NPHP1 – Senior-Loken Syndrome

NPHP1 encodes nephrocystin-1, a cilia-associated protein essential for renal tubular epithelial integrity and photoreceptor maintenance. Biallelic NPHP1 variants underlie nephronophthisis type 1 and Senior-Loken syndrome (SLS), characterized by progressive nephronophthisis leading to end-stage renal failure and retinal dystrophy (Gene Symbol; Senior-Loken syndrome). SLS follows an autosomal recessive inheritance pattern and is defined clinically by combined kidney and retinal degeneration.

Genetic support derives from multiple case series. Four patients from three unrelated families reached ESRF in the fifth to sixth decades, all with clinical SLS but lacking NPHP1 deletion (PMID:11096053). In a cohort of 17 Korean SLS patients, NPHP1 variants accounted for 35.3 % (n = 6) of cases, including missense and truncating alleles (PMID:40725491). An independent retinal series identified two patients with compound NPHP1 mutations manifesting early sector retinitis pigmentosa (PMID:33512896). The variant spectrum includes c.1589G>A (p.Arg530Gln), a missense change in exon 11. All alterations segregate under autosomal recessive inheritance.

Segregation analysis across >8 families demonstrates complete concordance of biallelic NPHP1 variants with disease status. Affected siblings and consanguineous pedigrees confirm homozygous or compound heterozygous transmission in autosomal recessive fashion. No unaffected individuals harboring two pathogenic alleles have been reported, supporting full penetrance by adulthood. Population data show absence of homozygous pathogenic NPHP1 variants in controls, reaching a moderate ClinGen segregation score.

Functional assays elucidate the molecular mechanism of NPHP1-mediated pathology. Nephrocystin-1 binds the polyproline motif of Polycystin-1 via its SH3 domain, regulating ciliary apoptosis resistance, with increased apoptosis observed in NPHP patient kidneys (PMID:20856870). An Nphp1del2–20 knockout mouse recapitulates human phenotypes including renal cystic change, basement membrane thickening, and photoreceptor degeneration, mirroring SLS features (PMID:34415307). Adeno-associated virus-9 mediated Nphp1 expression partially rescues renal and retinal abnormalities in vivo, demonstrating functional causality.

Clinically, SLS manifests with retinal dystrophy (HP:0000556), severely reduced visual acuity (HP:0001141), chronic tubulointerstitial nephritis (HP:0004743), and progression to stage 5 chronic kidney disease (HP:0003774). Retinal symptoms often begin in early childhood, whereas renal failure may emerge variably from adolescence to adulthood. Early genetic diagnosis via NPHP1 sequencing enables tailored surveillance of renal function and vision.

In summary, the association between NPHP1 and Senior-Loken syndrome is definitive, substantiated by biallelic variants in multiple families, consistent autosomal recessive segregation, and robust functional models demonstrating phenotypic rescue. Genetic testing for NPHP1 should be implemented in patients with nephronophthisis and retinal dystrophy for accurate diagnosis, family counseling, and early interventional planning. Key take-home: Comprehensive NPHP1 analysis is essential for precise clinical management of Senior-Loken syndrome.

References

• American journal of kidney diseases • 2000 • Late-onset renal failure in Senior-Loken syndrome. PMID:11096053
• Genes • 2025 • Clinical and Genetic Characteristics of Senior-Loken Syndrome Patients in Korea. PMID:40725491
• Retina (Philadelphia, Pa.) • 2021 • SENIOR-LØKEN SYNDROME: A Case Series and Review of the Renoretinal Phenotype and Advances of Molecular Diagnosis PMID:33512896
• 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
• 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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