title: A mutation in myotilin causes spheroid body myopathy.
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.
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202-5251, USA. tforoud@iupui.edu
authors.forename: T
authors.initials: T
authors.lastname: Foroud
authors.forename: N
authors.initials: N
authors.lastname: Pankratz
authors.forename: A P
authors.initials: AP
authors.lastname: Batchman
authors.forename: M W
authors.initials: MW
authors.lastname: Pauciulo
authors.forename: R
authors.initials: R
authors.lastname: Vidal
authors.forename: L
authors.initials: L
authors.lastname: Miravalle
authors.forename: H H
authors.initials: HH
authors.lastname: Goebel
authors.forename: L J
authors.initials: LJ
authors.lastname: Cushman
authors.forename: B
authors.initials: B
authors.lastname: Azzarelli
authors.forename: H
authors.initials: H
authors.lastname: Horak
authors.forename: M
authors.initials: M
authors.lastname: Farlow
authors.forename: W C
authors.initials: WC
authors.lastname: Nichols
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D025063:Chromosome Disorders / Q000235:genetics; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D064211:Connectin; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008840:Microfilament Proteins; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics
chemical_list: D064211:Connectin; D003598:Cytoskeletal Proteins; D005819:Genetic Markers; C577290:MYOT protein, human; D008840:Microfilament Proteins; D009124:Muscle Proteins