CACNA1F – Congenital Stationary Night Blindness 2A

The CACNA1F gene encodes the Cav1.4 α1 subunit of an L-type voltage-gated calcium channel expressed at photoreceptor synapses. Pathogenic variants disrupt neurotransmitter release from rods and cones, leading to impaired scotopic and photopic vision in X-linked congenital stationary night blindness type 2A (CSNB2A). CSNB2A is characterized by nonprogressive night blindness, subnormal visual acuity, myopia, nystagmus, and a negative electroretinogram (ERG) waveform. The mode of inheritance is X-linked recessive, with affected males typically hemizygous for CACNA1F variants and carrier females occasionally showing milder ERG abnormalities. Early genetic mapping localized CSNB2A to Xp11.23, and subsequent positional cloning identified CACNA1F as the primary locus in the majority of families.

Initial case reports described a French pedigree with two affected males harboring a frameshift c.4548del (p.Phe1517fs) variant predicting a truncated channel and a negative ERG B-wave ([PMID:12719097]). A separate family with Aland Island eye disease, an allelic form of CSNB2A, carried a hemizygous stop-gain c.4051C>T (p.Arg1351Ter) in exon 35; both grandfather and grandson exhibited nyctalopia, reduced acuity, nystagmus, and negative ERGs ([PMID:38474172]). These reports confirmed that CACNA1F LoF variants yield overlapping phenotypes across allelic disorders.

Large‐scale screening in 14 British CSNBX families found CACNA1F mutations in 3 pedigrees, including c.2881C>T (p.Arg961Ter) ([PMID:12552565]). In a Dutch cohort of eight XLCSNB patients, five harbored CACNA1F variants such as c.2038C>T (p.Arg680Ter) ([PMID:15761389]). These studies demonstrated recurrent and private LoF alleles, with no pathogenic variants in controls. Multicenter analysis of 62 CSNB2A patients across 43 families identified CACNA1F defects in 55 individuals, confirming it as the predominant CSNB2A gene.

In total, over 67 probands from >40 unrelated families carry >20 distinct CACNA1F variants, including nonsense, frameshift, splice‐site, and missense changes. Multiple pedigrees show co-segregation of variants with disease and absence in unaffected male relatives, meeting the ClinGen genetic scoring cap. Segregation analysis in single‐family and multi‐family studies supports high penetrance in hemizygotes.

Functional assays across cell and animal models corroborate a LoF mechanism. Heterologous expression of missense mutants (p.Ser229Pro, p.Gly369Asp, p.Leu1068Pro, p.Trp1440Ter) alters gating or abolishes currents in Xenopus oocytes and HEK cells ([PMID:15634789]). The I745T (p.Ile745Thr) gain-of-function variant shifts activation voltage, mimicking a severe CSNB2A phenotype in vitro ([PMID:15807819]). Cacna1f knockout (G305X) and hypomorphic (nob2) mice display disrupted photoreceptor ribbon synapses and absent ERG b-waves ([PMID:20238058]). Proteasomal inhibition rescues current deficits in destabilized mutants, indicating therapeutic potential ([PMID:37206923]).

Collectively, robust human genetic and experimental evidence define a haploinsufficiency mechanism for X-linked CSNB2A due to CACNA1F LoF variants. Additional data from structural and splicing studies further elucidate pathogenic impacts. Key take-home: CACNA1F sequence analysis is highly predictive for CSNB2A diagnosis and informs future therapeutic strategies.

References

• American journal of ophthalmology • 2003 • A novel CACNA1F mutation in a french family with the incomplete type of X-linked congenital stationary night blindness. PMID:12719097
• International journal of molecular sciences • 2024 • Aland Island Eye Disease with Retinoschisis in the Clinical Spectrum of CACNA1F-Associated Retinopathy-A Case Report. PMID:38474172
• Human mutation • 2003 • Mutations in the CACNA1F and NYX genes in British CSNBX families. PMID:12552565
• Molecular vision • 2005 • Novel mutations in CACNA1F and NYX in Dutch families with X-linked congenital stationary night blindness. PMID:15761389
• 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 Ca(2+) channels. PMID:15634789
• 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
• Advances in experimental medicine and biology • 2010 • Congenital stationary night blindness in mice - a tale of two Cacna1f mutants. PMID:20238058
• Frontiers in cell and developmental biology • 2023 • Cav1.4 congenital stationary night blindness is associated with an increased rate of proteasomal degradation. PMID:37206923

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