title: Genetic heterogeneity in microcornea-cataract: five novel mutations in CRYAA, CRYGD, and GJA8.
abstract: OBJECTIVE
  To unravel the molecular genetic background in families with congenital cataract in association with microcornea (CCMC, OMIM 116150).
  
  
  METHODS
  CCMC families were recruited from a national database on hereditary eye diseases; DNA was procured from a national gene bank on hereditary eye diseases and by blood sampling from one large family. Genomewide linkage analysis, fine mapping, and direct genomic DNA sequencing of nine cataract candidate genes were applied. Restriction enzyme digests confirmed identified mutations.
  
  
  RESULTS
  Analyses of 10 Danish families with hereditary congenital cataract and microcornea revealed five novel mutations. Three of these affected the crystallin, alpha-A gene (CRYAA), including two mutations (R12C and R21W) in the crystallin domain and one mutation (R116H) in the small heat shock domain. One mutation (P189L) affected the gap junction protein alpha 8 (GJA8), and one mutation (Y134X) was detected in crystallin gamma-D (CRYGD).
  
  
  CONCLUSIONS
  The identification of a CRYGD mutation adds another gene to those that may be mutated in CCMC and underscores the genetic heterogeneity of this condition. Three CRYAA mutations at the R116 position, in association with CCMC, suggest that R116 represents a CCMC-mutational hotspot. The CCMC phenotype demonstrates variable expression with regard to cataract morphology and age of appearance. Clinical heterogeneity, including additional malformation of the anterior segment of the eye, confirm that dedicated cataract genes may be involved in the largely unknown developmental molecular mechanisms involved in lens-anterior segment interactions.
authors.affiliation: Wilhelm Johannsen Centre for Functional Genome Research, Department G, Institute of Medical Biochemistry and Genetics, Panum Institute, University of Copenhagen, Copenhagen, Denmark. larsh@imbg.ku.dk
authors.forename: Lars
authors.initials: L
authors.lastname: Hansen
authors.forename: Wenliang
authors.initials: W
authors.lastname: Yao
authors.forename: Hans
authors.initials: H
authors.lastname: Eiberg
authors.forename: Klaus Wilbrandt
authors.initials: KW
authors.lastname: Kjaer
authors.forename: Kirsten
authors.initials: K
authors.lastname: Baggesen
authors.forename: J Fielding
authors.initials: JF
authors.lastname: Hejtmancik
authors.forename: Thomas
authors.initials: T
authors.lastname: Rosenberg
mesh_terms: D000595:Amino Acid Sequence; D002386:Cataract / Q000151:congenital / Q000235:genetics*; D002874:Chromosome Mapping; D017630:Connexins / Q000235:genetics*; D003315:Cornea / Q000002:abnormalities*; D003459:Crystallins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005124:Eye Abnormalities / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D018740:Genetic Heterogeneity; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D038222:gamma-Crystallins; D000099264:Connexin 50
chemical_list: D017630:Connexins; D003459:Crystallins; D005136:Eye Proteins; D038222:gamma-Crystallins; D000099264:Connexin 50; C511246:CRYAA protein, human; C504903:CRYGD protein, human