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An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy
K Kobayashi1, Y Nakahori, M Miyake
1Laboratory of Genome Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Japan.
Abstract:
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.
Insights
Fukuyama-type congenital muscular dystrophy (FCMD) is caused by a retrotransposal insertion in the fukutin gene. This insertion disrupts gene expression, leading to muscular dystrophy and brain malformations in affected individuals.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Fukuyama-type congenital muscular dystrophy (FCMD) is a common autosomal recessive disorder in Japan.
- FCMD is characterized by congenital muscular dystrophy and brain malformation (micropolygria) due to neuronal migration defects.
Purpose of the Study:
- To identify the genetic cause of FCMD.
- To investigate the molecular mechanism underlying FCMD pathogenesis.
Main Methods:
- Gene mapping to identify the FCMD candidate region on chromosome 9q31.
- Analysis of retrotransposal insertion within the candidate gene interval.
- Gene expression studies in normal individuals and FCMD patients.
- Confirmation of gene mutation through independent point mutations.
Main Results:
- A retrotransposal insertion of tandemly repeated sequences was identified in 87% of FCMD chromosomes with the founder haplotype.
- The insertion is located in the 3' untranslated region of a novel gene encoding a 461-amino-acid protein, named fukutin.
- The fukutin gene is expressed in normal tissues but not in FCMD patients with the insertion.
- Two independent point mutations in the fukutin gene confirmed its role in FCMD.
- Fukutin is predicted to be a secreted protein.
Conclusions:
- FCMD is caused by mutations in the fukutin gene.
- The identified retrotransposal insertion is the primary cause of FCMD in patients carrying the founder haplotype.
- This study identifies FCMD as the first human disease linked to an ancient retrotransposal integration event.