Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganization and absent inner dynein arms.
Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganization and absent inner dynein arms.
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DOI：
10.1002/humu.22261
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发表时间：
2013-03
期刊：
影响因子：
3.9
通讯作者：
Mitchison, Hannah M.
中科院分区：
文献类型：
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作者：
Antony, Dinu;Becker-Heck, Anita;Zariwala, Maimoona A.;Schmidts, Miriam;Onoufriadis, Alexandros;Forouhan, Mitra;Wilson, Robert;Taylor-Cox, Theresa;Dewar, Ann;Jackson, Claire;Goggin, Patricia;Loges, Niki T.;Olbrich, Heike;Jaspers, Martine;Jorissen, Mark;Leigh, Margaret W.;Wolf, Whitney E.;Daniels, M. Leigh Anne;Noone, Peadar G.;Ferkol, Thomas W.;Sagel, Scott D.;Rosenfeld, Margaret;Rutman, Andrew;Dixit, Abhijit;O'Callaghan, Christopher;Lucas, Jane S.;Hogg, Claire;Scambler, Peter J.;Emes, Richard D.;Chung, Eddie M. K.;Shoemark, Amelia;Knowles, Michael R.;Omran, Heymut;Mitchison, Hannah M.
原发性纤毛运动障碍（PCD）是一种由纤毛和精子运动障碍引起的遗传异质性疾病。约12%的病例显示9+2微管纤毛结构紊乱和内部动力蛋白臂（IDA）丢失，历史上称为“放射状辐条缺陷”。我们对54个“辐射状轮辐缺陷”家族中的CCDC 39和CCDC 40进行了测序，因为这是迄今为止鉴定出的导致这种缺陷的两个基因。我们在69%（37/54）的家族中发现了双等位基因突变，包括鉴定出25个（19个新的）突变等位基因（12个在CCDC 39中，13个在CCDC 40中）。所有的突变都是无义的，剪接和移码预测早期蛋白质截短，这表明这种缺陷是由赋予完全蛋白质丢失的“无效”等位基因引起的。大多数家庭（73%; 27/37）有纯合突变，包括来自远交人群的家庭。鉴定了一个主要的推定热点突变，CCDC 40 c.248delC，以及几个其他可能的热点突变。总之，这些发现突出了CCDC 39和CCDC 40在PCD与轴丝解体和IDA损失中的关键作用，并且这些基因代表了受这种纤毛表型影响的家族中遗传检测的主要候选基因。我们发现，放射状辐条结构在这些患者中基本上是完整的，并建议这种纤毛超微结构异常被称为“IDA和连接蛋白-动力蛋白调节复合物（N-DRC）缺陷”，而不是“放射状辐条缺陷”。
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder caused by cilia and sperm dysmotility. About 12% of cases show perturbed 9+2 microtubule cilia structure and inner dynein arm (IDA) loss, historically termed ‘radial spoke defect’. We sequenced CCDC39 and CCDC40 in 54 ‘radial spoke defect’ families, as these are the two genes identified so far to cause this defect. We discovered biallelic mutations in a remarkable 69% (37/54) of families, including identification of 25 (19 novel) mutant alleles (12 in CCDC39 and 13 in CCDC40). All the mutations were nonsense, splice and frameshift predicting early protein truncation, which suggests this defect is caused by ‘null’ alleles conferring complete protein loss. Most families (73%; 27/37) had homozygous mutations, including families from outbred populations. A major putative hotspot mutation was identified, CCDC40 c.248delC, as well as several other possible hotspot mutations. Together, these findings highlight the key role of CCDC39 and CCDC40 in PCD with axonemal disorganisation and IDA loss, and these genes represent major candidates for genetic testing in families affected by this ciliary phenotype. We show that radial spoke structures are largely intact in these patients and propose this ciliary ultrastructural abnormality be referred to as ‘IDA and nexin-dynein regulatory complex (N-DRC) defect’, rather than ‘radial spoke defect’.
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影响因子：
4.8
作者：
Lin, Jianfeng;Tritschler, Douglas;Nicastro, Daniela
通讯作者：
Nicastro, Daniela
影响因子：
9.8
作者：
Knowles, Michael R.;Leigh, Margaret W.;Zariwala, Maimoona A.
通讯作者：
Zariwala, Maimoona A.
影响因子：
4
作者：
Blanchon, Sylvain;Legendre, Marie;Amselem, Serge
通讯作者：
Amselem, Serge
影响因子：
9.8
作者：
Kott, Esther;Duquesnoy, Philippe;Amselem, Serge
通讯作者：
Amselem, Serge
DOI：
10.1093/bioinformatics/btp698
发表时间：
2010-03-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Li H;Durbin R
通讯作者：
Durbin R