title: alpha-Mannosidosis in the guinea pig: cloning of the lysosomal alpha-mannosidase cDNA and identification of a missense mutation causing alpha-mannosidosis.
abstract: alpha-Mannosidosis is a lysosomal storage disorder caused by deficient activity of the lysosomal alpha-mannosidase. We report here the sequencing and expression of the lysosomal alpha-mannosidase cDNA from normal and alpha-mannosidosis guinea pigs. The amino acid sequence of the guinea pig enzyme displayed 82-85% identity to the lysosomal alpha-mannosidase in other mammals. The cDNA of the alpha-mannosidosis guinea pig contained a missense mutation, 679C>T, leading to substitution of arginine by tryptophan at amino acid position 227 (R227W). The R227W allele segregated with the alpha-mannosidosis genotype in the guinea pig colony and introduction of R227W into the wild-type sequence eliminated the production of recombinant alpha-mannosidase activity in heterologous expression studies. Furthermore, the guinea pig mutation has been found in human patients. Our results strongly indicate that the 679C>T mutation causes alpha-mannosidosis and suggest that the guinea pig will be an excellent model for investigation of pathogenesis and evaluation of therapeutic strategies for human alpha-mannosidosis.
authors.affiliation: Department of Medical Genetics, University Hospital of Tromsø, Norway. thomasb@fagmed.uit.no
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.forename: John J
authors.initials: JJ
authors.lastname: Hopwood
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D019556:COS Cells / Q000378:metabolism; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000096:biosynthesis / Q000737:chemistry; D004195:Disease Models, Animal; D015316:Genetic Therapy; D006168:Guinea Pigs; D008361:Mannosidases / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D016415:Sequence Alignment; D013045:Species Specificity; D043323:alpha-Mannosidase; D008363:alpha-Mannosidosis / Q000201:enzymology / Q000235:genetics*
chemical_list: D018076:DNA, Complementary; D008361:Mannosidases; D043323:alpha-Mannosidase