Homozygosity mapping and targeted genomic sequencing reveal the gene responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred
Homozygosity mapping and targeted genomic sequencing reveal the gene responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred
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DOI：
10.1101/gr.126110.111
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发表时间：
2011-12-01
期刊：
影响因子：
7
通讯作者：
Ozcelik, Tayfun
中科院分区：
文献类型：
--
作者：
Gulsuner, Suleyman;Tekinay, Ayse Begum;Ozcelik, Tayfun
人类姿势和步态所需的脑-小脑结构发育的生物学基础尚不清楚。我们研究了一个来自土耳其的大近亲家族，该家族表现出与四足运动、智力迟钝和脑小脑发育不全相关的极其罕见的表型，与染色体17p13.1-13.3上7.1 mb的纯合性区域有关。患者大脑弥散加权成像及纤维束造影显示小脑、胼胝体形态异常，小脑上、中、下胚轴萎缩最为明显。结构磁共振成像显示几个皮质区域的形态异常，包括胼胝体、中央前回和Brodmann区BA6、BA44和BA45。对三名受影响个体和两名专性携带者的整个纯合区进行靶向测序，发现了一个私人错义突变WDR81 p.P856L，该突变与该病症在大家庭中共分离。突变位于WDR81的高度保守区域，两侧是n端BEACH结构域和c端WD40 β -propeller结构域。预测WDR81是一种跨膜蛋白。它在小脑和胼胝体中高度表达，特别是在小脑浦肯野细胞层中。WDR81是继VLDLR和CA8之后，与人类四足运动有关的第三个基因。
The biological basis for the development of the cerebro-cerebellar structures required for posture and gait in humans is poorly understood. We investigated a large consanguineous family from Turkey exhibiting an extremely rare phenotype associated with quadrupedal locomotion, mental retardation, and cerebro-cerebellar hypoplasia, linked to a 7.1-Mb region of homozygosity on chromosome 17p13.1-13.3. Diffusion weighted imaging and fiber tractography of the patients' brains revealed morphological abnormalities in the cerebellum and corpus callosum, in particular atrophy of superior, middle, and inferior peduncles of the cerebellum. Structural magnetic resonance imaging showed additional morphometric abnormalities in several cortical areas, including the corpus callosum, precentral gyrus, and Brodmann areas BA6, BA44, and BA45. Targeted sequencing of the entire homozygous region in three affected individuals and two obligate carriers uncovered a private missense mutation, WDR81 p.P856L, which cosegregated with the condition in the extended family. The mutation lies in a highly conserved region of WDR81, flanked by an N-terminal BEACH domain and C-terminal WD40 beta-propeller domains. WDR81 is predicted to be a transmembrane protein. It is highly expressed in the cerebellum and corpus callosum, in particular in the Purkinje cell layer of the cerebellum. WDR81 represents the third gene, after VLDLR and CA8, implicated in quadrupedal locomotion in humans.