Berg Thomas, Hopwood John J
Department of Medical Genetics, University Hospital of Tromsø, Norway.
Biochim Biophys Acta. 2002 Mar 16;1586(2):169-76. doi: 10.1016/s0925-4439(01)00081-3.
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.
α-甘露糖苷贮积症是一种由溶酶体α-甘露糖苷酶活性缺乏引起的溶酶体贮积病。我们在此报告正常和患α-甘露糖苷贮积症豚鼠的溶酶体α-甘露糖苷酶cDNA的测序及表达情况。豚鼠该酶的氨基酸序列与其他哺乳动物的溶酶体α-甘露糖苷酶有82 - 85%的同源性。患α-甘露糖苷贮积症豚鼠的cDNA含有一个错义突变679C>T，导致第227位氨基酸处的精氨酸被色氨酸取代（R227W）。在豚鼠群体中，R227W等位基因与α-甘露糖苷贮积症基因型共分离，并且在异源表达研究中，将R227W引入野生型序列会消除重组α-甘露糖苷酶活性的产生。此外，在人类患者中也发现了豚鼠的这种突变。我们的结果有力地表明679C>T突变导致了α-甘露糖苷贮积症，并提示豚鼠将成为研究人类α-甘露糖苷贮积症发病机制和评估治疗策略的优良模型。
