De Novo Mutations in CHAMP1 Cause Intellectual Disability with Severe Speech Impairment
De Novo Mutations in CHAMP1 Cause Intellectual Disability with Severe Speech Impairment
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DOI：
10.1016/j.ajhg.2015.08.003
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发表时间：
2015-09-03
影响因子：
9.8
通讯作者：
Lessel, Davor
中科院分区：
文献类型：
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作者：
Hempel, Maja;Cremer, Kirsten;Lessel, Davor
CHAMP1编码的蛋白质在运动舞蹈微管附着和染色体分离的调节中具有功能，已知这两者对于神经发育都是重要的。通过三重全外显子组测序，我们在5个受智力残疾影响的无关个体中鉴定了CHAMP1的从头有害突变，这些智力残疾具有严重的言语障碍、运动发育迟缓、肌肉张力减退和类似的畸形特征，包括短人中和帐篷状上唇和外翻的下唇。除了两个移码突变和一个无义突变外，我们在两个受影响的个体中发现了相同的无义突变，c.1192C> T（p.Arg398 *）。所有的突变，如果导致一个稳定的蛋白质，预计将导致功能上重要的锌指结构域的蛋白质，调节CHAMP1定位到染色体和有丝分裂纺锤体的C末端的损失，从而提供了一个机制的理解其致病性。因此，我们确定CHAMP1中的有害从头突变是智力残疾的原因。
CHAMP1 encodes a protein with a function in kinetochore-microtubule attachment and in the regulation of chromosome segregation, both of which are known to be important for neurodevelopment. By trio whole-exome sequencing, we have identified de novo deleterious mutations in CHAMP1 in five unrelated individuals affected by intellectual disability with severe speech impairment, motor developmental delay, muscular hypotonia, and similar dysmorphic features including short philtrum and a tented upper and everted lover lip. In addition to two frameshift and one nonsense mutations, we found an identical nonsense mutation, c.1192C>T (p.Arg398*), in two affected individuals. All mutations, if resulting in a stable protein, are predicted to lead to the loss of the functionally important zinc-finger domains in the C terminus of the protein, which regulate CHAMP1 localization to chromosomes and the mitotic spindle, thereby providing a mechanistic understanding for their pathogenicity. We thus establish deleterious de novo mutations in CHAMP1 as a cause of intellectual disability.