Haploinsufficiency of a Spliceosomal GTPase Encoded by EFTUD2 Causes Mandibulofacial Dysostosis with Microcephaly
Haploinsufficiency of a Spliceosomal GTPase Encoded by EFTUD2 Causes Mandibulofacial Dysostosis with Microcephaly
复制标题
DOI：
10.1016/j.ajhg.2011.12.023
复制
发表时间：
2012-02-10
影响因子：
9.8
通讯作者：
Boycott, Kym M.
中科院分区：
文献类型：
--
作者：
Lines, Matthew A.;Huang, Lijia;Boycott, Kym M.
下颌面发育不良伴小头畸形 (MFDM) 是一种罕见的散发性综合征，包括颅面畸形、小头畸形、发育迟缓和可识别的畸形外观。主要后遗症，包括后鼻孔闭锁、感音神经性听力损失和腭裂，在受影响的个体中都有很大比例。我们展示了 12 名无关的 MFDM 个体的详细临床结果；这 12 个人构成了迄今为止报告的最大群体。为了定义 MFDM 的病因，我们对四个无关的受影响个体进行了全外显子组测序，并在所有四个个体中鉴定了 EFTUD2 杂合突变或缺失。对另外 8 名 MFDM 患者的验证研究表明，所有受测试的受影响个体均存在致病性 EFTUD2 突变。在 MFDM 中可以看到一系列 EPTUD2 突变类型，包括无效等位基因和移码，这与单倍体不足相一致；迄今为止评估的所有案例中的隔离都是从头开始的。 U5-116kD 是 EFTUD2 编码的蛋白质，是一种高度保守的剪接体 GTP 酶，在催化剪接和剪接后复合物拆卸中发挥核心调节作用。 MFDM 是由于主要剪接体缺陷导致的快速多发性畸形综合征。我们的研究结果显着扩展了已报道的人类剪接体表型的范围，并为进一步研究特雷彻柯林斯综合征等相关疾病铺平了道路。
Mandibulofacial dysostosis with microcephaly (MFDM) is a rare sporadic syndrome comprising craniofacial malformations, microcephaly, developmental delay, and a recognizable dysmorphic appearance. Major sequelae, including choanal atresia, sensorineural hearing loss, and cleft palate, each occur in a significant proportion of affected individuals. We present detailed clinical findings in 12 unrelated individuals with MFDM; these 12 individuals compose the largest reported cohort to date. To define the etiology of MFDM, we employed whole-exome sequencing of four unrelated affected individuals and identified heterozygous mutations or deletions of EFTUD2 in all four. Validation studies of eight additional individuals with MFDM demonstrated causative EFTUD2 mutations in all affected individuals tested. A range of EPTUD2-mutation types, including null alleles and frameshifts, is seen in MFDM, consistent with haploinsufficiency; segregation is de novo in all cases assessed to date. U5-116kD, the protein encoded by EFTUD2, is a highly conserved spliceosomal GTPase with a central regulatory role in catalytic splicing and post-splicing-complex disassembly. MFDM is the fast multiple-malformation syndrome attributed to a defect of the major spliceosome. Our findings significantly extend the range of reported spliceosomal phenotypes in humans and pave the way for further investigation in related conditions such as Treacher Collins syndrome.