NPHP4 – Nephronophthisis

Nephronophthisis (NPH) is an autosomal recessive cystic kidney disorder marked by tubular basement membrane disruption, interstitial fibrosis, tubular cysts, and progressive renal failure, often reaching end-stage by the second decade. NPHP4 encodes nephrocystin-4, a ciliary protein critical for renal tubular integrity and function. Biallelic loss-of-function variants in NPHP4 are consistently observed in affected individuals, establishing a clear genotype–phenotype correlation.

Clinical validity for NPHP4–NPH is Definitive based on identification of 6 unrelated families with LoF mutations (PMID:12205563), segregation of a homozygous variant in a consanguineous pedigree of 3 siblings (PMID:14750102), and replication in multiple cohorts encompassing >30 probands (PMID:31810733).

Genetic evidence is Strong: autosomal recessive inheritance, segregation in 6 families (PMID:12205563), and case series with 4 siblings showing variable expressivity (PMID:25818963). The variant spectrum includes nonsense, frameshift, splice-site, and large deletions, exemplified by c.79G>T (p.Glu27Ter) in six families.

Functional evidence is Moderate: nephrocystin-4 interacts with RPGRIP1 in photoreceptors, disrupted by pathogenic NPHP4 variants (PMID:16339905), and Nphp4 knockout mice exhibit photoreceptor degeneration and male infertility, supporting ciliary dysfunction (PMID:21078623). Zebrafish knockdown recapitulates laterality and renal phenotypes, confirming conserved biological roles.

No robust conflicting evidence has emerged; isolated heterozygous variants are prevalent but not disease-causing, and no studies have refuted biallelic NPHP4 pathogenicity.

In summary, biallelic NPHP4 mutations cause nephronophthisis via loss of ciliary nephrocystin-4 function, validated by genetic and experimental data. Diagnostic genetic testing for NPHP4 should be included in NPH panels, and immunostaining for NPHP4 in respiratory epithelia may accelerate diagnosis. Key take-home: NPHP4 analysis is critical for early identification and management of autosomal recessive nephronophthisis.

References

• American Journal of Human Genetics • 2002 • A gene mutated in nephronophthisis and retinitis pigmentosa encodes a novel protein, nephroretinin PMID:12205563
• American Journal of Kidney Diseases • 2004 • Clinical and histological presentation of 3 siblings with mutations in the NPHP4 gene. PMID:14750102
• The Turkish Journal of Pediatrics • 2014 • Diverse phenotypic expression of NPHP4 mutations in four siblings. PMID:25818963
• American Journal of Kidney Diseases • 2020 • Adult-Diagnosed Nonsyndromic Nephronophthisis in Australian Families Caused by Biallelic NPHP4 Variants. PMID:31810733
• Proceedings of the National Academy of Sciences of the United States of America • 2005 • Interaction of nephrocystin-4 and RPGRIP1 is disrupted by nephronophthisis or Leber congenital amaurosis-associated mutations. PMID:16339905
• Human Molecular Genetics • 2011 • NPHP4 is necessary for normal photoreceptor ribbon synapse maintenance and outer segment formation, and for sperm development. PMID:21078623

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