Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition
Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition
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DOI：
10.1136/jmg.2005.036657
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发表时间：
2006-05-01
影响因子：
4
通讯作者：
Bernier, FP
中科院分区：
文献类型：
--
作者：
Davey, KM;Parboosingh, JS;Bernier, FP
背景：在加拿大Dariusleut huterite人群中发现了一种新的常染色体隐性遗传病，扩张型心肌病伴共济失调（DCMA）综合征，其特征是早发扩张型心肌病伴传导缺陷、非进行性小脑性共济失调、睾丸发育不良、生长衰竭和3-甲基戊二酸尿症。目的：绘制DCMA综合征并确定其潜在的突变。方法：使用纯合子作图方法对近亲huterite家族进行全基因组扫描，以确定DCMA相关染色体区域。通过测序对该区域的候选基因进行突变分析。然后使用逆转录酶聚合酶链反应和生物信息学分析来表征突变并确定其对蛋白质产物的影响。结果：发现DCMA综合征与染色体3q26.33的2.2 Mb区域相关。在DNAJC19基因中发现了一个与疾病相关的突变：IVS3-1 G -> C，编码一个功能未知的DNAJ结构域蛋白（Entrez基因ID 131118）。结论：DNAJC19蛋白先前定位于心肌细胞的线粒体，并与包括两种酵母线粒体内膜蛋白mdjp2和Tim14在内的几个物种的蛋白具有相同的序列和组织相似性。Tim14是酵母内线粒体膜前序转位酶的一个组成部分，提示DCMA的独特表型可能是线粒体蛋白输入缺陷的结果。这只是已确定的由该途径缺陷引起的第二种人类疾病。
Background: A novel autosomal recessive condition, dilated cardiomyopathy with ataxia ( DCMA) syndrome, has been identified in the Canadian Dariusleut Hutterite population, characterised by early onset dilated cardiomyopathy with conduction defects, non-progressive cerebellar ataxia, testicular dysgenesis, growth failure, and 3-methylglutaconic aciduria.Objective: To map DCMA syndrome and identify the mutation underlying this condition.Methods: A genome wide scan was undertaken on consanguineous Hutterite families using a homozygosity mapping approach in order to identify the DCMA associated chromosomal region. Mutation analysis was carried out on positional candidate genes in this region by sequencing. Reverse transcriptase polymerase chain reaction and bioinformatics analyses were then used to characterise the mutation and determine its effect on the protein product.Results: The association of DCMA syndrome with a 2.2 Mb region of chromosome 3q26.33 was found. A disease associated mutation was identified: IVS3-1 G -> C in the DNAJC19 gene, encoding a DNAJ domain containing protein of previously unknown function (Entrez Gene ID 131118).Conclusions: The DNAJC19 protein was previously localised to the mitochondria in cardiac myocytes, and shares sequence and organisational similarity with proteins from several species including two yeast mitochondrial inner membrane proteins, Mdj2p and Tim14. Tim14 is a component of the yeast inner mitochondrial membrane presequence translocase, suggesting that the unique phenotype of DCMA may be the result of defective mitochondrial protein import. It is only the second human disorder caused by defects in this pathway that has been identified.