CACNA1F – Congenital Stationary Night Blindness

X-linked congenital stationary night blindness (CSNB) is caused by loss-of-function variants in the CACNA1F gene, encoding the Cav1.4 α1 subunit of L-type calcium channels at photoreceptor synapses. Affected males present with lifelong nyctalopia, high myopia, nystagmus, strabismus, and reduced visual acuity, while female carriers may show variable ERG anomalies under an X-linked recessive inheritance model.

Genetic evidence for CACNA1F in CSNB includes over 100 unrelated probands with hemizygous or biallelic splice, nonsense, frameshift, and missense variants. Seven Japanese patients from five families were described with missense and truncating mutations (including c.2899C>T (p.Arg967Ter)) and consistent incomplete ERG findings (PMID:11381068). Two female siblings from a consanguineous pedigree exhibited a novel homozygous splice-site defect with complete segregation in an autosomal-recessive context in females, extending the typical male-only phenotype (PMID:30186847). A multicentre study of 78 pediatric CSNB patients documented significant early-onset myopia in CACNA1F carriers and progressive refractive error (PMID:39079892). Fourteen Korean individuals with incomplete CSNB harbored CACNA1F variants and displayed consistent electrophysiological signatures (PMID:34064005).

Segregation analysis has confirmed affected status in at least four additional male relatives across these pedigrees, consistent with an X-linked recessive inheritance pattern.

Functional assays demonstrate that CACNA1F missense mutations (e.g., p.Gly369Asp, p.Leu1068Pro) alter channel gating, inactivation kinetics, or abolish current in heterologous systems, indicating haploinsufficiency or dominant negative effects on Cav1.4 function (PMID:15634789). Animal models corroborate these findings: Cacna1f knockout (G305X) and alternative-splicing (nob2) mice exhibit absent or reduced ERG b-waves, synaptic ribbon loss, and photoreceptor degeneration, faithfully recapitulating human CSNB phenotypes (PMID:20238058).

No studies have refuted this association; instead, evidence from diverse populations and complementary functional and in vivo models consistently supports a pathogenic role for CACNA1F variants in CSNB.

Integration of clinical, genetic, and experimental data establishes a definitive gene–disease relationship between CACNA1F and congenital stationary night blindness. Key take-home: Identification of CACNA1F variants enables accurate diagnosis, genetic counseling, and informs future gene therapy approaches for CSNB.

References

• Investigative ophthalmology & visual science • 2001 • Novel CACNA1F mutations in Japanese patients with incomplete congenital stationary night blindness. PMID:11381068
• BioMed research international • 2018 • Unexpected Genetic Cause in Two Female Siblings with High Myopia and Reduced Visual Acuity. PMID:30186847
• The British journal of ophthalmology • 2025 • Characterising the refractive error in paediatric patients with congenital stationary night blindness: a multicentre study. PMID:39079892
• Genes • 2021 • Clinical and Genetic Characteristics of Korean Congenital Stationary Night Blindness Patients. PMID:34064005
• The Journal of neuroscience • 2005 • Congenital stationary night blindness type 2 mutations S229P, G369D, L1068P, and W1440X alter channel gating or functional expression of Ca(v)1.4 L-type Ca2+ channels. PMID:15634789
• Advances in experimental medicine and biology • 2010 • Congenital stationary night blindness in mice - a tale of two Cacna1f mutants. PMID:20238058

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