Diseases Of Aminoacid Transport: Genetic, Molecular and Biochemical Studies

氨基酸是所有生物的基本组成部分。它们被细胞表面高度特异性的泵吸收并保留在体内。通过了解控制氨基酸的机制，我们不仅可以发现正常生物学中常见的途径，还可以揭示人类疾病的机制。具体来说，氨基酸尿症包括一些氨基酸运输的遗传性疾病，导致特定氨基酸的吸收和保留失败。哈特纳普病是一种中性氨基酸运输的遗传性疾病，可导致对太阳敏感的皮疹、控制运动和行走困难以及包括智力迟钝在内的其他神经系统症状。哈特纳普病的一个主要特征是其临床变异性。我们最近确定了哈特纳普病的主要遗传原因，并将该基因命名为SLC6A19。我们希望研究观察到的临床变异性是否是SLC6A19和其他可能基因的遗传变化和变异性的结果。另外两种有待研究的氨基酸尿是二羧酸尿和亚氨基糖尿；两者的临床结果也各不相同，从正常到智力迟钝不等。由于这些疾病的相对罕见性，我们很幸运能够独家获得世界上最大的新生儿氨基酸性尿症筛查项目（位于加拿大）和澳大利亚其他临床队列确定的个体。我们将进行基因检测，首次在任何地方定位和或确认与这些疾病有关的基因，然后根据功能分析寻求解释其临床变异性。我们已经建立了一个团队的研究人员与互补的技能，从三个网站，包括澳大利亚氨基酸尿协会。该项目的研究结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方法产生影响。

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.