NPHP4 – Senior-Loken syndrome

Senior-Loken syndrome (SLS) is an autosomal recessive ciliopathy defined by nephronophthisis and early-onset retinal dystrophy, representing a syndromic overlap of renal failure and photoreceptor degeneration. NPHP4 was first implicated in SLS through direct sequencing in 250 patients with nephronophthisis, Senior-Loken syndrome, or Cogan syndrome, identifying biallelic NPHP4 variants in 6/250 patients (2.4%) and single heterozygous variants in 20/250 patients PMID:15776426. In a Korean cohort of 17 genetically confirmed SLS patients, NPHP4 mutations accounted for 29.4% of cases, with five unrelated probands harboring biallelic changes including the recurrent c.694C>T (p.Arg232Cys) PMID:40725491. Combining these studies yields 11 unrelated SLS probands with NPHP4 variants, establishing a reproducible genetic link.

NPHP4-associated SLS follows an autosomal recessive inheritance pattern with variants spanning missense, nonsense, and splice-site classes. The initial sequencing effort described 23 novel NPHP4 sequence variants across 26 patients, of which 63% of biallelic mutations were predicted loss-of-function and 5% of heterozygous variants were truncating, with no clear genotype–phenotype correlations observed PMID:15776426.

Functionally, nephrocystin-4 interacts directly with RPGRIP1 in photoreceptor cells, and this interaction is abrogated by NPHP4 missense mutations such as p.Gly754Arg, mirroring disruption seen in Leber congenital amaurosis and implicating defective ciliary protein networks in retinal degeneration PMID:16339905. In Nphp4(nmf192) knockout mice, homozygous loss of Nphp4 causes rapid photoreceptor ribbon synapse degeneration, outer segment malformation, and extinguished rod and cone electroretinogram responses by nine weeks, validating a loss-of-function mechanism relevant to the ocular component of SLS PMID:21078623.

There is no conflicting evidence disputing the NPHP4–SLS association. Together, genetic and experimental data fulfill ClinGen criteria for a moderate clinical validity classification, with corroboration from human cohorts and complementary in vitro and in vivo studies. Key take-home sentence: NPHP4 biallelic loss-of-function variants cause Senior-Loken syndrome and should be included in genetic testing panels to enable early diagnosis and management.

References

• Human mutation • 2005 • Mutational analysis of the NPHP4 gene in 250 patients with nephronophthisis. PMID:15776426
• Genes • 2025 • Clinical and Genetic Characteristics of Senior-Loken Syndrome Patients in Korea. PMID:40725491
• 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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