Molecular genetics of type 1 glycogen storage diseases

Glycogen storage disease type 1 (GSD-1), also known as von Gierke disease, is caused by a deficiency in the activity of the enzyme glucose-6-phosphata se (G6Pase). It is an autosomal recessive disorder characterized by hypogly cemia, hepatomegaly, kidney enlargement growth retardation, lactic acidemia , hyperlipidemia and hyperuricemia. The disease presents with both clinical and biochemical heterogeneity consistent with the existence of two major s ubgroups, GSD-1a and GSD-1b, which have been confirmed at the molecular gen etic level. GSD-1a, the most prevalent form, is caused by mutations in the G6Pase gene that abolish or greatly reduce enzymatic activity. The gene map s to chromosome 17q21 and encodes a microsomal transmembrane protein. Anima l models of GSD-1a exist and are being exploited to delineate the disease m ore precisely. It has been proposed that GSD-1b is caused by a defect in th e microsomal glucose-6-phosphate transporter. The gene responsible for GSD- 1b has been mapped to chromosome 11q23 and a cDNA encoding a microsomal tra nsmembrane protein has been identified. The function of this putative GSD-1 b protein remains to be determined. These recent developments, along with n ewly characterized animal models of GSD-1a, ave increasing our understandin g of the interrelationship between the components of the G6Pase complex and type 1 glycogen storage diseases.