IQCB1 – Senior-Loken syndrome

Senior-Loken syndrome (SLSN) is an autosomal recessive ciliopathy characterized by juvenile nephronophthisis (HP:0000090) and early-onset retinopathy (HP:0000488). The IQCB1 gene (NPHP5) encodes nephrocystin-5, an IQ-domain protein that localizes to photoreceptor connecting cilia and renal epithelial primary cilia, essential for ciliogenesis (PMID:15723066).

IQCB1 was first implicated in SLSN by positional cloning in a cohort of 10 probands, all exhibiting combined renal failure and rod-cone dystrophy (PMID:15723066). Subsequent screening in 222 Leber congenital amaurosis patients identified frameshift and nonsense IQCB1 variants in 11 individuals, several of whom later developed nephronophthisis (PMID:20881296). A Korean retrospective series reported biallelic IQCB1 mutations in 5 unrelated SLSN patients, some presenting with Leber congenital amaurosis-like retinal degeneration and variable renal impairment at diagnosis (PMID:40725491). Across these studies, biallelic pathogenic IQCB1 variants have been identified in over 26 probands from nearly 20 unrelated families.

Pathogenic variants in IQCB1 are predominantly truncating alleles, including essential splice-site, nonsense, and frameshift changes. A representative allele is c.751dup (p.Ser251fs), which introduces a premature termination codon leading to loss of protein function. No recurrent founder variants have been reported, and deep-intronic or hypomorphic alleles are rare.

Clinical expressivity is variable: all IQCB1-deficient individuals develop retinal degeneration, whereas onset of nephronophthisis ranges from infancy to adolescence. In the Leber congenital amaurosis cohort, four patients maintained normal renal function at last follow-up, highlighting incomplete penetrance of renal disease (PMID:20881296).

Functional assays demonstrate that disease-causing truncations of nephrocystin-5 abrogate binding to CEP290 and impair ciliogenesis in vitro, a defect reversible by antagonists of negative ciliogenic regulators. These data confirm a loss-of-function mechanism consistent with the human phenotype (PMID:23446637).

No conflicting reports have emerged to dispute the IQCB1–SLSN relationship. Robust genetic evidence accumulated over nearly two decades, combined with mechanistic validation, supports a definitive causal association. IQCB1 genetic testing is clinically indicated in patients presenting with early retinal dystrophy or nephronophthisis to facilitate timely diagnosis and management of Senior-Loken syndrome.

References

• Nature genetics • 2005 • Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. PMID:15723066
• Investigative ophthalmology & visual science • 2011 • IQCB1 mutations in patients with leber congenital amaurosis. PMID:20881296
• Human molecular genetics • 2013 • Pathogenic NPHP5 mutations impair protein interaction with Cep290, a prerequisite for ciliogenesis. PMID:23446637
• Genes • 2025 • Clinical and Genetic Characteristics of Senior-Loken Syndrome Patients in Korea. PMID:40725491

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