Kobayashi K, Nakahori Y, Miyake M, Matsumura K, Kondo-Iida E, Nomura Y, Segawa M, Yoshioka M, Saito K, Osawa M, Hamano K, Sakakihara Y, Nonaka I, Nakagome Y, Kanazawa I, Nakamura Y, Tokunaga K, Toda T
Laboratory of Genome Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Japan.
Nature. 1998 Jul 23;394(6691):388-92. doi: 10.1038/28653.
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. We previously mapped the FCMD gene to a region of less than 100 kilobases which included the marker locus D9S2107 on chromosome 9q31. 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 from a single ancestor. 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.
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疾病之一（发病率为每10000例出生中有0.7 - 1.2例），其特征是由于神经元迁移缺陷导致先天性肌营养不良并伴有脑畸形（微小多脑回）。我们先前将FCMD基因定位到小于100千碱基的区域，该区域包括9号染色体9q31上的标记位点D9S2107。我们还描述了一种单倍型，超过80%的FCMD染色体共享该单倍型，这表明大多数携带FCMD突变的染色体可能源自单一祖先。在此我们报告，在所有携带始祖单倍型（87%）的FCMD染色体的该候选基因区间内存在串联重复序列的逆转座插入。插入序列约3千碱基长，位于一个编码新的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，但在携带插入序列的FCMD患者中不表达。两个独立的点突变证实该基因的突变是FCMD的病因。我们将预测的蛋白质命名为福库汀，它含有一个氨基末端信号序列，这与转染实验结果共同表明福库汀是一种分泌蛋白。据我们所知，FCMD是首例由古老的逆转座整合引起的人类疾病。
