title: Mutation analysis identifies GUCY2D as the major gene responsible for autosomal dominant progressive cone degeneration.
abstract: OBJECTIVE
  Heterozygous mutations in the GUCY2D gene, which encodes the membrane-bound retinal guanylyl cyclase-1 protein (RetGC-1), have been shown to cause autosomal dominant inherited cone degeneration and cone-rod degeneration (adCD, adCRD). The present study was a comprehensive screening of the GUCY2D gene in 27 adCD and adCRD unrelated families of these rare disorders.
  
  
  METHODS
  Mutation analysis was performed by direct sequencing as well as PCR and subsequent restriction length polymorphism analysis (PCR/RFLP). Haplotype analysis was performed in selected patients by using microsatellite markers.
  
  
  RESULTS
  GUCY2D gene mutations were identified in 11 (40%) of 27 patients, and all mutations clustered to codon 838, including two known and one novel missense mutation: p.R838C, p.R838H, and p.R838G. Haplotype analysis showed that among the studied patients only two of the six analyzed p.R838C mutation carriers shared a common haplotype and that none of the p.R838H mutation carriers did.
  
  
  CONCLUSIONS
  GUCY2D is a major gene responsible for progressive autosomal dominant cone degeneration. All identified mutations localize to codon 838. Haplotype analysis indicates that in most cases these mutations arise independently. Thus, codon 838 is likely to be a mutation hotspot in the GUCY2D gene.
authors.affiliation: Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University Tübingen, Tübingen, Germany.
authors.forename: Veronique B D
authors.initials: VB
authors.lastname: Kitiratschky
authors.forename: Robert
authors.initials: R
authors.lastname: Wilke
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Renner
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kellner
authors.forename: Maria
authors.initials: M
authors.lastname: Vadalà
authors.forename: David G
authors.initials: DG
authors.lastname: Birch
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
authors.forename: Eberhart
authors.initials: E
authors.lastname: Zrenner
authors.forename: Susanne
authors.initials: S
authors.lastname: Kohl
mesh_terms: D003062:Codon; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D004596:Electroretinography; D005260:Female; D020022:Genetic Predisposition to Disease; D006162:Guanylate Cyclase / Q000235:genetics* / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012374:Rod Cell Outer Segment / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
chemical_list: D003062:Codon; D011956:Receptors, Cell Surface; C110715:guanylate cyclase 1; D004247:DNA; D006162:Guanylate Cyclase