A mutation in myotilin causes spheroid body myopathy

Neurology. 2005 Dec 27;65(12):1936-40. doi: 10.1212/01.wnl.0000188872.28149.9a.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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*
  • Inclusion Bodies / metabolism
  • Inclusion Bodies / pathology
  • Male
  • Microfilament Proteins
  • Middle Aged
  • Muscle Proteins / genetics*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / physiopathology*
  • Muscular Diseases / genetics*
  • Muscular Diseases / pathology
  • Muscular Diseases / physiopathology
  • Mutation / genetics*
  • Pedigree
  • Point Mutation / genetics


  • Connectin
  • Cytoskeletal Proteins
  • Genetic Markers
  • MYOT protein, human
  • Microfilament Proteins
  • Muscle Proteins