title: Structural and functional abnormalities of retinal ribbon synapses due to Cacna2d4 mutation.
abstract: OBJECTIVE
  In a spontaneous mutant substrain of C57BL/10 mice, severely affected retinal ribbon-type synapses have been described. The retinopathy was accompanied by a substantial loss in the activities of the second-order neurons. Rod photoreceptor responses were maintained with reduced amplitude, whereas cone activities were absent. This study was conducted to identify the genetic defect underlying this hitherto unknown autosomal recessive cone-rod dysfunction.
  
  
  METHODS
  Genome-wide linkage analysis and screening of positional candidate genes were used to identify the causative mutation. Tissue-specific transcriptional activity of the defective gene was determined by Northern blot analysis and RT-PCR approaches. The number of cone photoreceptors was estimated by immunohistochemistry.
  
  
  RESULTS
  The mutation was localized to a 275-kb region of chromosome 6. Within this candidate interval, a homozygous frameshift mutation (c.2367insC) was identified in the Cacna2d4 gene of affected animals. This gene codes for an L-type calcium channel auxiliary subunit of the alpha2delta type. The mutation introduces a premature stop codon that truncates one third of the predicted Cacna2d4 protein. A severe reduction in Cacna2d4 transcript levels observed in mutant retinas probably results in the lack of Cacna2d4 protein. The mutation leads to significant loss of rods, whereas the number of cone cells remains unaffected until 6 weeks of age.
  
  
  CONCLUSIONS
  The Cacna2d4 mutation underlies a novel channelopathy leading to cone-rod dysfunction in the visual system of mice and provides a new candidate gene for human retinal disorders including night blindness, retinitis pigmentosa, and cone-rod dystrophies.
authors.affiliation: Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland.
authors.forename: Katharina A
authors.initials: KA
authors.lastname: Wycisk
authors.forename: Birgit
authors.initials: B
authors.lastname: Budde
authors.forename: Silke
authors.initials: S
authors.lastname: Feil
authors.forename: Sergej
authors.initials: S
authors.lastname: Skosyrski
authors.forename: Francesca
authors.initials: F
authors.lastname: Buzzi
authors.forename: John
authors.initials: J
authors.lastname: Neidhardt
authors.forename: Esther
authors.initials: E
authors.lastname: Glaus
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Klaus
authors.initials: K
authors.lastname: Ruether
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Berger
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D020746:Calcium Channels, L-Type / Q000235:genetics*; D004252:DNA Mutational Analysis; D004596:Electroretinography; D016368:Frameshift Mutation; D008040:Genetic Linkage; D005838:Genotype; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D012160:Retina / Q000503:physiopathology*; D012162:Retinal Degeneration / Q000235:genetics* / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission
chemical_list: C512890:Cacna2d4 protein, mouse; D020746:Calcium Channels, L-Type; D012333:RNA, Messenger