An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy
An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy
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作者：
Kobayashi, K;Nakahori, Y;Toda, T
福山型先天性肌营养不良症（FCMD）是日本最常见的常染色体隐性遗传疾病之一（发病率为每10，000名新生儿0.7-1.2例），其特征为与神经元迁移缺陷导致的脑畸形（小多肌畸形）相关的先天性肌营养不良症（1）。我们先前将FCMD基因定位到染色体9 q31上的标记位点D9 S2107的少于100个内切酶的区域（参考文献2-4）。我们还描述了一种超过80%的FCMD染色体所共有的单倍型，表明大多数携带FCMD突变的染色体可能来自单一祖先（5）。在这里，我们报告说，有一个retrotranslation插入串联重复序列在这个候选基因的间隔在所有FCMD染色体携带创始人单倍型（87%）。插入的序列长约3个组氨酸，位于编码新的461个氨基酸蛋白质的基因的3'非翻译区。该基因在正常个体的各种组织中表达，但在携带插入的FCMD患者中不表达。两个独立的点突变证实了该基因的突变是FCMD的原因。预测的蛋白质，我们称之为fukaline，含有氨基末端信号序列，这与转染实验的结果表明，fukaline是一种分泌蛋白。据我们所知，FCMD是第一个由古老的逆转录酶整合引起的人类疾病。
Fukuyama-type congenital muscular dystrophy (FCMD), one of the most common autosomal recessive disorders in Japan (incidence is 0.7-1.2 per 10,000 births), is characterized by congenital muscular dystrophy associated with brain malformation (micropolygria) due to a defect in the migration of neurons(1). We previously mapped the FCMD gene to a region of less than 100 kilobases which included the marker locus D9S2107 on chromosome 9q31 (refs 2-4). We have also described a haplotype that is shared by more than 80% of FCMD chromosomes, indicating that most chromosomes bearing the FCMD mutation could be derived hom a single ancestor(5). Here we report that there is a retrotransposal insertion of tandemly repeated sequences within this candidate-gene interval in all FCMD chromosomes carrying the founder haplotype (87%). The inserted sequence is about 3 kilobases long and is located in the 3' untranslated region of a gene encoding a new 461-amino-acid protein. This gene is expressed in various tissues in normal individuals, but not in FCMD patients who carry the insertion. Two independent point mutations confirm that mutation of this gene is responsible for FCMD. The predicted protein, which we term fukutin, contains an amino-terminal signal sequence, which together with results from transfection experiments suggests that fukutin is a secreted protein. To our knowledge, FCMD is the first human disease to be caused by an ancient retrotransposal integration.