A mutation in myotilin causes spheroid body myopathy.
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.
Foroud
T
T
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202-5251, USA. tforoud@iupui.edu
Pankratz
N
N
Batchman
A P
AP
Pauciulo
M W
MW
Vidal
R
R
Miravalle
L
L
Goebel
H H
HH
Cushman
L J
LJ
Azzarelli
B
B
Horak
H
H
Farlow
M
M
Nichols
W C
WC
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
D064211:Connectin; D003598:Cytoskeletal Proteins; D005819:Genetic Markers; C577290:MYOT protein, human; D008840:Microfilament Proteins; D009124:Muscle Proteins