Genetic heterogeneity in microcornea-cataract: five novel mutations in CRYAA, CRYGD, and GJA8.

Abstract

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, 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: Lars Hansen, Wenliang Yao, Hans Eiberg, Klaus Wilbrandt Kjaer, Kirsten Baggesen, J Fielding Hejtmancik, Thomas Rosenberg
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 48 Issue 9 Pg. 3937-44 (Sep 2007) ISSN: 0146-0404 [Print] United States
• PMID: 17724170 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CRYAA protein, human
• CRYGD protein, human
• Connexins
• Crystallins
• Eye Proteins
• connexin 50
• gamma-Crystallins

Topics

• Amino Acid Sequence
• Cataract (congenital, genetics)
• Chromosome Mapping
• Connexins (genetics)
• Cornea (abnormalities)
• Crystallins (genetics)
• DNA Mutational Analysis
• Eye Abnormalities (genetics)
• Eye Proteins (genetics)
• Female
• Genes, Dominant
• Genetic Heterogeneity
• Humans
• Male
• Molecular Sequence Data
• Mutation
• Pedigree
• Phenotype
• Polymerase Chain Reaction
• Sequence Analysis, DNA
• gamma-Crystallins