AN ANCIENT RETROTRANSPOSAL INSERTION CAUSES FUKUYAMA-TYPE CONGENITAL MUSCULAR-DYSTROPHY

Fukuyama-type congenital muscular dystrophy (FCMD), one of the most co mmon autosomal recessive disorders in Japan (incidence is 0.7-1.2 per 10,000 births), is characterized by congenital muscular dystrophy asso ciated with brain malformation (micropolygria) due to a defect in the migration of neurons(1). We previously mapped the FCMD gene to a regio n of less than 100 kilobases which included the marker locus D9S2107 o n chromosome 9q31 (refs 2-4). We have also described a haplotype that is shared by more than 80% of FCMD chromosomes, indicating that most c hromosomes bearing the FCMD mutation could be derived hom a single anc estor(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 s equence is about 3 kilobases long and is located in the 3' untranslate d 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 p atients who carry the insertion. Two independent point mutations confi rm that mutation of this gene is responsible for FCMD. The predicted p rotein, which we term fukutin, contains an amino-terminal signal seque nce, which together with results from transfection experiments suggest s that fukutin is a secreted protein. To our knowledge, FCMD is the fi rst human disease to be caused by an ancient retrotransposal integrati on.