Human lissencephaly with cerebellar hypoplasia due to mutations in TUBA1A: expansion of the foetal neuropathological phenotype
Human lissencephaly with cerebellar hypoplasia due to mutations in TUBA1A: expansion of the foetal neuropathological phenotype
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DOI：
10.1007/s00401-010-0684-z
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发表时间：
2010-06-01
影响因子：
12.7
通讯作者：
Laquerriere, Annie
中科院分区：
文献类型：
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作者：
Lecourtois, Magalie;Poirier, Karine;Laquerriere, Annie
神经元迁移障碍占相当数量的皮质畸形，最严重的形式是由无脑。经典无脑畸形已被证明是由LIS 1（PAFAH 1B 1; MIM#601545）、DCX（Doublecortin; MIM#300121）、ARX（Aristaless-related homeobox gene; MIM#300382）、ARBN（Reelin; MIM#600514）和VLDLR（Very low density lipoprotein receptor; MIM#224050）突变引起的。最近，位于染色体12q13.12上的α-微管蛋白1a基因（TUBA 1A）的新生错义突变也与或多或少严重的皮质发育缺陷相关，导致最严重的无脑回畸形病例中的完全无脑回。我们在这里报告的大脑病变在36周的妊娠女性胎儿与一个新的从头错义突变的TUBA 1A基因，提出了最严重的产前表型迄今为止报道。使用常规的免疫组化和共聚焦显微镜，我们显示的证据，除了在神经元迁移和分化的缺陷轴突运输缺陷，这种形式的无脑回畸形的病理生理学提供了新的见解。
Neuronal migration disorders account for a substantial number of cortical malformations, the most severe forms being represented by lissencephalies. Classical lissencephaly has been shown to result from mutations in LIS1 (PAFAH1B1; MIM#601545), DCX (Doublecortin; MIM#300121), ARX (Aristaless-related homeobox gene; MIM#300382), RELN (Reelin; MIM#600514) and VLDLR (Very low density lipoprotein receptor; MIM#224050). More recently, de novo missense mutations in the alpha-tubulin 1a gene (TUBA1A) located on chromosome 12q13.12, have also been associated with more or less severe defects of cortical development, resulting in complete agyria in the most severe cases of lissencephaly. We report here the cerebral lesions in a 36 weeks' gestation female foetus with a novel de novo missense mutation in the TUBA1A gene, presenting the most severe antenatal phenotype reported so far. Using routine immunohistochemistry and confocal microscopy, we show evidence for defects in axonal transport in addition to defects in neuronal migration and differentiation, giving new insights to the pathophysiology of this form of lissencephaly.