Mutations in DNAJB13, Encoding an HSP40 Family Member, Cause Primary Ciliary Dyskinesia and Male Infertility
Mutations in DNAJB13, Encoding an HSP40 Family Member, Cause Primary Ciliary Dyskinesia and Male Infertility
复制标题
DOI：
10.1016/j.ajhg.2016.06.022
复制
发表时间：
2016-08-04
影响因子：
9.8
通讯作者：
Amselem, Serge
中科院分区：
文献类型：
--
作者：
El Khouri, Elma;Thomas, Lucie;Amselem, Serge
原发性纤毛运动障碍（PCD）是一种常染色体隐性遗传疾病，由于运动纤毛的功能或超微结构缺陷。受影响的个人显示经常性尿道感染;大多数男性不育的精子鞭毛功能障碍的结果。迄今为止，绝大多数PCD相关基因编码动力蛋白臂（DA）的组成部分，这是纤毛运动所必需的多蛋白-ATP酶复合物，或参与DA组装的蛋白质。为了鉴定以中央复合体（CC）缺陷但正常DA结构为特征的PCD表型的分子基础，在类似于15%的病例中发现的表型，我们在患有PCD和原因不明的CC缺陷的男性个体中进行了全外显子组测序。该分析结合全基因组SNP基因分型，鉴定了DNAJB 13（c.833T>G）中的纯合突变，DNAJB 13是编码HSP 40共伴侣蛋白的基因，其在有鞭毛的衣原体中的直系同源物定位于径向辐条。体外研究表明，这种错义取代（p.Met278Arg），其中涉及几个HSP 40家族成员的高度保守的残基，导致蛋白质不稳定，并触发蛋白酶体降解，结果证实了缺乏内源性DNAJB 13在纤毛和精子从这个人。随后的DNAJB 13分析在第二个家族中鉴定了另一个纯合突变;对从气道细胞获得的DNAJB 13转录物的研究表明，该突变（c.68+1G>C）导致与功能丧失突变一致的剪接缺陷。总的来说，这项研究确定了DNAJB 13中的突变是PCD的原因，揭示了DNAJB 13在人类纤毛和鞭毛轴丝的正确形成和功能中发挥的关键作用。
Primary ciliary dyskinesia (PCD) is an autosomal-recessive disease due to functional or ultra-structural defects of motile cilia. Affected individuals display recurrent respiratory-tract infections; most males are infertile as a result of sperm flagellar dysfunction. The great majority of the PCD-associated genes identified so far encode either components of dynein arms (DAs), which are multiprotein-ATPase complexes essential for ciliary motility, or proteins involved in DA assembly. To identify the molecular basis of a PCD phenotype characterized by central complex (CC) defects but normal DA structure, a phenotype found in similar to 15% of cases, we performed whole-exome sequencing in a male individual with PCD and unexplained CC defects. This analysis, combined with whole-genome SNP genotyping, identified a homozygous mutation in DNAJB13 (c.833T>G), a gene encoding a HSP40 co-chaperone whose ortholog in the flagellated alga Chlamydomonas localizes to the radial spokes. In vitro studies showed that this missense substitution (p.Met278Arg), which involves a highly conserved residue of several HSP40 family members, leads to protein instability and triggers proteasomal degradation, a result confirmed by the absence of endogenous DNAJB13 in cilia and sperm from this individual. Subsequent DNAJB13 analyses identified another homozygous mutation in a second family; the study of DNAJB13 transcripts obtained from airway cells showed that this mutation (c.68+1G>C) results in a splicing defect consistent with a loss-of-function mutation. Overall, this study, which establishes mutations in DNAJB13 as a cause of PCD, unveils the key role played by DNAJB13 in the proper formation and function of ciliary and flagellar axonemes in humans.