The proposed research is aimed at a better understanding of three human hereditary metabolic myopathies: 1. Acid maltase deficiency (AMD). In preliminary studies we found that incubation of AMD muscle homogenates with a preparation from rabbit gastric mucosa enriched in glycosyltransferases resulted in correction of the enzyme defect, suggesting that AMD may be due to impaired glycosylation of the lysosomal hydrolase, a glycoprotein. We also found that treatment of normal or AMD tissue extracts with neuraminidase causes the appearance of a maltase isoenzyme normally present only in kidney. Our research plans include: a) to seek direct evidence of glycosylation of the newly formed enzyme; b) if glycosylation of acid maltase can be demonstrated, to measure glycosyltransferases in AMD tissues; c) to study the effect of neuraminidase on the electropurified human placental acid maltase. 2. Carnitine palmityltransferase (CPT) deficiency, and 3. Adenylate deaminase (AMPD) deficiency: In these diseases, one of which (CPT deficiency) was first described in our laboratory, the molecular basis of the enzyme defect is obscure. We propose: a) to purify and characterize the enzymes from normal human muscle, b) to obtain antibodies, c) to determine by immunological assays if inactive enzyme protein is present in muscle of patients, d) in CPT deficiency, to investigate the nature of residual activity, e) to study the expression of the enzyme defect in other accessible tissues (leukocytes; fibroblast and muscle cultures), f) to establish the mode of transmission by studying muscle biopsies of affected and non-affected relatives.
| Den, H; Shanske, S; DiMauro, S (1986) Targeting of lysosomal enzymes: N-acetylglucosamine-1-phosphotransferase during muscle development. Muscle Nerve 9:261-4 |
