Glucose-6-phosphatase mutation G188R confers an atypical glycogen storage disease type 1b phenotype

Glycogen storage disease type la (GSD la) is caused by a deficiency in micr osomal glucose-6-phosphatase (G6Pase). A variant (GSD Ib) is caused by a de fect in the transport of glucose-6-phosphate (G6P) into the microsome and i s associated with chronic neutropenia and neutrophil dysfunction. Mutually exclusive mutations in the G6Pase gene and the G6P transport gene establish GSD la and GSD Ib as independent molecular processes and are consistent wi th a multicomponent translocase catalytic model. A modified translocase/cat alytic unit model based on biochemical data in a G6Pase knockout mouse has also been proposed for G6Pase catalysis, This model suggests coupling of G6 Pase activity and G6P transport. A 5-mo-old girl with hypoglycemia, hepatom egaly, and lactic acidemia was diagnosed with GSD la. She also developed ne utropenia, neutrophil dysfunction, and recurrent infections characteristic of GSD Ib. Homozygous G188R mutations of the G6Pase gene were identified, b ut no mutations in the G6P translocase gene were found. We have subsequentl y identified a sibling and two unrelated patients with similar genotypic/ph enotypic characteristics. The unusual association of neutrophil abnormaliti es in patients with homozygous G188R mutations in the G6Pase gene supports a modified translocase/catalytic unit model.