Microphthalmia and cataract in rats with a novel point mutation in connexin 50 - L7Q.
OBJECTIVE
We isolated an autosomal semi-dominant cataract from our inbred SHR/OlaIpcv rat colony. Heterozygotes express pulverulent cataract with smaller eyes; homozygotes express marked microphthalmia with hypoplastic lens. We call this mutation Dca (for dominant cataract). In this study, we focus on the identification of the responsible gene.


METHODS
We performed linkage mapping using 93 F2(SHR-Dca x PD) hybrids and a panel of microsatellite markers. In a separate group of animals with a SHR genetic background, we examined the lenses histologically using Epon semi-thin sections and toluidine blue staining. We also assessed the weight of the eyes as an immediate measure for microphthalmia.


RESULTS
We mapped the Dca gene to chromosome 2, spanning 8.6 Mbp between markers D2Rat134 and D2Rat186. By sequencing the most plausible candidate gene, Gja8 (coding for connexin 50), we found a T to A transversion at codon 7, leading to a substitution of glutamine for leucin (L7Q). L7Q lies within the NH(2)-terminal cytosolic domain, presumably involved in voltage gating. Histology revealed disturbances in cell to cell contacts in the lens.


CONCLUSIONS
L7Q is a novel mutation in connexin 50 (Gja8), causing semi-dominant pulverulent cataracts. Dca rats can serve as a model for cataract development. A study on the properties of the mutant protein may offer an insight into the connexin channel function.
Liska
Frantisek
F
Institute of Biology and Medical Genetics of the 1st Faculty of Medicine and General Teaching Hospital, Charles University in Prague, Prague, Czech Republic. frantisek.liska@lf1.cuni.cz
Chylíková
Blanka
B
Martínek
Jindrich
J
Kren
Vladimír
V
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002386:Cataract / Q000235:genetics* / Q000473:pathology; D002874:Chromosome Mapping; D017630:Connexins / Q000737:chemistry / Q000235:genetics*; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics*; D005973:Glutamine / Q000235:genetics*; D040582:Inheritance Patterns / Q000235:genetics; D007908:Lens, Crystalline / Q000473:pathology; D008239:Lysine / Q000235:genetics*; D008850:Microphthalmos / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics*; D051381:Rats; D000099264:Connexin 50
D017630:Connexins; D005136:Eye Proteins; D005973:Glutamine; D008239:Lysine; D000099264:Connexin 50