Subcortical band heterotopia in rare affected males can be caused by missense mutations in DCX (XLIS) or LIS1
Subcortical band heterotopia in rare affected males can be caused by missense mutations in DCX (XLIS) or LIS1
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DOI：
10.1093/hmg/8.9.1757
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发表时间：
1999-09-01
影响因子：
3.5
通讯作者：
Ledbetter, DH
中科院分区：
文献类型：
--
作者：
Pilz, DT;Kuc, J;Ledbetter, DH
皮质下带状异位（SBH）是在皮质和脑室表面之间的中央白色物质中发现的双侧对称灰质带状，包括无脑回畸形（无脑回-厚脑回-带状）畸形谱中较轻的一端。我们现在已经在所研究的11个男孩中的3个中鉴定了DCX或LIS 1基因中的突变，这首次证明DCX或LIS 1的突变可以导致男性中的SBH或混合性厚脑回-SBH（PCH-SBH）。检测到的所有三种变化都是错义突变，预测是种系起源的。包括一例PCH-SBH患儿DCX第4外显子的错义突变（R78 H）、一例轻度SBH患儿及其母亲DCX第4外显子的错义突变（R89 G）和一例SBH患儿LIS 1第6外显子的错义突变（S169 P）。尽管其他在相同外显子中发生错义突变的患者也患有弥漫性无脑畸形，因此，特定氨基酸变化对蛋白质的影响似乎可能决定了表型的严重程度，一些突变使蛋白质能够残留功能并允许正常迁移在更大比例的神经元中。然而，我们预计LIS 1和DCX的体细胞嵌合突变也将被证明是导致男性SBH的重要机制。
Subcortical band heterotopia (SBH) are bilateral and symmetric ribbons of gray matter found in the central white matter between the cortex and the ventricular surface, which comprises the less severe end of the lissencephaly (agyria-pachygyria-band) spectrum of malformations. Mutations in DCX (also known as XLIS) have previously been described in females with SBH, We have now identified mutations in either the DCX or LIS1 gene in three of 11 boys studied, demonstrating for the first time that mutations of either DCX or LIS1 can cause SBH or mixed pachygyria-SBH (PCH-SBH) in males, Ail three changes detected are missense mutations, predicted to be of germline origin. They include a missense mutation in exon 4 of DCX in a boy with PCH-SBH (R78H), a different missense mutation in exon 4 of DCX in a boy with mild SBH and in his mildly affected mother (R89G) and a missense mutation in exon 6 of LIS1 in a boy with SBH (S169P), The missense mutations probably account for the less severe brain malformations, although other patients with missense mutations in the same exons have had diffuse lissencephaly, Therefore, it appears likely that the effect of the specific amino acid change on the protein determines the severity of the phenotype, with some mutations enabling residual protein function and allowing normal migration in a larger proportion of neurons. However, we expect that somatic mosaic mutations of both LIS1 and DCX will also prove to be an important mechanism in causing SBH in males.