g(m2)-ganglioside and Muscular-Atrophy--Spinal

Topics: beta-N-Acetylhexosaminidases; G(M2) Ganglioside; Genes, Recessive; Hexosaminidase A; Humans; Muscular Atrophy, Spinal; Mutation; Prognosis; Tay-Sachs Disease

Progressive proximal muscle weakness is present both in spinal muscular atrophy (SMA) type III (Kugelberg-Welander disease) and in GM2 gangliosidosis, diseases that segregate in an autosomal recessive fashion. The SMN gene for SMA and the HEXA gene for GM2 gangliosidosis were investigated in a woman with progressive proximal muscle weakness, long believed to be SMA type III (Kugelberg-Welander type). She and her family underwent biochemical studies for GM2 gangliosidosis. Analysis of SMN excluded SMA. Biochemical studies on GM2 gangliosidosis showed deficiency in hexosaminidase A activity and increased GM2 ganglioside accumulation in the patient's fibroblasts. The HEXA gene was first analyzed for the Gly269-->Ser mutation characteristic for adult GM2 gangliosidosis. Since the patient was carrying the adult mutation heterozygously, all 14 exons and adjacent intron sequences were analyzed. A novel mutation in exon 1 resulting in an A-to-T change in the initiation codon (ATG to TTG) was identified. The adult patient is a compound heterozygote, with each allele containing a different mutation. Although mRNA was transcribed from the novel mutant allele, expression experiments showed no enzyme activity, suggesting that neither the TTG nor an alternative codon serve as an initiation codon in the HEXA gene.

Topics: Adult; Base Sequence; beta-N-Acetylhexosaminidases; DNA, Complementary; Female; Fibroblasts; G(M2) Ganglioside; Gene Amplification; Hexosaminidase A; Humans; Leukocytes; Muscular Atrophy, Spinal; Pedigree; Point Mutation; RNA, Messenger

The GM2 activator locus (GM2A) had previously been considered as a candidate gene for some forms of spinal muscular atrophy (SMA; mapped to 5q11.2-q13.3). It was eliminated as a possible candidate because PCR-based mapping failed to localize the gene to chromosome 5, as was previously reported using an ELISA-based methodology. However, we demonstrated that the PCR primers used preferentially amplified a processed pseudogene (GM2AP) that we mapped to chromosome 3 and that GM2A was located on chromosome 5. In this report, we reconsider the candidacy of GM2A by refining its localization on chromosome 5 using fluorescence in situ hybridization. We localize GM2A to 5q31.3-q33.1; thus, it is not a candidate gene for SMA.

Topics: Cells, Cultured; Chromosome Mapping; Chromosomes, Human, Pair 5; DNA Primers; G(M2) Activator Protein; G(M2) Ganglioside; Humans; In Situ Hybridization, Fluorescence; Muscular Atrophy, Spinal; Polymerase Chain Reaction; Proteins; Pseudogenes