TY - JOUR
T1 - Targeted sequencing and identification of genetic variants in sporadic inclusion body myositis
AU - Weihl, Conrad C.
AU - Baloh, Robert H.
AU - Lee, Youjin
AU - Chou, Tsui Fen
AU - Pittman, Sara K.
AU - Lopate, Glenn
AU - Allred, Peggy
AU - Jockel-Balsarotti, Jennifer
AU - Pestronk, Alan
AU - Harms, Matthew B.
N1 - Publisher Copyright:
© 2014 Elsevier B.V..
PY - 2015/4/1
Y1 - 2015/4/1
N2 - Sporadic inclusion body myositis (sIBM) has clinical, pathologic and pathomechanistic overlap with some inherited muscle and neurodegenerative disorders. In this study, DNA from 79 patients with sIBM was collected and the sequencing of 38 genes associated with hereditary inclusion body myopathy (IBM), myofibrillar myopathy, Emery-Dreifuss muscular dystrophy, distal myopathy, amyotrophic lateral sclerosis and dementia along with C9orf72 hexanucleotide repeat analysis was performed. No C9orf72 repeat expansions were identified, but; 27 rare (minor allele frequency <1%) missense coding variants in several other genes were identified. One patient carried a p.R95C missense mutation in VCP and another carried a previously reported p.I27V missense mutation in VCP. Mutations in VCP cause IBM associated with Paget's disease of the bone (PDB) and fronto-temporal dementia (IBMPFD). Neither patient had a family history of weakness or manifested other symptoms reported with VCP mutations such as PDB or dementia. In vitro analysis of these VCP variants found that they both disrupted autophagy similar to other pathogenic mutations. Although no clear genetic etiology has been implicated in sIBM pathogenesis, our study suggests that genetic evaluation in sIBM may be clinically meaningful and lend insight into its pathomechanism.
AB - Sporadic inclusion body myositis (sIBM) has clinical, pathologic and pathomechanistic overlap with some inherited muscle and neurodegenerative disorders. In this study, DNA from 79 patients with sIBM was collected and the sequencing of 38 genes associated with hereditary inclusion body myopathy (IBM), myofibrillar myopathy, Emery-Dreifuss muscular dystrophy, distal myopathy, amyotrophic lateral sclerosis and dementia along with C9orf72 hexanucleotide repeat analysis was performed. No C9orf72 repeat expansions were identified, but; 27 rare (minor allele frequency <1%) missense coding variants in several other genes were identified. One patient carried a p.R95C missense mutation in VCP and another carried a previously reported p.I27V missense mutation in VCP. Mutations in VCP cause IBM associated with Paget's disease of the bone (PDB) and fronto-temporal dementia (IBMPFD). Neither patient had a family history of weakness or manifested other symptoms reported with VCP mutations such as PDB or dementia. In vitro analysis of these VCP variants found that they both disrupted autophagy similar to other pathogenic mutations. Although no clear genetic etiology has been implicated in sIBM pathogenesis, our study suggests that genetic evaluation in sIBM may be clinically meaningful and lend insight into its pathomechanism.
KW - Amyotrophic lateral sclerosis
KW - Hereditary inclusion body myopathy
KW - Inclusion body myositis
KW - Myofibrillar myopathy
KW - VCP
UR - http://www.scopus.com/inward/record.url?scp=84925234233&partnerID=8YFLogxK
U2 - 10.1016/j.nmd.2014.12.009
DO - 10.1016/j.nmd.2014.12.009
M3 - Article
C2 - 25617006
AN - SCOPUS:84925234233
SN - 0960-8966
VL - 25
SP - 289
EP - 296
JO - Neuromuscular Disorders
JF - Neuromuscular Disorders
IS - 4
ER -