Radboud University Nijmegen Medical Centre, Department of Human Genetics, Nijmegen, The Netherlands.
J Med Genet. 2012 Mar;49(3):179-83. doi: 10.1136/jmedgenet-2011-100542.
DYNC1H1 encodes the heavy chain protein of the cytoplasmic dynein 1 motor protein complex that plays a key role in retrograde axonal transport in neurons. Furthermore, it interacts with the LIS1 gene of which haploinsufficiency causes a severe neuronal migration disorder in humans, known as classical lissencephaly or Miller-Dieker syndrome.
To describe the clinical spectrum and molecular characteristics of DYNC1H1 mutations.
A family based exome sequencing approach was used to identify de novo mutations in patients with severe intellectual disability.
In this report the identification of two de novo missense mutations in DYNC1H1 (p.Glu1518Lys and p.His3822Pro) in two patients with severe intellectual disability and variable neuronal migration defects is described.
Since an autosomal dominant mutation in DYNC1H1 was previously identified in a family with the axonal (type 2) form of Charcot- Marie-Tooth (CMT2) disease and mutations in Dync1h1 in mice also cause impaired neuronal migration in addition to neuropathy, these data together suggest that mutations in DYNC1H1 can lead to a broad phenotypic spectrum and confirm the importance of DYNC1H1 in both central and peripheral neuronal functions.
DYNC1H1 编码细胞质动力蛋白 1 马达蛋白复合物的重链蛋白，在神经元的逆行轴突运输中发挥关键作用。此外，它与 LIS1 基因相互作用，后者的单倍不足会导致人类严重的神经元迁移障碍，称为经典无脑回或 Miller-Dieker 综合征。
描述 DYNC1H1 突变的临床谱和分子特征。
采用基于家族的外显子组测序方法鉴定严重智力残疾患者的新生突变。
本报告描述了两名严重智力残疾且存在可变神经元迁移缺陷的患者中 DYNC1H1 的两个新生错义突变（p.Glu1518Lys 和 p.His3822Pro）。
由于 DYNC1H1 中的常染色体显性突变先前在具有轴索（2 型）形式的 Charcot-Marie-Tooth（CMT2）疾病的家族中被鉴定，并且 Dync1h1 中的突变除了神经病之外还导致神经元迁移受损，这些数据共同表明 DYNC1H1 中的突变可导致广泛的表型谱，并证实 DYNC1H1 在中枢和周围神经元功能中的重要性。
