Isolation of a gene for Fukuyama-type congenital muscular dystrophy and genetic diagnosis

福山型先天性肌营养不良症基因的分离及基因诊断

• 批准号: 07670699
• 负责人: TODA Tatsushi
• 金额: $ 1.41万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07670699/
• 关键词: Fukuyama-type congenital muscular dystrophy (FCMD); chromosome 9q31; linkage disequilibrium; founder-haplotype; genetic diagnosis; prenatal dianosis; brain anomaly; ポジショナルクローニング; 9番染色体長腕31; 連鎖不平衡; コスミドコンティグ; 創始者染色体; 9番染色体長腕引; 連鎖不平衡マッピング; 酵母人

Fukuyama-type congenital muscular dystrophy (FCMD), the second most common form of muscular dystrophy in Japan, is an autosomal recessive severe muscular dystrophy, associated with brain anomalies.1. Following our initial mapping of the FCMD locus to chromosome 9q31-33, we found linkage disequilibrium between FCMD and mfd220 on 9q31 and then constructed the YAC contig encompassing mfd220.2. By using linkage-disequilibrium mapping, we narrowd the candidate region to <100 kb containing D9S2107 and constructed the consmid contig harboring D9S2107.3. We examined haplotypes of FCMD chromosomes at a few loci around D9S2107. The results indicated that 80% of FCMD-bearing chromosomes carried an ancestral haplotype and that 95% of FCMD patients carried ancestral haplotypes homozygously or heterozygously. There were only a few haplotypes other than the founder one. We predicted the gene location extremely proximal to marker E6 by founder-haplotype mapping.4. We screened genomic rearrangements in FCMD using each clone of the cosmid contig around D9S2107 as a probe. A -3 kb insertion was found near the marker E6, which lies -50 kb proximal to D9S2107, in most FCMD chromosomes with the founder haplotype (86%). The frequency of this insertion in normal chromosomes matched well that of FCMD carrier.5. We performed prenatal dianoses of 10 and several FCMD familes. All the results were correct. Also, we conducted genetic diagnosis of 30-40 families. We demonstrated that breaches in the glia limitans may be the primary cause of the micropolygyria in FCMD by pathological study of an FCMD fetus.

福山型先天性肌肉营养不良症（FCMD）是日本第二大最常见的肌肉营养不良的形式，是一种常染色体隐性严重的严重肌肉营养不合，与脑异常有关。1。在将FCMD基因座与9q31-33染色体的初始映射后，我们在9q31上发现了FCMD和MFD220之间的连锁不平衡，然后构建了包含MFD220.2的YAC重叠群。通过使用链接区绘制映射，我们将候选区域缩小到包含D9S2107的<100 kb，并构建了带有D9S2107.3的Consmid Contig。我们检查了D9S2107附近几个基因座的FCMD染色体的单倍型。结果表明，80％的含FCMD的染色体携带祖先单倍型，而95％的FCMD患者则携带祖先单倍型纯粹或杂合。除了创始人外，只有少数单倍型。我们预测了创建者 - 型型映射的基因位置非常靠近标记E6的位置4。我们使用D9S2107附近的宇宙重叠群的每个克隆作为探针筛选了FCMD中的基因组重排。在大多数FCMD染色体中，均与创始人单倍型（86％）的大多数FCMD染色体（86％），在标记E6附近发现了-3 kb插入。这种插入在正常染色体中的频率与FCMD载体的频率很好。5。我们进行了10和几个FCMD家族的产前黛安。所有结果都是正确的。另外，我们对30-40个家庭进行了遗传诊断。我们证明，通过对FCMD胎儿的病理研究，在Glia Limitans中的破坏可能是FCMD中微地位的主要原因。

项目成果

Toda T,Watanabe T,Matsubara K,etal.: "Three-dimensional MR imaging of brain surfree anomalies in Fukuyama-type congenital muscular dystrophy." Muscle and Nerve. 18. 508-517 (1995)

Toda T、Watanabe T、Matsubara K 等人：“福山型先天性肌营养不良症脑部无异常的三维 MR 成像。”

Kondo-Iida E, ...., Toda T.: "Molecular genetic evidence of clinical heterogeneity in Fukuyama type congenital muscular dystrophy." Hum Genet. 99. 427-432 (1997)

Kondo-Iida E, ...., Toda T.：“福山型先天性肌营养不良症临床异质性的分子遗传学证据。”

Toda T.et al.: "Linkage-disequilibrium mapping narrows the Fukuyama-type congenital muscular dystrophy (FCMD) candidate region to <100 kb." Am J Hum Genet. 59. 1313-1320 (1996)

Toda T.等人：“连锁不平衡图谱将福山型先天性肌营养不良症 (FCMD) 候选区域缩小至 <100 kb。”

Toda T,Miyake M,Nakahori Y,et al.: "Toward identification of the Fukuyama type congenital musculor dystroply(FCMD)gene." Brain and Development. (in press).

Toda T、Miyake M、Nakahori Y 等人：“福山型先天性肌营养不良 (FCMD) 基因的鉴定”。

Toda T,……: "Linkage-disequilibrium mapping narrows the Fukuyama-type congenital muscular dystrophy(FCMD)candidate region to<100kb." Am J Hum Genet. 59. 1313-1320 (1996)

Toda T，……：“连锁不平衡图谱将福山型先天性肌营养不良症 (FCMD) 候选区域缩小至 <100kb。” Am J Hum Genet。59. 1313-1320 (1996)