Neutral amino acid transport in epithelial cells and its malfunction in Hartnup disorder
Neutral amino acid transport in epithelial cells and its malfunction in Hartnup disorder
复制标题
DOI：
10.1042/bst0330233
复制
发表时间：
2005-02-01
影响因子：
3.9
通讯作者：
Rasko, JEJ
中科院分区：
文献类型：
--
作者：
Bröer, S;Cavanaugh, JA;Rasko, JEJ
Hartnup病是一种常染色体隐性遗传的肾脏和胃肠道中性氨基酸转运异常。相应的转运活性已在肾和肠细胞中表征，并命名为系统B-0。人们认为，这种疾病中氨基酸的吸收失败可以通过富含蛋白质的饮食来弥补。然而，结合不良的饮食和其他因素，Hartnup患者可能会出现更严重的症状，包括光敏糙皮病样皮疹，小脑共济失调和其他神经系统症状。纯合性映射在日本家庭和连锁分析六个澳大利亚家系放置Hartnup疾病基因在染色体5 p15的一个位点。这种精细定位促进了间隔内的候选基因方法，这导致从小鼠和人肾脏中克隆和表征钠依赖性神经递质转运蛋白家族的新成员（B（0）AT 1，SLC 6A 19），其显示系统B-0的所有特性。通量实验和电生理记录表明，该转运蛋白是Na+依赖性和Cl-非依赖性的，产电的，并积极运输大多数中性氨基酸。原位杂交显示在小肠绒毛和肾脏近端小管中有强表达。B（0）AT 1的表达仅限于肾脏、肠和皮肤。在SLC 6A 19中共鉴定出10个突变，它们以预测的隐性方式与疾病共分离，大多数受影响的个体是复合杂合子。与野生型等位基因相比，这些突变导致体外中性氨基酸转运功能改变。其中一个突变发生在1956年描述的原始Hartnup家族的成员中，从而将SLC 6A 19定义为“Hartnup”基因。
Hartnup disorder is an autosomal recessive abnormality of renal and gastrointestinal neutral amino acid transport. A corresponding transport activity has been characterized in kidney and intestinal cells and named system B-0. The failure to resorb amino acids in this disorder is thought to be compensated by a protein-rich diet. However, in combination with a poor diet and other factors, more severe symptoms can develop in Hartnup patients, including a photosensitive pellagra-like skin rash, cerebellar ataxia and other neurological symptoms. Homozygosity mapping in a Japanese family and linkage analysis on six Australian pedigrees placed the Hartnup disorder gene at a locus on chromosome 5p15. This fine mapping facilitated a candidate gene approach within the interval, which resulted in the cloning and characterization of a novel member of the sodium-dependent neurotransmitter transporter family (B(0)AT1, SLC6A19) from mouse and human kidney, which shows all properties of system B-0. Flux experiments and electrophysiological recording showed that the transporter is Na+ dependent and CI- independent, electrogenic and actively transports most neutral amino acids. in situ hybridization showed strong expression in intestinal villi and in the proximal tubule of the kidney. Expression of B(0)AT1 was restricted to kidney, intestine and skin. A total of ten mutations have been identified in SLC6A19 that co-segregate with disease in the predicted recessive manner, with the majority of affected individuals being compound heterozygotes. These mutations lead to altered neutral amino acid transport function compared to the wild-type allele in vitro. One of the mutations occurs in members of the original Hartnup family described in 1956, thereby defining SLC6A19 as the 'Hartnup'-gene.