Mutations in ANKRD11 Cause KBG Syndrome, Characterized by Intellectual Disability, Skeletal Malformations, and Macrodontia
Mutations in ANKRD11 Cause KBG Syndrome, Characterized by Intellectual Disability, Skeletal Malformations, and Macrodontia
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DOI：
10.1016/j.ajhg.2011.06.007
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发表时间：
2011-08-12
影响因子：
9.8
通讯作者：
Tekin, Mustafa
中科院分区：
文献类型：
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作者：
Sirmaci, Asli;Spiliopoulos, Michail;Tekin, Mustafa
KBG综合征的特征是与上中切牙的巨齿相关的智力残疾以及明显的颅面表现、身材矮小和骨骼异常。虽然被认为是遗传的起源，具体的潜在缺陷是未知的。通过全外显子组测序，我们鉴定了编码锚蛋白重复结构域11（也称为含锚蛋白重复辅因子1）的ANKRD 11中的有害杂合突变。一个剪接位点突变，c.7570-1G>C（p.Glu2524_Lys2525del），与疾病共分离的一个家庭与三个受影响的成员，而在一个单纯的情况下，从头截断突变，c.2305delT（p.Ser769GlnfsX8），被检测到。桑格测序显示在其他三个单纯病例中有额外的从头截短ANKRD 11突变。已知ANKRD 11与核受体复合物相互作用以修饰转录激活。我们证明，ANKRD 11主要定位于神经元的细胞核，并在神经元去极化时在离散的内含物中积累，这表明它在神经可塑性中起作用。我们的研究结果表明，ANKRD 11突变引起KBG综合征，并概述了ANKRD 11在颅面，牙齿，骨骼和中枢神经系统发育和功能中的基本作用。
KBG syndrome is characterized by intellectual disability associated with macrodontia of the upper central incisors as well as distinct craniofacial findings, short stature, and skeletal anomalies. Although believed to be genetic in origin, the specific underlying defect is unknown. Through whole-exome sequencing, we identified deleterious heterozygous mutations in ANKRD11 encoding ankyrin repeat domain 11, also known as ankyrin repeat-containing cofactor 1. A splice-site mutation, c.7570-1G>C (p.Glu2524_Lys2525del), cosegregated with the disease in a family with three affected members, whereas in a simplex case a de novo truncating mutation, c.2305delT (p.Ser769GlnfsX8), was detected. Sanger sequencing revealed additional de novo truncating ANKRD11 mutations in three other simplex cases. ANKRD11 is known to interact with nuclear receptor complexes to modify transcriptional activation. We demonstrated that ANKRD11 localizes mainly to the nuclei of neurons and accumulates in discrete inclusions when neurons are depolarized, suggesting that it plays a role in neural plasticity. Our results demonstrate that mutations in ANKRD11 cause KBG syndrome and outline a fundamental role of ANKRD11 in craniofacial, dental, skeletal, and central nervous system development and function.