Identification of mutations in Type IV glycogen storage disease
- Duke Univ. Medical Center, Durham, NC (United States); and others
Type IV glycogen storage disease (GSD IV, Andersen disease) is caused by a deficiency of glycogen branching enzyme (GBE) activity, which results in the accumulation of glycogen with unbranched, long, outer chains in the tissues. The molecular basis of the disease is not known. We studied four patients with the disease; three with typical presentation of progressive liver cirrhosis and failure, and one with severe and fatal neonatal hypotonia and cardiomyopathy. Southern blot analysis with EcoRI or MspI did not detect gross DNA rearrangement, deletion or duplication in patients` glycogen branching enzyme genes. Northern analysis with total cellular RNAs isolated from skin fibroblast MI strains of three patients with typical clinical presentation showed a normal level and size (2.95 kb) of GBE mRNA hybridization band in two and absent mRNA hybridization band in the remaining one. The patient with atypical severe neonatal hypotonia demonstrated a less intense and smaller size (2.75 kb) of mRNA hybridization band. A 210 hp deletion from nucleotide sequence 873 to 1082 which causes 70 amino acids missing from amino acid sequence 262 to 331 was detected in all 17 clones sequenced from the fatal hypotonia patient. This deletion is located in the region which is highly conserved between prokaryotic, yeast and human GBE polypeptide sequences, and also includes the first of the four regions which constitute the catalytic active sites of most of amylolytic enzymes. A point mutation C-T (1633) which changes the amino acid from Arginine to Cystine was found in 19 of 20 cDNA clones from a patient with classical clinical presentation. This point mutation was unique to this patient and was not observed in three other patients or normal controls. This is the first report on the molecular basis of GSD IV and our data indicated the presence of extensive genetic heterogeneity in the disease.
- OSTI ID:
- 133281
- Report Number(s):
- CONF-941009-; ISSN 0002-9297; TRN: 95:005313-0008
- Journal Information:
- American Journal of Human Genetics, Vol. 55, Issue Suppl.3; Conference: 44. annual meeting of the American Society of Human Genetics, Montreal (Canada), 18-22 Oct 1994; Other Information: PBD: Sep 1994
- Country of Publication:
- United States
- Language:
- English
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