title: An MIP/AQP0 mutation with impaired trafficking and function underlies an autosomal dominant congenital lamellar cataract.
abstract: Autosomal dominant congenital cataracts have been associated with mutations of genes encoding several soluble and membrane proteins. By candidate gene screening, we identified a novel mutation in MIP (c.494 G > A) that segregates with a congenital lamellar cataract within a south Indian family and causes the replacement of a highly conserved glycine by aspartate (G165D) within aquaporin0 (AQP0). Unlike wild type AQP0, expression of AQP0-G165D in Xenopus oocytes did not facilitate swelling in hypotonic medium. In transfected HeLa cells, wild type AQP0 localized at the plasma membrane while AQP0-G165D was retained within the secretory pathway, and localized mainly within the endoplasmic reticulum. These results suggest that mutation of this conserved glycine residue leads to improper trafficking of AQP0-G165D and loss of water channel function. They emphasize the importance of AQP0 for maintenance of lens transparency and identify a critical residue that is conserved among aquaporins, but has not previously been associated with disease-associated replacement.
authors.affiliation: Department of Genetics, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Chennai, India.
authors.forename: G
authors.initials: G
authors.lastname: Senthil Kumar
authors.forename: John W
authors.initials: JW
authors.lastname: Kyle
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Minogue
authors.forename: K
authors.initials: K
authors.lastname: Dinesh Kumar
authors.forename: K
authors.initials: K
authors.lastname: Vasantha
authors.forename: Viviana M
authors.initials: VM
authors.lastname: Berthoud
authors.forename: Eric C
authors.initials: EC
authors.lastname: Beyer
authors.forename: S T
authors.initials: ST
authors.lastname: Santhiya
mesh_terms: D000818:Animals; D020346:Aquaporins / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D001834:Body Water / Q000378:metabolism; D002386:Cataract / Q000151:congenital* / Q000235:genetics* / Q000378:metabolism; D002387:Cataract Extraction; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000502:physiology; D005799:Genes, Dominant; D006801:Humans; D007223:Infant; D019654:Lens Implantation, Intraocular; D007908:Lens, Crystalline / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D020125:Mutation, Missense; D009865:Oocytes / Q000378:metabolism; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D021381:Protein Transport / Q000235:genetics; D014162:Transfection; D014982:Xenopus laevis
chemical_list: D020346:Aquaporins; D005136:Eye Proteins; C030328:aquaporin 0