RFLPS FOR LINKAGE ANALYSIS IN FAMILIES WITH GLYCOGEN-STORAGE-DISEASE TYPE-III

Human glycogen debranching enzyme (DE) is a 160 kDa protein with a polypeptide chain that contains two independent catalytic sites, both required for activity. Glycogen storage disease type III (GSD III, McKusick 232400), is an inborn error of glycogen metabolism due to a deficiency of glycogen debranching enzyme activity. The clinical features of GSD III are variable, in part owing to differences in tissue expression of the defective enzyme. Thus, three major subtypes have been identified with different clinical phenotypes: GSD IIIa patients (78%) lack DE activity in both liver and muscle, GSD IIIb patients (15%) lack DE activity in liver but have normal activity in muscle, and GSD IIId patients (7%) lack only the transferase activity but have normal quantities of immunoreactive material in both tissues (Hers et al 1989). The gene coding for human debranching enzyme has been cloned and the nucleotide sequence has been determined (Yang et al 1992a). The debrancher mRNA comprises a 4545 base pair coding region and a 2371 base pair 3' nontranslated region. The muscle and liver isoforms are generated via differential RNA transcription, with an alternative first exon usage, from a single debrancher gene (Yang et al 1992b). The gene comprises 35 exons, which span at least 78 kb of DNA (Bao et al 1993). The gene has been localized to chromosome 1 at band p21 (Yang-Feng et al 1992). The prevalence of GSD III among North-African Jews appears to be unusually high (1:5400). All North-African patients with GSD III that are being followed in our institution suffer from both hypoglycaemia and myopathy, suggesting that they are all of the GSD IIIa subtype (Moses et al 1973, 1986). This study presents the initial attempt to characterize the mutations causing GSD III in the Israeli population, mainly that of North-African extraction.