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Genetic Heterogeneity in Microcornea-Cataract: Five Novel Mutations in CRYAA, CRYGD, and GJA8

¹From the Wilhelm Johannsen Centre for Functional Genome Research and ²Department G, Institute of Medical Biochemistry and Genetics, and Panum Institute, University of Copenhagen, Copenhagen, Denmark; the ³Section on Ophthalmic Molecular Genetics, Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland; the ⁴Department of Ophthalmology, Aalborg University Hospital, Denmark; and the ⁵Gordon Norrie Centre for Genetic Eye Diseases, Kennedy Institute–National Eye Clinic, Hellerup, Denmark.

PURPOSE. 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, -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 8 (GJA8), and one mutation (Y134X) was detected in crystallin -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.