CACNA1F – Inherited Retinal Dystrophy

CACNA1F encodes the Ca(v)1.4 L-type calcium channel α1F subunit, which is essential for photoreceptor neurotransmitter release. Pathogenic variants in CACNA1F cause X-linked incomplete congenital stationary night blindness (CSNB2), classified under the umbrella of inherited retinal dystrophies. The disorder follows an X-linked recessive inheritance pattern with hemizygous males typically affected and heterozygous females showing variable penetrance.

Human genetic evidence includes a 9-month-old boy presenting with isolated upward saccadic intrusions whose hemizygous CACNA1F pathogenic allele confirmed an iCSNB diagnosis (PMID:36567043). A large New Zealand pedigree segregating the recurrent c.2234T>C (p.Ile745Thr) variant across affected males and symptomatic female carriers further substantiates the association (PMID:15807819).

In a Chinese family affected by cone-rod dystrophy 3 (CORDX3), a novel splice-site mutation c.3847-2A>G co-segregated in two affected siblings, with skewed X-chromosomal inactivation correlating with milder female phenotype (PMID:36165086). Segregation in these three independent kindreds reinforces the genotype–phenotype link.

The variant spectrum comprises missense alleles that disrupt channel gating (e.g., p.Ser229Pro, p.Gly369Asp, p.Leu1068Pro, p.Trp1440Ter), splice-site mutations (c.3847-2A>G), and truncating changes such as p.Gly305Ter. The I745T (p.Ile745Thr) variant exemplifies gain-of-function effects in CSNB2.

Functional studies in heterologous systems demonstrate that CSNB2-associated missense mutations abrogate or alter voltage-dependent activation/inactivation, reducing Ca2+ currents and photoreceptor signaling (PMID:15634789). Proteasomal degradation assays reveal that multiple clinical missense variants exhibit decreased channel stability and current amplitude, which can be partially rescued by proteasome inhibitors (PMID:37206923).

Murine models corroborate human findings: the G305X null mutant shows loss of synaptic ribbons and absence of ERG b-wave, whereas the nob2 hypomorphic allele preserves partial channel function (PMID:20238058). The I745T gain-of-function IT mouse recapitulates photoreceptor dysfunction, outer plexiform layer disorganization, and reduced ERG b-wave amplitude, linking channel gating defects to retinal pathology (PMID:24051672).

These combined genetic and functional data satisfy ClinGen criteria for a Strong gene–disease association. CACNA1F testing is clinically valuable for diagnosing X-linked IRD, guiding genetic counseling, and informing potential therapeutic strategies.

References

• Journal of AAPOS | 2023 | Upward saccadic intrusions as the presenting feature for incomplete congenital stationary night blindness. PMID:36567043
• Clinical & experimental ophthalmology | 2005 | Clinical manifestations of a unique X-linked retinal disorder in a large New Zealand family with a novel mutation in CACNA1F, the gene responsible for CSNB2. PMID:15807819
• Molecular genetics & genomic medicine | 2022 | Identification of a novel CACNA1F mutation in a Chinese family with CORDX3. PMID:36165086
• 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
• Frontiers in cell and developmental biology | 2023 | Cav1.4 congenital stationary night blindness is associated with an increased rate of proteasomal degradation. PMID:37206923
• Advances in experimental medicine and biology | 2010 | Congenital stationary night blindness in mice - a tale of two Cacna1f mutants. PMID:20238058
• Channels (Austin, Tex.) | 2013 | Cav1.4 IT mouse as model for vision impairment in human congenital stationary night blindness type 2. PMID:24051672

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