Diseases Of Aminoacid Transport: Genetic, Molecular and Biochemical Studies

氨基酸是所有生物的基本组成部分。它们被细胞表面的高度特异性泵吸收并保留在体内。通过了解控制氨基酸的机制，我们不仅可以揭示正常生物学的共同途径，还可以揭示人类疾病的机制。具体而言，氨基酸尿症包括许多导致特定氨基酸摄取和保留失败的氨基酸转运遗传性疾病。Hartnup病是一种遗传性中性氨基酸转运障碍，可导致对阳光敏感的皮疹，难以控制运动和行走以及其他神经系统症状，包括智力迟钝。Hartnup病的一个主要特征是其临床变异性。我们最近确定了Hartnup病的主要遗传原因，并命名为SLC 6A 19基因。我们希望检查观察到的临床变异性是否是SLC 6A 19和其他可能基因的遗传变化和变异性的结果。另外两种待研究的氨基酸尿症是二羧酸氨基酸尿症和亚氨基甘氨酸尿症;两者的临床后果也是可变的，从正常到精神发育迟滞。由于这些疾病相对罕见，我们很幸运能够独家访问由世界上最大的新生儿氨基酸尿症筛查计划确定的个人，总部设在加拿大，以及澳大利亚的其他临床队列。我们将进行基因检测，以定位和/或确认与这些疾病有关的基因，然后根据功能分析来解释它们的临床变异性。我们已经建立了一个研究人员团队，他们来自澳大利亚氨基酸尿症联盟的三个地点，具有互补的技能。该项目的成果将对包括运动神经元疾病在内的其他重要医学疾病的病因和可能的治疗产生影响。

Aminoacids are essential building blocks of all living things. They are taken up and retained in the body by highly specific pumps on the surface of cells. By understanding the mechanisms that control aminoacids, we will not only uncover pathways common to normal biology but also shed light on mechanisms of disease in humans. Specifically, the aminoacidurias include a number of inherited diseases of aminoacid transport that result in failure of uptake and retention of particular aminoacids. Hartnup disease is an inherited disorder of neutral aminoacid transport that can lead to a sun-sensitive skin rash, difficulties in controlling movements and walking and other neurological symptoms including mental retardation. A major feature of Hartnup disease is its clinical variability. We have recently identified the main genetic cause for Hartnup disease, and named the gene SLC6A19. We wish to examine whether the clinical variability observed is a consequence of genetic changes and variability in SLC6A19 and other possible genes. Two other aminoacidurias to be studied are dicarboxylic aminoaciduria and iminoglycinuria; both of which are also variable in their clinical consequences ranging from normality to mental retardation. Owing to the relative rarity of these disorders, we are fortunate to have exclusive access to individuals identified by the largest neonatal screening programme for aminoacidurias in the world, based in Canada, and other clinical cohorts within Australia. We will undertake genetic testing to localise and-or confirm the gene(s) involved in these diseases for the first time anywhere and then seek to explain their clinical variability based on functional analyses. We have established a team of researchers with complementary skills from three sites comprising the Australian Aminoaciduria Consortium. Outcomes from this project should impact on the causes and possible therapies for other important medical diseases including motor neurone disease.