segregation, and molecular evidence across 11 probands, together with in vivo and in vitro functional concordance, support a Strong gene–disease association for NPHP3 in autosomal recessive nephronophthisis type 3. Key take-home: truncating and splice variants in NPHP3 are clinically actionable causes of early-onset cystic kidney disease.

References

• Nephrology, dialysis, transplantation • 2001 • Evidence for further genetic heterogeneity in nephronophthisis. PMID:11274269
• American journal of human genetics • 2008 • Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia. PMID:18371931
• European journal of human genetics • 2018 • Human urine-derived renal epithelial cells provide insights into kidney-specific alternate splicing variants. PMID:30002499
• Human mutation • 2021 • A discarded synonymous variant in NPHP3 explains nephronophthisis and congenital hepatic fibrosis in several families. PMID:34212438
• Nephron • 2023 • Identification of a Splicing Variant c.3813-3A>G in NPHP3 by Reanalysis of Whole Exome Sequencing in a Chinese Boy with Nephronophthisis. PMID:36878198
• NPJ genomic medicine • 2020 • Diagnostic utility of whole-genome sequencing for nephronophthisis. PMID:33024573

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