Studies on the molecular genetics and diagnostic and therapeutic procedures for myotonic dystrophy and allied disorders

强直性肌营养不良及相关疾病的分子遗传学以及诊断和治疗方法的研究

• 批准号: 10557078
• 负责人: MOMOI Mariko
• 金额: $ 3.2万
• 依托单位: JICHI MEDICAL SCHOOL
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10557078/
• 关键词: myotonic dystrophy; trinucleotide repeat disorder; hemiplegic migraine; spinocerebellar degeneration; late-onset cerebellar ataxia; caspase-8; caspase-12; 先天性筋ジストロフィー; 細胞死; caspase-3; 三塩基対リピート疾患; 脆弱X症候群; Pfu polymerase ポリメラーゼ; 毛根; 遺伝子診断; 筋強

Myotonic dystrophy is a neurodegenerative disorder in which abnormal extension of trinucleotide sequence is a causative gene abnormality, We have found a boy and mother who presented with myotonia, peripheral muscular atrophy, and mental retardation in the boy. DMPK analyses found that they did not carry the expanded trinucleotide repeat nor deletion or base substitutions. ZNF9 analyses showed that they did not have CCTG expansion in exon13. The presence of such cases suggested that multiple causative genes are involved in myotonic dystrophy. To investigate the olecular processes of neurodegeneration of trinucleotide disorders, the relation of polyQ aggregation and caspase-8 or caspase-12 activation was analyzed using antisera that specifically recognizes activated caspases. These studies suggested that polyQ aggregates induced caspase-12 activation and apoptosis via ER stress.A family that presented with hemiplegic migrain and late-onset cerebellar ataxia was reported. A missense mutation in CACNA1A gene was detected. This suggested that CACN1A gene is causing a wide-variety of neurodegenerative diseases.

强直性肌营养不良是一种神经退行性疾病，其中三核苷酸序列异常延伸是一种致病基因异常。我们发现一名男孩和母亲出现肌强直、外周肌萎缩和男孩智力低下的症状。 DMPK 分析发现它们不携带扩展的三核苷酸重复序列，也不携带缺失或碱基替换。 ZNF9 分析表明，它们在外显子 13 中没有 CCTG 扩展。此类病例的存在表明强直性肌营养不良涉及多个致病基因。为了研究三核苷酸疾病神经变性的分子过程，使用特异性识别活化的 caspase 的抗血清分析了 PolyQ 聚集与 caspase-8 或 caspase-12 活化的关系。这些研究表明，polyQ 聚集体通过 ER 应激诱导 caspase-12 激活和细胞凋亡。据报道，有一个家族出现偏瘫性偏头痛和迟发性小脑性共济失调。检测到 CACNA1A 基因错义突变。这表明 CACN1A 基因正在引起多种神经退行性疾病。

项目成果

Ichihashi K,Tano S,Momoi MY.: "Three-dimensional echoencep halography in infants."Neurosonography. 12. 320-325 (1999)

Ichihashi K，Tano S，Momoi MY.：“婴儿三维回声脑光描记术。”神经超声检查。

Nakamura M, Yamagata T, Momoi MY.: "CACNA1A gene mutation in individuals with familial hemiplegic migraine(FHM) and late-onset pure spinocerebellar ataxiaa(SCA)"Pediatric Neurology. (In press). (2002)

Nakamura M、Yamagata T、Momoi MY.：“家族性偏瘫性偏头痛 (FHM) 和迟发性单纯性脊髓小脑共济失调 (SCA) 个体中的 CACNA1A 基因突变”小儿神经病学。

Igarash H, Momoi MY, Yamagata T, et al.: "Hypertrophic cardiomyopathy in congenital myotonic dystrophy"Pediatric Neurology. 18. 366-369 (1998)

Igarash H、Momoi MY、Yamagata T 等人：“先天性强直性肌营养不良中的肥厚性心肌病”小儿神经病学。

Mukasa T,Momoi T,Momoi MY.: "Activation of caspase-3 apoptotic oathways in skeletal msucle fibers in laminin a2-deificient mice."Biochem Biophys Res Ciommun. 260. 139-142 (1999)

Mukasa T、Momoi T、Momoi MY.：“层粘连蛋白 a2 缺陷小鼠骨骼肌纤维中 caspase-3 凋亡途径的激活。”Biochem Biophys Res Ciommun。

Kouroku Y, Fujita E et al.: "Localization of active form of capase-8 in mouse L929 cells induces by TNF treatment and polyglutonine aggregales"Biochem. Biophys. Res Commun. 261(in press). (2000)

Kouroku Y、Fujita E 等人：“通过 TNF 处理和多聚谷氨酸聚集体诱导小鼠 L929 细胞中活性形式的 capase-8 的定位”Biochem。