期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 88, 期 5, 页码 523-535出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2011.03.019
关键词
-
资金
- Higher Education Commission of Pakistan
- Action Research
- Wellcome Trust
- MRC [G0700089]
- Wellcome Trust [GR082557]
- Yale Program on Neurogenetics
- Yale Center for Human Genetics and Genomics
- National Institutes of Health [RC2NS070477]
- Medical Research Council [G0700089, G9900837] Funding Source: researchfish
- MRC [G9900837, G0700089] Funding Source: UKRI
We investigated three families whose offspring had extreme microcephaly at birth and profound mental retardation. Brain scans and postmortem data showed that affected individuals had brains less than 10% of expected size (<= 10 standard deviation) and that in addition to a massive reduction in neuron production they displayed partially deficient cortical lamination tinicrolissencephaly). Other body systems were apparently unaffected and overall growth was normal. We found two distinct homozygous mutations of NDE1, c.83+1G>T (p.Ala29GlnfsX114) in a Turkish family and c.684_685del (p.Pro229TrpfsX85) in two families of Pakistani origin. Using patient cells, we found that c.83+1G>T led to the use of a novel splice site and to a frameshift after NDE1 exon 2. Transfection of tagged NDE1 constructs showed that the c.684_685del mutation resulted in a NDE1 that was unable to localize to the centrosome. By staining a patient-derived cell line that carried the c.83+1G>T mutation, we found that this endogeneously expressed mutated protein equally failed to localize to the centrosome. By examining human and mouse embryonic brains, we determined that NDE1 is highly expressed in neuroepithelial cells of the developing cerebral cortex, particularly at the centrosome. We show that NDE1 accumulates on the mitotic spindle of apical neural precursors in early neurogenesis. Thus, NDE1 deficiency causes both a severe failure of neurogenesis and a deficiency in cortical lamination. Our data further highlight the importance of the centrosome in multiple aspects of neurodevelopment.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据