Uyanik G, Morris-Rosendahl D J, Stiegler J, Klapecki J, Gross C, Berman Y, Martin P, Dey L, Spranger S, Korenke G C, Schreyer I, Hertzberg C, Neumann T E, Burkart P, Spaich C, Meng M, Holthausen H, Adès L, Seidel J, Mangold E, Buyse G, Meinecke P, Schara U, Zeschnigk C, Muller D, Helland G, Schulze B, Wright M L, Kortge-Jung S, Hehr A, Bogdahn U, Schuierer G, Kohlhase J, Aigner L, Wolff G, Hehr U, Winkler J
Department of Neurology, University of Regensburg, Regensburg, Germany.
Neurology. 2007 Jul 31;69(5):442-7. doi: 10.1212/01.wnl.0000266629.98503.d0.
Lissencephaly is a neuronal migration disorder leading to absent or reduced gyration and a broadened but poorly organized cortex. The most common form of lissencephaly is isolated, referred as classic or type 1 lissencephaly. Type 1 lissencephaly is mostly associated with a heterozygous deletion of the entire LIS1 gene, whereas intragenic heterozygous LIS1 mutations or hemizygous DCX mutations in males are less common.
Eighteen unrelated patients with type 1 lissencephaly were clinically and genetically assessed. In addition, patients with subcortical band heterotopia (n = 1) or lissencephaly with cerebellar hypoplasia (n = 2) were included.
Fourteen new and seven previously described LIS1 mutations were identified. We observed nine truncating mutations (nonsense, n = 2; frameshift, n = 7), six splice site mutations, five missense mutations, and one in-frame deletion. Somatic mosaicism was assumed in three patients with partial subcortical band heterotopia in the occipital-parietal lobes or mild pachygyria. We report three mutations in exon 11, including a frameshift which extends the LIS1 protein, leading to type 1 lissencephaly and illustrating the functional importance of the WD domains at the C terminus. Furthermore, we present two patients with novel LIS1 mutations in exon 10 associated with lissencephaly with cerebellar hypoplasia type a.
In contrast to previous reports, our data suggest that neither type nor position of intragenic mutations in the LIS1 gene allows an unambiguous prediction of the phenotypic severity. Furthermore, patients presenting with mild cerebral malformations such as subcortical band heterotopia or cerebellar hypoplasia should be considered for genetic analysis of the LIS1 gene.
无脑回畸形是一种神经元迁移障碍性疾病，可导致脑回缺如或减少，以及大脑皮层变宽但结构紊乱。无脑回畸形最常见的形式是孤立性的，称为经典型或1型无脑回畸形。1型无脑回畸形大多与整个LIS1基因的杂合缺失相关，而男性中LIS1基因内杂合突变或半合子DCX突变则较少见。
对18例无关的1型无脑回畸形患者进行了临床和基因评估。此外，还纳入了1例皮质下带状异位患者和2例伴有小脑发育不全的无脑回畸形患者。
共鉴定出14个新的LIS1突变和7个先前描述的突变。我们观察到9个截短突变（无义突变2个；移码突变7个）、6个剪接位点突变、5个错义突变和1个框内缺失。3例枕顶叶部分皮质下带状异位或轻度巨脑回患者被推测存在体细胞镶嵌现象。我们报告了外显子11中的3个突变，包括一个使LIS1蛋白延长的移码突变，导致1型无脑回畸形，并说明了C末端WD结构域的功能重要性。此外，我们还介绍了2例在外显子10中携带与a型伴有小脑发育不全的无脑回畸形相关的新型LIS1突变的患者。
与先前的报道相反，我们的数据表明，LIS1基因内突变的类型和位置均无法明确预测表型严重程度。此外，对于表现为轻度脑畸形如皮质下带状异位或小脑发育不全的患者，应考虑进行LIS1基因的遗传分析。
