Mutations of the EPHA2 receptor tyrosine kinase gene cause autosomal dominant congenital cataract.
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.
Zhang
Tianxiao
T
Department of Ophthalmology, China Medical University, Shenyang, China.
Hua
Rui
R
Xiao
Wei
W
Burdon
Kathryn P
KP
Bhattacharya
Shomi S
SS
Craig
Jamie E
JE
Shang
Dandan
D
Zhao
Xiuli
X
Mackey
David A
DA
Moore
Anthony T
AT
Luo
Yang
Y
Zhang
Jinsong
J
Zhang
Xue
X
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
D012333:RNA, Messenger; D036104:Receptor, EphA2