Abstract | BACKGROUND: Spheroid body myopathy (SBM) is a rare, autosomal dominant, neuromuscular disorder, which has only been previously reported in a single large kindred. Identification of the mutated gene in this disorder may provide insight regarding abnormal neuromuscular function. METHODS: The authors completed a detailed clinical evaluation on an extensive kindred diagnosed with SBM. Genome-wide linkage analysis was performed to localize the disease gene to a specific chromosomal region. Further marker genotyping and screening of a positional, functional candidate gene were completed to detect the disease-causing mutation. Pathologic analysis of muscle biopsy was performed on three individuals. Biochemical studies were performed on one muscle biopsy specimen from an affected individual. RESULTS: Linkage to chromosome 5q23-5q31 was detected with a lod score of 2.9. Genotyping of additional markers in a larger sample of family members produced a maximum lod score of 6.1 and narrowed the critical interval to 12.2 cM. Screening of the candidate gene titin immunoglobulin domain protein (TTID, also known as MYOT) detected a cytosine-to-thymine mutation in exon 2 of all clinically affected family members. Similar pathologic changes were present in all muscle biopsy specimens. Immunohistologic and biochemical analysis revealed that the TTID protein, also known as myotilin, is a component of the insoluble protein aggregate. CONCLUSIONS: A novel mutation in the TTID gene results in the clinical and pathologic phenotype termed "spheroid body myopathy." Mutations in this gene also cause limb-girdle muscular dystrophy 1A and are associated with myofibrillar myopathy.
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Authors | T Foroud, N Pankratz, A P Batchman, M W Pauciulo, R Vidal, L Miravalle, H H Goebel, L J Cushman, B Azzarelli, H Horak, M Farlow, W C Nichols |
Journal | Neurology
(Neurology)
Vol. 65
Issue 12
Pg. 1936-40
(Dec 27 2005)
ISSN: 1526-632X [Electronic] United States |
PMID | 16380616
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Connectin
- Cytoskeletal Proteins
- Genetic Markers
- MYOT protein, human
- Microfilament Proteins
- Muscle Proteins
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Topics |
- Adult
- Aged
- Aged, 80 and over
- Chromosome Disorders
(genetics)
- Chromosome Mapping
- Chromosomes, Human, Pair 5
(genetics)
- Connectin
- Cytoskeletal Proteins
(genetics)
- DNA Mutational Analysis
- Exons
(genetics)
- Female
- Genes, Dominant
(genetics)
- Genetic Markers
(genetics)
- Genetic Predisposition to Disease
(genetics)
- Genetic Testing
- Humans
- Inclusion Bodies
(genetics, metabolism, pathology)
- Male
- Microfilament Proteins
- Middle Aged
- Muscle Proteins
(genetics)
- Muscle, Skeletal
(metabolism, pathology, physiopathology)
- Muscular Diseases
(genetics, pathology, physiopathology)
- Mutation
(genetics)
- Pedigree
- Point Mutation
(genetics)
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