title: Isolated inclusion body myopathy caused by a multisystem proteinopathy-linked hnRNPA1 mutation.
abstract: OBJECTIVE
  To identify the genetic cause of isolated inclusion body myopathy (IBM) with autosomal dominant inheritance in 2 families.
  
  
  METHODS
  Genetic investigations were performed using whole-exome and Sanger sequencing of the heterogeneous nuclear ribonucleoprotein A1 gene (hnRNPA1). The clinical and pathologic features of patients in the 2 families were evaluated with neurologic examinations, muscle imaging, and muscle biopsy.
  
  
  RESULTS
  We identified a missense p.D314N mutation in hnRNPA1, which is also known to cause familial amyotrophic lateral sclerosis, in 2 families with IBM. The affected individuals developed muscle weakness in their 40s, which slowly progressed toward a limb-girdle pattern. Further evaluation of the affected individuals revealed no apparent motor neuron dysfunction, cognitive impairment, or bone abnormality. The muscle pathology was compatible with IBM, lacking apparent neurogenic change and inflammation. Multiple immunohistochemical analyses revealed the cytoplasmic aggregation of hnRNPA1 in close association with autophagosomes and myonuclei. Furthermore, the aberrant accumulation was characterized by coaggregation with ubiquitin, sequestome-1/p62, valosin-containing protein/p97, and a variety of RNA-binding proteins (RBPs).
  
  
  CONCLUSIONS
  The present study expands the clinical phenotype of hnRNPA1-linked multisystem proteinopathy. Mutations in hnRNPA1, and possibly hnRNPA2B1, will be responsible for isolated IBM with a pure muscular phenotype. Although the mechanisms underlying the selective skeletal muscle involvement remain to be elucidated, the immunohistochemical results suggest a broad sequestration of RBPs by the mutated hnRNPA1.
authors.affiliation: Departments of Neurology (R.I., H.W., K.I., A.N., N.S., M.T., M.K., M.A.), Medical Genetics (R.I., A.N., T.N., Y.A.), the Division of Interdisciplinary Medical Science (M.S.), and the Division of Cell Proliferation (R.F., K.N.), United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; and Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP) and Department of Genome Medicine Development, Medical Genome Center, NCNP (S.M., I.N.), Tokyo, Japan.
authors.forename: Rumiko
authors.initials: R
authors.lastname: Izumi
authors.affiliation: Departments of Neurology (R.I., H.W., K.I., A.N., N.S., M.T., M.K., M.A.), Medical Genetics (R.I., A.N., T.N., Y.A.), the Division of Interdisciplinary Medical Science (M.S.), and the Division of Cell Proliferation (R.F., K.N.), United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; and Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP) and Department of Genome Medicine Development, Medical Genome Center, NCNP (S.M., I.N.), Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Warita
authors.affiliation: Departments of Neurology (R.I., H.W., K.I., A.N., N.S., M.T., M.K., M.A.), Medical Genetics (R.I., A.N., T.N., Y.A.), the Division of Interdisciplinary Medical Science (M.S.), and the Division of Cell Proliferation (R.F., K.N.), United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; and Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP) and Department of Genome Medicine Development, Medical Genome Center, NCNP (S.M., I.N.), Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Niihori
authors.affiliation: Departments of Neurology (R.I., H.W., K.I., A.N., N.S., M.T., M.K., M.A.), Medical Genetics (R.I., A.N., T.N., Y.A.), the Division of Interdisciplinary Medical Science (M.S.), and the Division of Cell Proliferation (R.F., K.N.), United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; and Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP) and Department of Genome Medicine Development, Medical Genome Center, NCNP (S.M., I.N.), Tokyo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Departments of Neurology (R.I., H.W., K.I., A.N., N.S., M.T., M.K., M.A.), Medical Genetics (R.I., A.N., T.N., Y.A.), the Division of Interdisciplinary Medical Science (M.S.), and the Division of Cell Proliferation (R.F., K.N.), United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; and Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP) and Department of Genome Medicine Development, Medical Genome Center, NCNP (S.M., I.N.), Tokyo, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Tateyama
authors.affiliation: Departments of Neurology (R.I., H.W., K.I., A.N., N.S., M.T., M.K., M.A.), Medical Genetics (R.I., A.N., T.N., Y.A.), the Division of Interdisciplinary Medical Science (M.S.), and the Division of Cell Proliferation (R.F., K.N.), United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; and Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP) and Department of Genome Medicine Development, Medical Genome Center, NCNP (S.M., I.N.), Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Suzuki
authors.affiliation: Departments of Neurology (R.I., H.W., K.I., A.N., N.S., M.T., M.K., M.A.), Medical Genetics (R.I., A.N., T.N., Y.A.), the Division of Interdisciplinary Medical Science (M.S.), and the Division of Cell Proliferation (R.F., K.N.), United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; and Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP) and Department of Genome Medicine Development, Medical Genome Center, NCNP (S.M., I.N.), Tokyo, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Nishiyama
authors.affiliation: Departments of Neurology (R.I., H.W., K.I., A.N., N.S., M.T., M.K., M.A.), Medical Genetics (R.I., A.N., T.N., Y.A.), the Division of Interdisciplinary Medical Science (M.S.), and the Division of Cell Proliferation (R.F., K.N.), United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; and Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP) and Department of Genome Medicine Development, Medical Genome Center, NCNP (S.M., I.N.), Tokyo, Japan.
authors.forename: Matsuyuki
authors.initials: M
authors.lastname: Shirota
authors.affiliation: Departments of Neurology (R.I., H.W., K.I., A.N., N.S., M.T., M.K., M.A.), Medical Genetics (R.I., A.N., T.N., Y.A.), the Division of Interdisciplinary Medical Science (M.S.), and the Division of Cell Proliferation (R.F., K.N.), United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; and Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP) and Department of Genome Medicine Development, Medical Genome Center, NCNP (S.M., I.N.), Tokyo, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Funayama
authors.affiliation: Departments of Neurology (R.I., H.W., K.I., A.N., N.S., M.T., M.K., M.A.), Medical Genetics (R.I., A.N., T.N., Y.A.), the Division of Interdisciplinary Medical Science (M.S.), and the Division of Cell Proliferation (R.F., K.N.), United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; and Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP) and Department of Genome Medicine Development, Medical Genome Center, NCNP (S.M., I.N.), Tokyo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Departments of Neurology (R.I., H.W., K.I., A.N., N.S., M.T., M.K., M.A.), Medical Genetics (R.I., A.N., T.N., Y.A.), the Division of Interdisciplinary Medical Science (M.S.), and the Division of Cell Proliferation (R.F., K.N.), United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; and Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP) and Department of Genome Medicine Development, Medical Genome Center, NCNP (S.M., I.N.), Tokyo, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Mitsuhashi
authors.affiliation: Departments of Neurology (R.I., H.W., K.I., A.N., N.S., M.T., M.K., M.A.), Medical Genetics (R.I., A.N., T.N., Y.A.), the Division of Interdisciplinary Medical Science (M.S.), and the Division of Cell Proliferation (R.F., K.N.), United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; and Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP) and Department of Genome Medicine Development, Medical Genome Center, NCNP (S.M., I.N.), Tokyo, Japan.
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
authors.affiliation: Departments of Neurology (R.I., H.W., K.I., A.N., N.S., M.T., M.K., M.A.), Medical Genetics (R.I., A.N., T.N., Y.A.), the Division of Interdisciplinary Medical Science (M.S.), and the Division of Cell Proliferation (R.F., K.N.), United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; and Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP) and Department of Genome Medicine Development, Medical Genome Center, NCNP (S.M., I.N.), Tokyo, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Aoki
authors.affiliation: Departments of Neurology (R.I., H.W., K.I., A.N., N.S., M.T., M.K., M.A.), Medical Genetics (R.I., A.N., T.N., Y.A.), the Division of Interdisciplinary Medical Science (M.S.), and the Division of Cell Proliferation (R.F., K.N.), United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (T.T.), National Hospital Organization Sendai-Nishitaga National Hospital, Sendai, Japan; Department of Neurology (M.T.), Iwate National Hospital, Ichinoseki, Japan; and Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP) and Department of Genome Medicine Development, Medical Genome Center, NCNP (S.M., I.N.), Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Aoki