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Aland Island Eye Disease (AIED) is an X-linked incomplete form of congenital stationary night blindness characterized by nyctalopia, nystagmus, variable myopia, and retinoschisis. It overlaps clinically with CSNB2A and CORDX3 and results from mutations in the CACNA1F gene encoding the Cav1.4 α1 subunit of a voltage-gated calcium channel. Cav1.4 channels mediate neurotransmission from rod and cone photoreceptors to bipolar cells, essential for scotopic and photopic vision. Loss- or gain-of-function CACNA1F variants disrupt photoreceptor synaptic signaling, leading to attenuated a-wave amplitudes and negative b-wave patterns on electroretinography. The allelic series includes incomplete CSNB (CSNB2A), cone-rod dystrophy type 3 (CORDX3), and AIED, reflecting a continuum of CACNA1F-associated retinopathies.
Genetic evidence is strong: thirty distinct CACNA1F mutations were identified in 33 families with incomplete CSNB/AIED overlap ([PMID:12111638]), spanning missense, nonsense, frameshift, and splice-site changes across all 48 exons. Twenty-four variants were unique to a German cohort, demonstrating robust allelic heterogeneity and clear segregation in multi-family pedigrees. No CACNA1F mutation was found in classic AIED families mapping to the CSNB2 locus, suggesting additional genetic modifiers may influence clinical presentation.
A 57-year-old male proband with lifelong nyctalopia, nystagmus, high myopia, diffuse retinal thinning, and unilateral retinoschisis—and his 2-month-old grandson—harbored a hemizygous stop-gain variant c.4051C>T (p.Arg1351Ter) in CACNA1F, previously reported in CSNB2A and CORDX3, thus expanding the AIED phenotype ([PMID:38474172]). Full-field ERG demonstrated markedly attenuated a-waves and abolished b-waves, consistent with a negative waveform pattern.
AIED follows an X-linked recessive inheritance mode, with affected males hemizygous for pathogenic CACNA1F alleles and carrier females typically asymptomatic or mildly affected. Co-segregation was observed in a two-generation family with one additional affected relative ([PMID:38474172]), supporting a causal relationship between CACNA1F variants and AIED.
Functional studies provide moderate evidence: mutations such as S229P, G369D, L1068P, and W1440X alter Cav1.4 gating or expression, yielding reduced or absent currents in oocytes and mammalian cells ([PMID:15634789], [PMID:16476079]). The I745T gain-of-function variant shifts activation voltage hyperpolarized, reducing photoreceptor dynamic range in both human patients and mouse models (IT line), with ERG deficits and synaptic disorganization ([PMID:24051672], [PMID:24466230]). These concordant assays confirm haploinsufficiency and altered gating as key pathogenic mechanisms.
Collectively, 30 variants in 33 families, segregation in multiple pedigrees, and extensive functional characterization establish a strong clinical validity for the association of CACNA1F with Aland Island Eye Disease. While additional modifiers likely contribute to phenotypic variability, CACNA1F testing is crucial for definitive diagnosis, genetic counseling, and patient stratification for emerging therapies. Key Take-home: CACNA1F variant screening provides reliable molecular diagnosis and informs management of AIED.
Gene–Disease AssociationStrong30 distinct variants in 33 families ([PMID:12111638]); multi-family segregation and concordant functional data Genetic EvidenceStrong30 distinct variants in 33 families ([PMID:12111638]) and one AIED proband ([PMID:38474172]), meeting genetic evidence cap Functional EvidenceModerateMultiple in vitro electrophysiological assays and animal models demonstrating altered Cav1.4 channel function ([PMID:15634789], [PMID:16476079], [PMID:24051672], [PMID:24466230]) |