title: Mutations of the EPHA2 receptor tyrosine kinase gene cause autosomal dominant congenital cataract.
abstract: Congenital cataracts (CCs) are clinically and genetically heterogeneous. Mutations in the same gene may lead to CCs differing in inheritance, morphology and severity. Loci for autosomal dominant posterior polar CC and total CC have both been mapped to the chromosomal 1p36 region harboring the EPHA2 receptor tyrosine kinase gene. Here, we report mutations of EPHA2 in three CC families from different ancestral groups. In a Chinese family with posterior polar CC, we identified a missense mutation, c.2819C>T (p.T940I), replacing a critical amino acid that functions at the receptor oligomerization interface. In a British family with posterior polar CC and an Australian family with total CC, we found a frameshift mutation (c.2915_2916delTG) and a splicing mutation (c.2826-9G>A), respectively. These two mutations are predicted to produce novel C-terminal polypeptides with 39 identical amino acids. Yeast two-hybrid analysis showed stronger interaction between the total CC-associated mutant EPHA2 and low molecular weight protein-tyrosine phosphatase, a negative regulator of EPHA2 signaling. Our results implicate the Eph-ephrin signaling system in development of human cataract and provide a novel insight into the molecular mechanism underlying the pathogenesis of human CCs.
authors.affiliation: Department of Ophthalmology, China Medical University, Shenyang, China.
authors.forename: Tianxiao
authors.initials: T
authors.lastname: Zhang
authors.forename: Rui
authors.initials: R
authors.lastname: Hua
authors.forename: Wei
authors.initials: W
authors.lastname: Xiao
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Burdon
authors.forename: Shomi S
authors.initials: SS
authors.lastname: Bhattacharya
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Craig
authors.forename: Dandan
authors.initials: D
authors.lastname: Shang
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhao
authors.forename: David A
authors.initials: DA
authors.lastname: Mackey
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.forename: Yang
authors.initials: Y
authors.lastname: Luo
authors.forename: Jinsong
authors.initials: J
authors.lastname: Zhang
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D002386:Cataract / Q000151:congenital* / Q000201:enzymology* / Q000235:genetics; D002681:China; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D005799:Genes, Dominant; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D012326:RNA Splicing / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D036104:Receptor, EphA2 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D020798:Two-Hybrid System Techniques
chemical_list: D012333:RNA, Messenger; D036104:Receptor, EphA2