title: Biallelic Mutations in MYPN, Encoding Myopalladin, Are Associated with Childhood-Onset, Slowly Progressive Nemaline Myopathy.
abstract: Nemaline myopathy (NM) is a common form of congenital nondystrophic skeletal muscle disease characterized by muscular weakness of proximal dominance, hypotonia, and respiratory insufficiency but typically not cardiac dysfunction. Wide variation in severity has been reported. Intranuclear rod myopathy is a subtype of NM in which rod-like bodies are seen in the nucleus, and it often manifests as a severe phenotype. Although ten mutant genes are currently known to be associated with NM, only ACTA1 is associated with intranuclear rod myopathy. In addition, the genetic cause remains unclear in approximately 25%-30% of individuals with NM. We performed whole-exome sequencing on individuals with histologically confirmed but genetically unsolved NM. Our study included individuals with milder, later-onset NM and identified biallelic loss-of-function mutations in myopalladin (MYPN) in four families. Encoded MYPN is a sarcomeric protein exclusively localized in striated muscle in humans. Individuals with identified MYPN mutations in all four of these families have relatively mild, childhood- to adult-onset NM with slowly progressive muscle weakness. Walking difficulties were recognized around their forties. Decreased respiratory function, cardiac involvement, and intranuclear rods in biopsied muscle were observed in two individuals. MYPN was localized at the Z-line in control skeletal muscles but was absent from affected individuals. Homozygous knockin mice with a nonsense mutation in Mypn showed Z-streaming and nemaline-like bodies adjacent to a disorganized Z-line on electron microscopy, recapitulating the disease. Our results suggest that MYPN screening should be considered in individuals with mild NM, especially when cardiac problems or intranuclear rods are present.
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan; Clinical Genetics Department, Yokohama City University Hospital, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Miyatake
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan; Department of Genome Medicine Development, Medical Genome Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan; Biomedical Informatics Laboratory, Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Mitsuhashi
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan; Department of Pathophysiology, Tokyo Medical University, Shinjuku-ku, Tokyo 160-8402, Japan.
authors.forename: Yukiko K
authors.initials: YK
authors.lastname: Hayashi
authors.affiliation: Department of Pediatrics, The Heart Institute, University of Tennessee Health Science Center, Memphis, TN 38103, USA.
authors.forename: Enkhsaikhan
authors.initials: E
authors.lastname: Purevjav
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan; Department of Education, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo-shi, Yamanashi 409-3898, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Nishikawa
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Koshimizu
authors.affiliation: Department of Neurology, National Hospital Organization Higashisaitama Hospital, Hasuda, Saitama 349-0196, Japan.
authors.forename: Mikiya
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Neurology, National Hospital Organization Higashisaitama Hospital, Hasuda, Saitama 349-0196, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Yatabe
authors.affiliation: Department of Neurology, National Hospital Organization Higashisaitama Hospital, Hasuda, Saitama 349-0196, Japan.
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Neurology, National Hospital Organization Higashisaitama Hospital, Hasuda, Saitama 349-0196, Japan.
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Ogata
authors.affiliation: Department of Neurology, National Hospital Organization Suzuka National Hospital, Suzuka, Mie 513-8501, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kuru
authors.affiliation: Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Shiina
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsurusaki
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Mizuguchi
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan; Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
authors.affiliation: Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ogata
authors.affiliation: Department of Neurology, National Hospital Organization Higashisaitama Hospital, Hasuda, Saitama 349-0196, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Kawai
authors.affiliation: Department of Pediatrics, The Heart Institute, University of Tennessee Health Science Center, Memphis, TN 38103, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Towbin
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan.
authors.forename: Ikuya
authors.initials: I
authors.lastname: Nonaka
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan.
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan. Electronic address: naomat@yokohama-cu.ac.jp.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
mesh_terms: D000328:Adult; D017668:Age of Onset; D000483:Alleles; D000818:Animals; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D055879:Gene Knock-In Techniques; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009154:Mutation; D017696:Myopathies, Nemaline / Q000235:genetics* / Q000473:pathology; D010375:Pedigree
chemical_list: C426225:MYPN protein, human; D009124:Muscle Proteins
keywords: MYPN; congenital myopathy; intranuclear rod myopathy; nemaline myopathy; whole-exome sequencing