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A mutation in myotilin causes spheroid body myopathy

From the Departments of Medical and Molecular Genetics (Drs. Foroud, Pankratz, and Cushman), Pathology and Laboratory Medicine (Drs. Vidal, Miravalle, and Azzarelli), and Neurology (Drs. Horak and Farlow), Indiana University School of Medicine, Indianapolis; Division of Human Genetics (Dr. Nichols, A.P. Batchman and M.W. Pauciulo), Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; and Department of Neuropathology (Dr. Goebel), Johannes Gutenberg University, Medical Center, Mainz, Germany.

Address correspondence and reprint requests to Dr. T. Foroud, Department of Medical and Molecular Genetics (IB 130), Indiana University School of Medicine, 975 West Walnut Street, Indianapolis, IN 46202-5251; e-mail: tforoud{at}iupui.edu

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.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the December 27 issue to find the title link for this article.

Supported by MO1 RR-00750.

Disclosure: The authors report no conflicts of interest.

Received March 15, 2005. Accepted in final form September 23, 2005.

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