Iwata-Otsubo Aiko, Ritter Alyssa L, Weckselbatt Brooke, Ryan Nicole R, Burgess David, Conlin Laura K, Izumi Kosuke
Division of Human Genetics, Department of Pediatrics, The Children's Hospital, Pennsylvania, Philadelphia.
Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital, Pennsylvania, Philadelphia.
Am J Med Genet A. 2018 Jan;176(1):241-245. doi: 10.1002/ajmg.a.38517. Epub 2017 Nov 12.
Dedicator of cytokinesis (DOCK) family are evolutionary conserved guanine nucleotide exchange factors (GEFs) for the Rho GTPases, Rac, and Cdc42. DOCK3 functions as a GEF for Rac1, and plays an important role in promoting neurite and axonal growth by stimulating actin dynamics and microtubule assembly pathways in the central nervous system. Here we report a boy with developmental delay, hypotonia, and ataxia due to biallelic DOCK3 deletion. Chromosomal single nucleotide polymorphism (SNP) microarray analysis detected a 170 kb homozygous deletion including exons 6-12 of the DOCK3 gene at 3p21.2. Symptoms of our proband resembles a phenotype of Dock3 knockout mice exhibiting sensorimotor impairments. Furthermore, our proband has clinical similarities with two siblings with compound heterozygous loss-of-function mutations of DOCK3 reported in [Helbig, Mroske, Moorthy, Sajan, and Velinov (); https://doi.org/10.1111/cge.12995]. Biallelic DOCK3 mutations cause a neurodevelopmental disorder characterized by unsteady gait, hypotonia, and developmental delay.
细胞分裂 dedicator（DOCK）家族是Rho GTPases、Rac和Cdc42进化保守的鸟嘌呤核苷酸交换因子（GEF）。DOCK3作为Rac1的GEF，通过刺激中枢神经系统中的肌动蛋白动力学和微管组装途径，在促进神经突和轴突生长中发挥重要作用。在此，我们报告一名因双等位基因DOCK3缺失而患有发育迟缓、肌张力减退和共济失调的男孩。染色体单核苷酸多态性（SNP）微阵列分析检测到3p21.2处一个170 kb的纯合缺失，包括DOCK3基因的外显子6 - 12。我们先证者的症状类似于表现出感觉运动障碍的Dock3基因敲除小鼠的表型。此外，我们的先证者与[Helbig、Mroske、Moorthy、Sajan和Velinov（）；https://doi.org/10.1111/cge.12995]报道的两名患有DOCK3复合杂合功能丧失突变的兄弟姐妹具有临床相似性。双等位基因DOCK3突变导致一种以步态不稳、肌张力减退和发育迟缓为特征的神经发育障碍。
