FAMILIAL GLUCOSE GALACTOSE MALABSORPTION

葡萄糖-半乳糖吸收不良（GGM）的特征是

Glucose-Galactose Malabsorption (GGM) is characterized by a neonatal onset of a several diarrhea that results in death unless the offending sugars are removed from the diet. It is caused by a defect in the brush border Na/glucose cotransporter (SGLT1). We have identified the transporter, cloned and mapped the gene, and found the mutations responsible for the disease in 33 patients. The goal now is to understand the molecular and cell biology of GGM. We plan to: continue screening new patients for mutations; determine how the mutations cause the malabsorption; devise new therapies to treat patients; and resolve whether or not carriers of GGM mutations have impaired glucose absorption. New patients will be screened using genomic DNA, PCR-amplification of exons, single strand conformational polymorphism (SSCP) gels, and sequencing. 90 percent of the mutations are in the gene coding region and result in the production of mutant and truncated proteins. Our hypothesis is that the truncated proteins are defective and that mutant proteins are not inserted into the plasma membrane. We will test this hypothesis by expressing mutants in Xenopus laevis oocytes an using electrophysiological, immunological, biochemical and microscopic techniques. Once the reason for impaired sugar transport is determined in the model expression system, we will test this in biopsy samples from the patients. In those cases where mutations cause a defect in trafficking SGLT1 protein between the endoplasmic reticulum and the plasma membrane, we will devise strategies to increase the delivery of SGLT1 to the plasma membrane. Finally, in kindreds where we have identified GGM mutations, we will screen family members for heterozygotes and normal homozygotes. Sugar absorption will be measured using H-breath tests to determine if carriers exhibit any symptoms of malabsorption. This study will enable us to identify and treat patients with sugar malabsorption due to mutations in the SGLT1 gene, and will provide unique information about the synthesis, trafficking and function of the cotransporter.