Azmanov Dimitar N, Kowalczuk Sonja, Rodgers Helen, Auray-Blais Christiane, Giguère Robert, Rasko John E J, Bröer Stefan, Cavanaugh Juleen A
Medical Genetics Research Unit, Australian National University (ANU) Medical School, Canberra, Australian Capital Territory (ACT), Australia.
Hum Mutat. 2008 Oct;29(10):1217-21. doi: 10.1002/humu.20777.
Hartnup disorder is an autosomal recessive impairment of amino acid transport in kidney and intestine. Mutations in SLC6A19 have been shown to cosegregate with the disease in the predicted recessive manner; however, in two previous studies (Seow et al., Nat Genet 2004;36:1003-1007; Kleta et al., Nat Genet 2004;36:999-1002), not all causative alleles were identified in all affected individuals, raising the possibility that other genes may contribute to Hartnup disorder. We have now investigated six newly acquired families of Australian and Canadian (Province of Quebec) origin and resequenced the entire coding region of SLC6A19 in families with only a single disease allele identified. We also studied one American family in whom no mutations had been identified in a previous study (Kleta et al., Nat Genet 2004;36:999-1002). We have identified seven novel mutations in SLC6A19 that show functional obliteration of the protein in vitro, explaining Hartnup disorder in all reported families so far. We demonstrate that Hartnup disorder is allelically heterogeneous with two mutated SLC6A19 alleles, whether identical or not, necessary for manifestation of the characteristic aminoaciduria in affected individuals. This study resolves the previous hypothesis that other genes contribute to the Hartnup phenotype.
哈同普病是一种常染色体隐性疾病，表现为肾脏和肠道中氨基酸转运功能受损。已证实，溶质载体家族6成员19（SLC6A19）基因的突变以预期的隐性方式与该疾病共分离；然而，在之前的两项研究中（Seow等人，《自然遗传学》，2004年；36卷：1003 - 1007页；Kleta等人，《自然遗传学》，2004年；36卷：999 - 1002页），并非在所有受影响个体中都鉴定出了所有致病等位基因，这增加了其他基因可能导致哈同普病的可能性。我们现在研究了六个新获得的澳大利亚和加拿大（魁北克省）血统的家系，并对仅鉴定出一个疾病等位基因的家系中的SLC6A19整个编码区进行了重测序。我们还研究了一个美国家系，在之前的一项研究中（Kleta等人，《自然遗传学》，2004年；36卷：999 - 1002页）未在该家系中鉴定出突变。我们在SLC6A19中鉴定出了七个新的突变，这些突变在体外显示出蛋白质功能丧失，解释了迄今为止所有报道家系中的哈同普病。我们证明，哈同普病在等位基因上是异质性的，两个突变的SLC6A19等位基因，无论是否相同，都是受影响个体出现特征性氨基酸尿所必需的。这项研究解决了之前关于其他基因导致哈同普表型的假设。
