CACNA1F – Cone-rod Dystrophy

Cone-rod dystrophy (CORD) is an inherited retinal degeneration characterized by early cone photoreceptor loss followed by rod dysfunction, leading to central vision decline and color vision defects. CACNA1F encodes the Cav1.4 L-type calcium channel α1F subunit at photoreceptor synaptic terminals, essential for sustained neurotransmitter release. Variants in CACNA1F have been implicated in X-linked CORD (CORDX3), expanding its known phenotypic spectrum beyond congenital stationary night blindness (CSNB2).

In a Chinese cohort of 163 unrelated CORD probands, CACNA1F mutations were identified in 2.5% (4 probands) by whole exome sequencing and validated by Sanger sequencing and segregation analysis (PMID:26992781). An independent exome-sequencing study of 47 Chinese CORD families found a hemizygous CACNA1F mutation in one family (1/47), confirming the X-linked recessive inheritance (PMID:23776498).

Targeted analysis of six Chinese families with diverse CORD inheritance patterns identified pathogenic CACNA1F variants in two X-linked pedigrees: a hemizygous frameshift c.2201del (p.Val734GlyfsTer17) and a hemizygous missense c.245G>A (p.Arg82Gln), both co-segregating with disease in affected males and unaffected female carriers (PMID:38028590).

Functional assays demonstrate that CACNA1F variants perturb channel gating, kinetics, or expression. The I745T (p.Ile745Thr) substitution causes a hyperpolarizing shift in activation and in vivo mouse models recapitulate CORD-like photoreceptor synaptic defects (PMID:15807819; PMID:24051672). Other CSNB2-associated missense mutations (e.g., p.Gly369Asp, p.Leu1068Pro, p.Trp1440Ter, p.Ser229Pro) abrogate or alter Cav1.4 currents in heterologous systems, supporting a loss-of-function mechanism (PMID:15634789).

Collectively, seven unrelated male probands with hemizygous CACNA1F variants and segregation in two pedigrees, combined with robust electrophysiological and animal model data, substantiate a Moderate clinical validity for CACNA1F in CORD. The pathogenic mechanism is primarily loss of Cav1.4 function, leading to impaired photoreceptor synaptic transmission and progressive cone-rod degeneration.

Key Take-home: CACNA1F genetic testing should be considered in male patients with X-linked cone-rod dystrophy, and functional assays of Cav1.4 channel activity can guide variant interpretation and potential therapeutic strategies.

References

• Experimental Eye Research • 2016 • Molecular genetics of cone-rod dystrophy in Chinese patients: New data from 61 probands and mutation overview of 163 probands. PMID:26992781
• PLOS One • 2013 • Exome sequencing of 47 chinese families with cone-rod dystrophy: mutations in 25 known causative genes. PMID:23776498
• (Unpublished title) • 2023 • Pathogenic variants in CACNA1F identified in two families with CORDX3. PMID:38028590
• 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
• 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

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