Mutations in the lysosomal [beta]-galactosidase gene that cause the adult form of GMI gangliosidosis
- Thomas Jefferson Univ., Philadelphia, PA (United States)
Three adult patients with acid-galactosidase deficiency/GM1 gangliosidosis who were from two unrelated families of Scandinavian descent were found to share a common point mutation in the coding region of the corresponding gene. The patients share common clinical features, including early dysarthria, mild ataxia, and bone abnormalities. When cDNA from the two patients in family 1 was PCR amplified and sequenced, most (39/41) of the clones showed a C-to-T transition (C[yields]T) at nucleotide 245 (counting from the initiation codon). This mutation changes the codon for the Thr(ACG) to Met(ATG). Mutant and normal sequences were also found in that position in genomic DNA, indicating the presence of another mutant allele. Genomic DNA from the patient in family 2 revealed the same point mutation in one allele. It was determined that in each family only the father carried the C[yields]T mutation. Expression studies showed that this mutation produced 3%-4% of [beta]-galactosidase activity, confirming its deleterious effects. The cDNA clones from the patients in family 1 that did not contain the C[yields]T revealed a 20-bp insertion of intronic sequence between nucleotides 75 and 76, the location of the first intron. Further analysis showed the insertion of a T near the 5[prime] splice donor site which led to the use of a cryptic splice site. It appears that the C[yields]T mutation results in enough functional enzyme to produce a mild adult form of the disease, even in the presence of a second mutation that likely produces nonfunctional enzyme. 31 refs., 7 figs., 1 tab.
- OSTI ID:
- 7199566
- Journal Information:
- American Journal of Human Genetics; (United States), Vol. 54:6; ISSN 0002-9297
- Country of Publication:
- United States
- Language:
- English
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GALACTOSIDASE
GENE MUTATIONS
GANGLIOSIDES
METABOLIC DISEASES
DNA SEQUENCING
POLYMERASE CHAIN REACTION
CARBOHYDRATES
DISEASES
ENZYMES
GENE AMPLIFICATION
GLYCOLIPIDS
GLYCOSYL HYDROLASES
HYDROLASES
LIPIDS
MUTATIONS
O-GLYCOSYL HYDROLASES
ORGANIC COMPOUNDS
PROTEINS
SACCHARIDES
STRUCTURAL CHEMICAL ANALYSIS
550400* - Genetics
550900 - Pathology