Mutation in the auxiliary calcium-channel subunit CACNA2D4 causes autosomal recessive cone dystrophy - PubMed (original) (raw)

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Mutation in the auxiliary calcium-channel subunit CACNA2D4 causes autosomal recessive cone dystrophy

Katharina Agnes Wycisk et al. Am J Hum Genet. 2006 Nov.

Abstract

Retinal signal transmission depends on the activity of high voltage-gated l-type calcium channels in photoreceptor ribbon synapses. We recently identified a truncating frameshift mutation in the Cacna2d4 gene in a spontaneous mouse mutant with profound loss of retinal signaling and an abnormal morphology of ribbon synapses in rods and cones. The Cacna2d4 gene encodes an l-type calcium-channel auxiliary subunit of the alpha (2) delta type. Mutations in its human orthologue, CACNA2D4, were not yet known to be associated with a disease. We performed mutation analyses of 34 patients who received an initial diagnosis of night blindness, and, in two affected siblings, we detected a homozygous nucleotide substitution (c.2406C-->A) in CACNA2D4. The mutation introduces a premature stop codon that truncates one-third of the corresponding open reading frame. Both patients share symptoms of slowly progressing cone dystrophy. These findings represent the first report of a mutation in the human CACNA2D4 gene and define a novel gene defect that causes autosomal recessive cone dystrophy.

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Figures

Figure 1.

Figure 1.

Mutation analysis of CACNA2D4 of index patient II-1. A, Pedigree of the family of patient II-1. Blackened symbols indicate affected status, the half-blackened symbol indicates mutation carrier, unblackened symbols indicate unaffected status, squares represent males, and circles represent females. Sequence analysis revealed a homozygous c.2406C→A mutation in the index patient and in his affected sister (II-2) as well as the carrier status of the father (I-1). Mutation analyses of the two unaffected siblings (II-3 and II-4) displayed homozygosity for the wild-type allele. B, Electropherograms show the respective DNA sequences of exon 25 of CACNA2D4. The homozygous c.2406C→A mutation in patient II-1 (left), the heterozygous mutation in the unaffected father I-1 (middle), and the wild-type allele of a control DNA sample (right) are indicated. The position of the mutated nucleotide is indicated by an arrow.

Figure 2.

Figure 2.

Schematic representation of CACNA2D4 transcript. The schematic drawing shows the longest transcript variant of human CACNA2D4 (GenBank accession number NM_172364.3) (fig. not to scale). Its ORF codes for a protein of 1,137 aa residues, posttranslationally cleaved into the α2 (aa 65–991; 232–3,204 bp) and the δ (aa 992–1137; 3,205–3,645 bp) peptides. The cleavage site between the α2 and δ peptides, encoded by an alanine residue at position 992 (exon 34), is indicated by an arrow. The locations of the conserved von Willebrand factor A (VWFA) domain and the calcium-channel and chemotaxis receptor (CACHE) domains are illustrated in the transcript scheme. The CACHE domains probably constitute binding sites for small ligands, whereas the VWFA domain is responsible for protein-protein interactions of the α2δ protein with α1 subunits. At the N-terminus, the CACNA2D4 protein also contains a putative signal peptide of 64 aa residues.,

Figure 3.

Figure 3.

Fundus photographs of patients II-1 and II-2. Fundus of patient II-1 (upper panels) and patient II-2 (lower panels) of the left eye (LE) and right eye (RE), respectively, show nearly normal appearance.

Figure 4.

Figure 4.

ERG of patients carrying the p.Y802X mutation and ERG recordings in the right eye of patients II-1 and II-2. The left panel shows representative recordings of an unaffected subject, the middle panel shows the recordings of patient II-1, and the right panel shows recordings of patient II-2. Rod responses (A), maximal combined responses (B), oscillatory potentials (C), single-flash cone responses (D), and 30-Hz flicker responses (E), each according to ISCEV standard, are shown. The negative-oriented a-wave of an ERG response reflects the hyperpolarization of photoreceptors due to a flash of light. The positive-oriented b-wave represents a summation of responses evoked by activities of secondary neurons during photoreceptor synaptic signal transmission. Both patients share a frequency doubling of the 30-Hz flicker ERG.

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References

Web Resources

    1. GenBank, http://www.ncbi.nlm.nih.gov/Genbank/ (for CACNA2D4 [accession number NM_172364.3])
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for CACNA2D4, CACNA1F, and CABP4)

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