IQCB1 – Leber Congenital Amaurosis

Leber congenital amaurosis (LCA) is a severe early-onset retinal dystrophy characterized by profound visual impairment and nystagmus. Mutations in IQCB1, also known as NPHP5, have been repeatedly implicated in autosomal recessive LCA and Senior-Loken syndrome, underscoring its role in photoreceptor ciliary integrity. Initial reports identified homozygous and compound heterozygous truncating variants in three isolated LCA patients and a subsequent cohort of 222 individuals, yielding 11 affected probands with frameshift or nonsense alleles in IQCB1 (PMID:20881296). Screening of 276 nonsyndromic LCA cases revealed biallelic NPHP5 mutations in nine probands (3.2 %), including alleles previously linked to nephronophthisis yet manifesting solely as retinal degeneration in childhood (PMID:21220633). Whole-exome sequencing of consanguineous families in Saudi Arabia found novel IQCB1 variants in 3 of 37 unassigned LCA pedigrees (PMID:21901789), while homozygosity mapping in South Indian kindreds detected a single IQCB1 mutation in one of eleven LCA families (PMID:26147992). More recently, a 6-month-old infant with compound heterozygous IQCB1 variants (c.1518_1519del (p.His506fs) and c.1381C>T (p.Arg461Ter)) presented with LCA, confirming autosomal recessive inheritance and trans segregation (PMID:36426739).

Inheritance of IQCB1-related LCA is autosomal recessive, with both homozygous and compound heterozygous loss-of-function alleles segregating in affected families. Parental and sibling testing across multiple studies has demonstrated consistent co-segregation of truncating variants with disease, including trans configuration of c.1518_1519del (p.His506fs) and c.1381C>T (p.Arg461Ter) in the index infant (PMID:36426739).

The variant spectrum is dominated by protein-truncating changes: frameshift (e.g., c.1518_1519del (p.His506fs)), nonsense (e.g., c.1381C>T (p.Arg461Ter)), splice-site, and small deletions. These alleles disrupt the IQCB1 coiled-coil domains essential for centriolar localization. c.1381C>T (p.Arg461Ter) has been reported in multiple unrelated individuals (PMID:36426739).

Functional studies delineate a clear loss-of-function mechanism. NPHP5 localizes to centrioles and binds CEP290 to initiate ciliogenesis; disease-associated truncations abolish this interaction and impair cilium formation in cell models. Rescue of ciliogenesis by antagonists of negative regulators confirms the critical requirement of IQCB1‐mediated CEP290 binding for photoreceptor ciliary function (PMID:23446637).

Clinically, IQCB1 mutation carriers present with early visual loss (HP:0000544), infantile nystagmus (HP:0001135), and hypermetropia (HP:0000548). Renal surveillance is recommended given variable onset of nephronophthisis, even in initially nonsyndromic cases. Molecular diagnosis of IQCB1-associated LCA informs prognosis, guides ocular and renal monitoring, and enables accurate recurrence risk counseling.

Key Take-home: Autosomal recessive loss-of-function variants in IQCB1 cause definitive LCA through impaired photoreceptor ciliogenesis, warranting inclusion of IQCB1 in gene panels and ongoing renal evaluation.

References

• Investigative ophthalmology & visual science • 2011 • IQCB1 mutations in patients with leber congenital amaurosis. PMID:20881296
• Archives of ophthalmology • 2011 • Variations in NPHP5 in patients with nonsyndromic leber congenital amaurosis and Senior-Loken syndrome. PMID:21220633
• Human mutation • 2011 • Whole-exome sequencing identifies ALMS1, IQCB1, CNGA3, and MYO7A mutations in patients with leber congenital amaurosis. PMID:21901789
• PloS one • 2015 • Homozygosity mapping in Leber congenital amaurosis and autosomal recessive retinitis pigmentosa in south Indian families. PMID:26147992
• Ophthalmic genetics • 2023 • Dual phenotype: co-occurring Leber congenital amaurosis and familial exudative vitreoretinopathy: a case report. PMID:36426739
• Human molecular genetics • 2013 • Pathogenic NPHP5 mutations impair protein interaction with Cep290, a prerequisite for ciliogenesis. PMID:23446637

Evidence Based Scoring (AI generated)