Phenotype determining alleles in GM1 gangliosidosis patients bearing novel GLB1 mutations.

[gm1 gangliosidosis]

GM 1 gangliosidosis manifests with progressive psychomotor deterioration and dysostosis of infantile , juvenile , or adult onset , caused by alterations in the structural gene coding for lysosomal acid beta -galactosidase (GLB 1 ). In addition , allelic variants of this gene can result in Morquio B disease (MBD ), a phenotype with dysostosis multiplex and entire lack of neurologic involvement . More than 100 sequence alterations in the GLB 1 gene have been identified so far , but only few could be proven to be predictive for one of the GM 1 gangliosidosis subtypes or MBD . We performed genotype analyses in 16 GM 1 gangliosidosis patients of all phenotypes and detected 28 different genetic lesions . Among these , p .I 55 FfsX 16 , p .W 65 X , p .F 10 7 L , p .H 112 P , p .C 127 Y , p .W 161 X , p .I 181 K , p .C 2 30 R , p .W 273 X , p .R 299 VfsX 5 , p .A 301 V , p .F 3 57 L , p .K 359 KfsX 23 , p .L 389 P , p .D 448 V , p .D 448 GfsX 8 , and the intronic mutation IVS 6 -8 A >G have not been published so far . Due to their occurrence in homozygous patients , four mutations could be correlated to a distinct GM 1 gangliosidosis phenotype . Furthermore , the missense mutations from heteroallelic patients and three artificial nonsense mutations were characterized by overexpression in COS -1 cells , and the subcellular localization of the mutant proteins in fibroblasts was assessed . The phenotype specificity of 10 alleles can be proposed on the basis of our results and previous data .