Copyright © 2006 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 79, Issue 5, 973-977, 1 November 2006
doi:10.1086/508944
Report
Mutation in the Auxiliary Calcium-Channel Subunit CACNA2D4 Causes Autosomal Recessive Cone Dystrophy
Katharina Agnes Wycisk*, a, Christina Zeitz*, a, Silke Feila, Mariana Wittmera, Ursula Forstera, John Neidhardta, Bernd Wissingerb, c, Eberhart Zrennerc, Robert Wilkec, Susanne Kohlb, c and Wolfgang Bergera, 
, 
a Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland
b Molecular Genetics Laboratory University Tuebingen, Tuebingen, Germany
c Department of Pathophysiology of Vision and Neuroophthalmology University Tuebingen, Tuebingen, Germany
d University Eye Hospital Tuebingen, Eberhard-Karls University Tuebingen, Tuebingen, Germany
Address for correspondence and reprints: Dr. Wolfgang Berger, Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland.* These two authors contributed equally to this work.
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 α2δ 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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