FAMILIAL GLUCOSE GALACTOSE MALABSORPTION

家族性葡萄糖半乳糖吸收不良

• 批准号: 6380708
• 负责人: ERNEST M WRIGHT
• 金额: $ 28.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6380708
• 关键词: Xenopus oocyte; breath tests; brush border membrane; carbohydrate transport; clinical research; endoplasmic reticulum; family genetics; galactose; gastrointestinal nutrient absorption; gene mutation; genetic disorder diagnosis; genetic mapping; glucose transport; glucose transporter; human subject; immunocytochemistry; inborn metabolism disorder; laboratory rabbit; malabsorption; membrane transport proteins; polymerase chain reaction; protein structure function; protein transport; single strand conformation polymorphism; transfection

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.

葡萄糖 - 半乳糖吸收不良（GGM）的特征是 除非 从饮食中除去违规糖。 它是由 刷子NA/葡萄糖共转运蛋白（SGLT1）中的缺陷。 我们 已经确定了转运蛋白，克隆并映射了基因，然后 发现33例患者中负责该疾病的突变。 现在的目标是了解 GGM。 我们计划：继续筛查新患者以进行突变； 确定突变如何引起吸收不良；设计新 治疗患者的疗法；并解决是否的运营商 GGM突变损害了葡萄糖的吸收。 新患者 将使用基因组DNA筛选，外显子的PCR扩增， 单链构象多态性（SSCP）凝胶和 测序。 90％的突变在基因编码中 区域并导致突变体和截断的产生 蛋白质。 我们的假设是截短的蛋白质是 有缺陷的突变蛋白未插入等离子体 膜。 我们将通过表达突变体中的突变体来检验 使用电生理学的Xenopus laevis卵母细胞 免疫学，生化和微观技术。 一旦 在模型中确定了糖运输受损的原因 表达系统，我们将在活检样本中测试 患者。 在突变导致缺陷的情况下 内质网和 质膜，我们将制定策略来增加 将SGLT1传递到质膜。 最后，在亲戚中 我们确定GGM突变的地方，我们将筛选家庭 杂合子和正常纯合子的成员。 糖 将使用H-呼吸测试来测量吸收 载体表现出任何吸收不良的症状。 这项研究会 使我们能够识别和治疗糖吸收不良的患者 由于SGLT1基因中的突变，将提供独特 有关合成，贩运和功能的信息 共转运者。

项目成果

Surprising versatility of Na+-glucose cotransporters: SLC5.

• DOI: 10.1152/physiol.00026.2004
• 发表时间: 2004-12
• 期刊: Physiology
• 影响因子: 8.4
• 作者: E. M. Wright;D. Loo;B. Hirayama;E. Turk

The molecular basis of inherited disorders of the gastrointestinal and hepatobiliary tracts. An update on recent progress.

胃肠道和肝胆道遗传性疾病的分子基础。

• 发表时间: 1995
• 期刊: Gastroenterology clinics of North America.
• 作者: Martin,MG;Turk,E
• 通讯作者: Turk,E

Evidence for the involvement of Ala 166 in coupling Na(+) to sugar transport through the human Na(+)/glucose cotransporter.

Ala 166 参与通过人 Na( )/葡萄糖协同转运蛋白将 Na( ) 与糖转运偶联的证据。

• DOI: 10.1021/bi011026l
• 发表时间: 2001
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Meinild,AK;Loo,DD;Hirayama,BA;Gallardo,E;Wright,EM
• 通讯作者: Wright,EM

Ligand-induced differences in secondary structure of the Vibrio parahaemolyticus Na+/galactose cotransporter.

配体诱导的副溶血性弧菌 Na /半乳糖协同转运蛋白二级结构的差异。

• DOI: 10.1021/bi025692d
• 发表时间: 2002
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: leCoutre,Johannes;Turk,Eric;Kaback,HRonald;Wright,ErnestM
• 通讯作者: Wright,ErnestM

Use of amniotic fluid amino acids in prenatal testing for argininosuccinic aciduria and citrullinaemia.

羊水氨基酸在精氨酸琥珀酸尿症和瓜氨酸血症产前检测中的应用。

• DOI: 10.1002/(sici)1097-0223(199605)16:5
• 发表时间: 1996
• 期刊: Prenatal diagnosis.
• 作者: Mandell,R;Packman,S;Laframboise,R;Golbus,MS;Schmidt,K;Workman,L;Saudubray,JM;Shih,VE
• 通讯作者: Shih,VE