Molecular basis of glycogen storage disease type 1.

摘要

In 1929, von Gierke reported, postmortem, a marked increase in the size of the livers of two young patients who had suffered frequent nosebleeds and other disabling symptoms. Enlargement of the livers and the kidneys of these two patients was shown to be due in large part to excessive deposits of glycogen. This defect was termed von Gierke disease and later glycogen storage disease type 1 (GSD1). GSD1 is a group of autosomal recessive disorders. These metabolic diseases typically manifest during the first year of life with severe hypoglycemia, hepatomegaly, hyperlipidemia, hyperuricemia and lactic acidemia. Cori and Cori (1952) showed that GSD1 is caused by the absence of glucose-6-phosphatase (G6PC) activity and Arion et al (1980) showed that the hydrolysis of glucose-6phosphate (G6P) requires the participation of translocases, and that genetic, deficiency of a translocase could cause GSD1. In addition, Arion et al (1980) proposed that the enzyme utilizes one transport system (G6PT1) to translocate G6P from the cytosol to the lumen of the ER and two transport systems to transport the reaction products, phosphate and glucose (G6PT2 and G6PT3, respectively), back to the cytoplasm and the intercellular milieu. Patients who are deficient in G6PC are diagnosed to have GSD1a; patients who are deficient in G6PT1 are diagnosed to have GSD1b; and patients who are deficient in G6PT2 are diagnosed to have GSD1c.;Despite the importance of the G6PC system in both clinical medicine and basic biochemistry, virtually nothing was known until recently about the molecular basis of GSD1. In this project, I have found that the mutation, 727G→T of the G6PC gene, is the common mutation causing GSD1a, and G149E of the G6PT1 gene is the common mutation causing GSD1b, in the Hong Kong Chinese population. These findings support the translocase-catalytic model of G6P hydrolysis. The finding of G6PT1 gene mutations in GSD1c patients suggests that most of these patients have been misdiagnosed previously. I have identified a novel single nucleotide polymorphism (SNP), 1176C, in the 3' untranslational region of the G6PC gene. With this SNP, I have shown that there is a common founder shared by both Chinese and Japanese GSD1a patients. This SNP will also be useful for carrier detection and prenatal diagnosis of GSD1a families where mutations cannot be identified in both mutant alleles. Finally, I have reported the first prenatal diagnosis of GSD1b using denaturing high-performance liquid chromatography. This new technique allows us to make a firm diagnosis of fetal GSD1b 14 minutes after PCR products were available for analysis. We can now provide prenatal diagnosis and carrier detection, and non-invasive definitive diagnosis of GSD1 families.