title: Mutation in the auxiliary calcium-channel subunit CACNA2D4 causes autosomal recessive cone dystrophy.
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.
authors.affiliation: Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland.
authors.forename: Katharina Agnes
authors.initials: KA
authors.lastname: Wycisk
authors.forename: Christina
authors.initials: C
authors.lastname: Zeitz
authors.forename: Silke
authors.initials: S
authors.lastname: Feil
authors.forename: Mariana
authors.initials: M
authors.lastname: Wittmer
authors.forename: Ursula
authors.initials: U
authors.lastname: Forster
authors.forename: John
authors.initials: J
authors.lastname: Neidhardt
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
authors.forename: Eberhart
authors.initials: E
authors.lastname: Zrenner
authors.forename: Robert
authors.initials: R
authors.lastname: Wilke
authors.forename: Susanne
authors.initials: S
authors.lastname: Kohl
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Berger
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D020746:Calcium Channels, L-Type / Q000235:genetics*; D018389:Codon, Nonsense / Q000235:genetics; D004247:DNA / Q000235:genetics; D004596:Electroretinography; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009755:Night Blindness / Q000235:genetics; D010375:Pedigree; D017354:Point Mutation; D017949:Retinal Cone Photoreceptor Cells / Q000002:abnormalities*; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology
chemical_list: C498838:CACNA2D4 protein, human; C512890:Cacna2d4 protein, mouse; D020746:Calcium Channels, L-Type; D018389:Codon, Nonsense; D004247:DNA