Establishment of X-linked mental retardation syndromes and genetic analysis

1)X连锁无芒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缺陷而发育为小脑。这些小鼠还表现出异常的迁移和分化的中间神经元含有GABA能intercneurons在神经节隆起和新皮质，以及异常的睾丸分化。这些特征概括了人类X连锁无脑畸形伴生殖器异常（XLAG）的一些临床特征。我们发现在ARX个体中存在多个影响XLAG和一些女性亲属的功能缺失突变，并得出结论：ARX突变导致XLAG。本报告是首次利用基因敲除小鼠的表型分析鉴定与X连锁人脑畸形相关的基因。2）Rett综合征（RTT）是一种X连锁显性神经发育障碍，其特征是认知和适应性退化，伴有自闭症行为， 关于我们 典型的手部运动癫痫和共济失调在RTT患者中，已经报道了超过120种不同的nmethyl-CpG结合蛋白2基因（MECP 2）突变，但尚未建立基因型-表型相关性。我们研究了221例临床诊断为RTT的日本散发患者的MECP 2突变，在146例患者中检测到40种不同的MECP 2突变。常见突变为T158 M、P152 R、R133 C和R306 C四种错义突变（40例）和R168 X、R255 X、R20 X、R294四种无义突变（38例）。与常见突变患者的表型比较，在非典型RTT患者（包括保留语音变异型）中，8 R133 C、R306 C和R294 X三种突变的检出率更高。另一方面，T1 q58 M和R168 X突变的患者具有RTT的典型临床特征。这些结果表明，RTT患者中存在MECP 2的基因型-表型相关性，尽管对成人RTT患者的大规模研究需要确定MECP 2中突变类型的更精确影响。3）我们在人类染色体8q23.3\q24.1.in上鉴定了编码具有cub和sushi多个结构域的跨膜蛋白的新的巨大基因，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区域上跨越超过1.2Mb。该基因与两个基因（8 p23上的CSMD 1基因和1 p34上的CSMD 2基因）在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CSMD 3。CSMD 3基因主要在成人和胎儿脑中表达。我们对7例BAFME 1/FAM患者的CSMD 3基因进行了突变分析，但在CSMD 3基因的编码序列中未发现突变。少

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