title: Molecular mechanism underlying a Cx50-linked congenital cataract.
abstract: Mutations in gap junctional channels have been linked to certain forms of inherited congenital cataract (D. Mackay, A. Ionides, V. Berry, A. Moore, S. Bhattacharya, and A. Shiels. Am. J. Hum. Genet. 60: 1474-1478, 1997; A. Shiels, D. Mackay, A. Ionides, V. Berry, A. Moore, and S. Bhattacharya. Am. J. Hum. Genet. 62: 526-532, 1998). We used the Xenopus oocyte pair system to investigate the functional properties of a missense mutation in the human connexin 50 gene (P88S) associated with zonular pulverulent cataract. The associated phenotype for the mutation is transmitted in an autosomal dominant fashion. Xenopus oocytes injected with wild-type connexin 50 cRNA developed gap junctional conductances of approximately 5 microS 4-7 h after pairing. In contrast, the P88S mutant connexin failed to form functional gap junctional channels when paired homotypically. Moreover, the P88S mutant functioned in a dominant negative manner as an inhibitor of human connexin 50 gap junctional channels when coinjected with wild-type connexin 50 cRNA. Cells injected with 1:5 and 1:11 ratios of P88S mutant to wild-type cRNA exhibited gap junctional coupling of approximately 8% and 39% of wild-type coupling, respectively. Based on these findings, we conclude that only one P88S mutant subunit is necessary per gap junctional channel to abolish channel function.
authors.affiliation: Department of Physiology and Biophysics, Finch University of Health Sciences/The Chicago Medical School, North Chicago, IL 60064, USA. jdp80134@mis.finchcms.edu
authors.forename: J D
authors.initials: JD
authors.lastname: Pal
authors.forename: V M
authors.initials: VM
authors.lastname: Berthoud
authors.forename: E C
authors.initials: EC
authors.lastname: Beyer
authors.forename: D
authors.initials: D
authors.lastname: Mackay
authors.forename: A
authors.initials: A
authors.lastname: Shiels
authors.forename: L
authors.initials: L
authors.lastname: Ebihara
mesh_terms: D000818:Animals; D002386:Cataract / Q000151:congenital* / Q000235:genetics*; D017630:Connexins; D004553:Electric Conductivity; D004594:Electrophysiology; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism; D005799:Genes, Dominant; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D007267:Injections; D015640:Ion Channel Gating / Q000502:physiology; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D020125:Mutation, Missense / Q000502:physiology; D009865:Oocytes / Q000378:metabolism; D010641:Phenotype; D018075:RNA, Complementary / Q000235:genetics / Q000494:pharmacology; D012016:Reference Values; D014981:Xenopus; D000099264:Connexin 50
chemical_list: D017630:Connexins; D005136:Eye Proteins; D007473:Ion Channels; D018075:RNA, Complementary; D000099264:Connexin 50