Establishment of X-linked mental retardation syndromes and genetic analysis

X连锁智力低下综合征的建立及遗传分析

• 批准号: 14570749
• 负责人: KONDO Ikuko
• 金额: $ 1.79万
• 依托单位: Ehime University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570749/
• 关键词: mental retardation; X chromosome; Rett syndrome; gene mutation; aristaless related homeobox geng(ARX); MECP2; X連鎖性知的障害; ARX遺伝子; MECP2遺伝子; 遺伝子座の解明; 細胞株の樹立

1)Male embryonic mice with mutations in the X-linked aristaless-related homeobox gene(ARX) developed with small brains due to suppressed proliferation and regional deficiencies in the forebrain. These mice also showed aberrant migration and differentiation of interneurons containing GABAergic intercneurons in the ganglionic eminence and neocortex as well as abnormal testicular differentiations. These characteristics recapitulate some of the clinical features of X-linked lissencephaly with abnormal genitalia(XLAG) in humans. We found multiple loss pf function mutations in ARX individuals affected XLAG and some female relatives, and conclude that mutations of ARX caused XLAG. The present report, to our knowledge the first to use phenotypic analysis of a knockout mouse to identify a gene associated with an X-linked human brain malformation.2)Rett syndrome(RTT) is an X-linked dominant neurodeveloprnental disorder characterized by cognitive and adapted regression with autistic behavior, ste … More reotypical hand movements, epilepsy and ataxia. Over 120 different mutations in the nmethyl-CpG binding protein 2 gene(MECP2) have been reported in patients with RTT, but a genotype-phenotype correlation has not been established. We have studied MECP2 mutations in 221 Japanese sporadic patients diagnosed clinically to having RTT and 40 different mutations in MECP2 have been detected in 146 patients. Common mutations were four missense mutations, T158M,P152R,R133C and R306C) observed in 40 cases and four nonsense mutations(R168X,R255X,R20X,R294) were detected in 38 cases. Comparing phenotypes in patients with common mutations, three mutations 8R133C,R306C and R294X were more frequently detected in patients with atypical RTT including preserved speech variant type. On the other hand, patients with T1q58M and R168X mutations have typical clinical features of RTT. These results suggest that there is a genotype-phenotype correlation of MECP2 in patients with RTT, although a large scale study of adult patients with RTT needs to determine more precise influence of mutation type in MECP2.3)We identified a novel giant gene encoding a transmembrane protein with cub and sushi multiple domains on the human chromosome 8q23.3\q24.1.in which benign adult familial myoclonus epilepsy type 1(BAFAMME/FAME, Omim:601068} has been mapped. This giant gene consists of 73 exons and spans over 1.2Mb on the genomic DNA regions. It showed significant homology to two genes, CSMD1 gene on 8p23 and CSMD2 gene on 1p34, at reduced amino acid sequence level and hence we designated as CSMD3. The CSMD3 gene was expressed mainly in adult and fetal brains. We performed mutation analysis on the CSMD3 gene for seven patients with BAFME1/FAM, but no mutation was found in the coding sequence of the CSMD3 gene. Less

1)带有X连锁干旱症相关同源异型盒基因(ARX)突变的雄性胚胎小鼠由于前脑的增殖抑制和区域性缺陷而发育成小脑。这些小鼠还表现出神经节隆起和新皮质内含有GABA能的中间神经元的异常迁移和分化以及睾丸分化的异常。这些特征概括了人类X连锁无脑生殖器异常(XLAG)的一些临床特征。我们在ARX个体中发现了影响XLAG和一些女性亲属的多个Pf功能缺失突变，从而得出了ARX突变导致XLAG的结论。据我们所知，本报告首次使用基因敲除小鼠的表型分析来确定与X-连锁人脑畸形相关的基因。2)Rett综合征(RTT)是一种X-连锁的显性神经发育障碍，其特征是自闭症行为的认知和适应性回归，ste…更典型的手部运动，癫痫和共济失调。在RTT患者中，已经报道了120多种不同的nyl-CpG结合蛋白2基因(MECP2)突变，但尚未建立基因-表型相关性。我们研究了221例临床诊断为RTT的日本散发性患者的MECP2突变，在146例患者中检测到40种不同的MECP2突变。常见突变有T158M、P152R、R133C和R306C 4个错义突变40例，R168X、R255X、R20X、R294 4个无义突变38例。比较常见突变患者的表型，在包括保留语音变异型在内的不典型RTT患者中，8R133C、R306C和R294X突变的发生率较高。另一方面，携带T1q58M和R168X突变的患者具有典型的RTT临床特征。这些结果表明，MECP2基因在RTT患者中存在表型-基因型相关性，尽管对成人RTT患者的大规模研究需要更准确地确定MECP2突变类型的影响。我们在人类染色体8q23.3\q24.1上发现了一个编码跨膜蛋白的新的巨型基因，该基因带有CUB和寿司多个结构域，其中良性成人家族性肌阵挛癫痫1型(BAFAMME/FAME，OMIM：601068)已被定位。这个巨大的基因由73个外显子组成，在基因组DNA区域跨度超过1.2mb。该基因与位于8p23的CSMD1基因和位于1p34的CSMD2基因在降低的氨基酸序列水平上具有显著的同源性，因此我们将其命名为CSMD3。CSMD3基因主要在成人和胎儿脑中表达。我们对7例BAFME1/FAM患者进行了CSMD3基因突变分析，但未发现CSMD3基因编码序列突变。较少

项目成果

Leonard H, Colyin L, Christodoulou J, Schiavello T, Williamson S, Davis M, Ravine D, Fyfe S, de Klerk N, Matsuishi T, Kondo I, Clarke A, Haskwell S, Yamashita Y.: "Patients with the R133C mutation : is their phenotype different from patients with Rett syn

Leonard H、Colyin L、Christodoulou J、Schiavello T、Williamson S、Davis M、Ravine D、Fyfe S、de Klerk N、Matsuishi T、Kondo I、Clarke A、Haskwell S、Yamashita Y.：“R133C 突变患者

Shimizu A, et al.: "A novel giant gene CSMD3 encoding a protein with CUB and sushi multiple domains"Biochemical and Biophysical Research Communications. 309. 143-154 (2003)

Shimizu A 等人：“编码具有 CUB 和 sushi 多个结构域的蛋白质的新型巨型基因 CSMD3”《生物化学和生物物理研究通讯》。

Shimizu A, et al.: "A novel giant gene CSMD3 encoding a protein with CUB and sushi multiple domains : a candidate gene for benign adult familial myoclonic epilepsy on human chromosome 8q23.3-q24.1"Biochemical and Biophysical Research Communications. 309.

Shimizu A 等人：“编码具有 CUB 和 sushi 多个结构域的蛋白质的新型巨型基因 CSMD3：人类染色体 8q23.3-q24.1 上良性成人家族性肌阵挛性癫痫的候选基因”生物化学和生物物理研究通讯。

Leonard H. et al.: "Patients with the R133C mutation : is their phenotype different from patients with Rett syndrome with other mutations?"J Med Genet. 40. e52 (2003)

Leonard H. 等人：“具有 R133C 突变的患者：他们的表型与具有其他突变的 Rett 综合征患者不同吗？”J Med Genet。

Leonard H.et al.: "Patients with the R133C mutation : is their phenotype different from Patients with Rett syndrome with other mutations?"J Med Genet. 40. e5 (2003)

Leonard H.等人：“具有 R133C 突变的患者：他们的表型与具有其他突变的 Rett 综合征患者不同吗？”J Med Genet。