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A mutation in myotilin causes spheroid body myopathy.

AbstractBACKGROUND:
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.
AuthorsT 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
JournalNeurology (Neurology) Vol. 65 Issue 12 Pg. 1936-40 (Dec 27 2005) ISSN: 1526-632X [Electronic] United States
PMID16380616 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Connectin
  • Cytoskeletal Proteins
  • Genetic Markers
  • MYOT protein, human
  • Microfilament Proteins
  • Muscle Proteins
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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