Brain and Eye Malformations Resembling Walker-Warburg Syndrome Are Recapitulated in Mice by Dystroglycan Deletion in the Epiblast
Brain and Eye Malformations Resembling Walker-Warburg Syndrome Are Recapitulated in Mice by Dystroglycan Deletion in the Epiblast
复制标题
DOI：
10.1523/jneurosci.2457-08.2008
复制
发表时间：
2008-10-15
影响因子：
5.3
通讯作者：
Campbell, Kevin P.
中科院分区：
文献类型：
--
作者：
Satz, Jakob S.;Barresi, Rita;Campbell, Kevin P.
Walker-Warburg综合征(WWS)是一种严重的先天性疾病，其特征是出生后一年内大脑和眼睛畸形并致死。已经在部分WWS患者中发现了基因突变，但大多数临床病例的病因尚不清楚。POMT1和POMT2是两个致病基因，在营养不良糖的翻译后生物合成途径中形成了一个活性酶复合体。Pomt1或Dstroglan基因的缺失会导致小鼠早期胚胎死亡。在这里，我们报告了外胚性葡萄糖营养不良特异性缺失的小鼠会出现与人类疾病临床谱系大致相似的脑和眼睛缺陷，包括异常神经元迁移、脑积水和眼睛前房和后房的畸形。基底膜的破裂与病理一致，揭示了营养不良多糖在大脑和眼睛的形态发生中的重要作用。这些发现证明了营养不良多糖在WWS中的中心作用，并表明翻译后加工过程中的新缺陷或营养不良多糖基因本身的突变可能是尚未发现致病突变的病例的基础。
Walker-Warburg syndrome (WWS) is a severe congenital disease that is characterized by brain and eye malformations and lethality during the first year of life. Genetic mutations have been identified in a subset of WWS patients, but a majority of clinical cases have unknown etiologies. POMT1 and POMT2, two of the causative genes, form an active enzyme complex in the posttranslational biosynthetic pathway of dystroglycan. Deletion of either Pomt1 or the dystroglycan gene causes early embryonic lethality in mice. Here we report that mice with epiblast-specific loss of dystroglycan develop brain and eye defects that broadly resemble the clinical spectrum of the human disease, including aberrant neuron migration, hydrocephalus, and malformations of the anterior and posterior chambers of the eye. Breaches of basement membranes coincide with the pathology, revealing an important function for dystroglycan in the morphogenesis of the brain and eye. These findings demonstrate the central role of dystroglycan in WWS and suggest that novel defects in posttranslational processing or mutations of the dystroglycan gene itself may underlie cases in which no causative mutation has been found.