Mutation in the auxiliary calcium-channel subunit CACNA2D4 causes autosomal recessive cone dystrophy.
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.
Wycisk
Katharina Agnes
KA
Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland.
Zeitz
Christina
C
Feil
Silke
S
Wittmer
Mariana
M
Forster
Ursula
U
Neidhardt
John
J
Wissinger
Bernd
B
Zrenner
Eberhart
E
Wilke
Robert
R
Kohl
Susanne
S
Berger
Wolfgang
W
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
C498838:CACNA2D4 protein, human; C512890:Cacna2d4 protein, mouse; D020746:Calcium Channels, L-Type; D018389:Codon, Nonsense; D004247:DNA