Refinement of a 400-kb critical region allows genotypic differentiation between isolated lissencephaly, Miller- Dieker syndrome, and other phenotypes secondary to deletions of 17p13.3
Refinement of a 400-kb critical region allows genotypic differentiation between isolated lissencephaly, Miller- Dieker syndrome, and other phenotypes secondary to deletions of 17p13.3
复制标题
DOI：
10.1086/374320
复制
发表时间：
2003-04-01
影响因子：
9.8
通讯作者：
Ledbetter, DH
中科院分区：
文献类型：
--
作者：
Cardoso, C;Leventer, RJ;Ledbetter, DH
17p13.3的缺失，包括Lis1基因，导致脑畸形脑畸形，其特征在于回旋和皮质增厚。但是，表型可以从分离的脑脑序列（ILS）到Miller-Dieker综合征（MDS）不等。在临床水平上，这两种表型可以通过存在明显的畸形面部特征和MDS中更严重的Lissencephaly等级来区分。先前的工作表明，MD的儿童的缺失比具有IL的儿童更大，但是MDS关键区域的确切界限和LIS1以外的其他因果基因从未得到充分确定。我们已经完成了从LIS1到端粒的17p13.3区域的物理和转录图。使用荧光原位杂交，我们绘制了19名ILS儿童，11个患有MDS的儿童和4个患有17p13.3缺失的儿童的缺失尺寸，无涉及LIS1。我们表明，在分子水平上区分IL与MDS的关键区域可以降低到400 kb。使用来自选定患者的体细胞杂种，我们已经确定了八个在被分类为MDS的患者中始终删除的基因。此外，删除基因CRK和14-3-3-3epsilon描述了最严重的Lissphaly等级的患者。根据最近的功能数据和创建小鼠模型，暗示了14-3-3-3epsilon在皮质发育中的作用，我们建议将其中一个或两个基因与LIS1的缺失结合使用，可能有助于更严重仅在MDS患者中才能看到lisscephaly的形式。
Deletions of 17p13.3, including the LIS1 gene, result in the brain malformation lissencephaly, which is characterized by reduced gyration and cortical thickening; however, the phenotype can vary from isolated lissencephaly sequence (ILS) to Miller-Dieker syndrome (MDS). At the clinical level, these two phenotypes can be differentiated by the presence of significant dysmorphic facial features and a more severe grade of lissencephaly in MDS. Previous work has suggested that children with MDS have a larger deletion than those with ILS, but the precise boundaries of the MDS critical region and causative genes other than LIS1 have never been fully determined. We have completed a physical and transcriptional map of the 17p13.3 region from LIS1 to the telomere. Using fluorescence in situ hybridization, we have mapped the deletion size in 19 children with ILS, 11 children with MDS, and 4 children with 17p13.3 deletions not involving LIS1. We show that the critical region that differentiates ILS from MDS at the molecular level can be reduced to 400 kb. Using somatic cell hybrids from selected patients, we have identified eight genes that are consistently deleted in patients classified as having MDS. In addition, deletion of the genes CRK and 14-3-3epsilon delineates patients with the most severe lissencephaly grade. On the basis of recent functional data and the creation of a mouse model suggesting a role for 14-3-3epsilon in cortical development, we suggest that deletion of one or both of these genes in combination with deletion of LIS1 may contribute to the more severe form of lissencephaly seen only in patients with MDS.