Biallelic Mutations in MYPN, Encoding Myopalladin, Are Associated with Childhood-Onset, Slowly Progressive Nemaline Myopathy

Satoko Miyatake, Satomi Mitsuhashi, Yukiko K. Hayashi, Enkhsaikhan Purevjav, Atsuko Nishikawa, Eriko Koshimizu, Mikiya Suzuki, Kana Yatabe, Yuzo Tanaka, Katsuhisa Ogata, Satoshi Kuru, Masaaki Shiina, Yoshinori Tsurusaki, Mitsuko Nakashima, Takeshi Mizuguchi, Noriko Miyake, Hirotomo Saitsu, Kazuhiro Ogata, Mitsuru Kawai, Jeffrey Towbin & 3 others Ikuya Nonaka, Ichizo Nishino, Naomichi Matsumoto

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)169-178
Number of pages10
JournalAmerican Journal of Human Genetics
Volume100
Issue number1
DOIs
StatePublished - Jan 5 2017

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Nemaline Myopathies
Mutation
Muscle Weakness
Skeletal Muscle
Mobility Limitation
Exome
Muscle Hypotonia
Striated Muscle
Nonsense Codon
Respiratory Insufficiency
Electron Microscopy
Phenotype
Muscles

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Biallelic Mutations in MYPN, Encoding Myopalladin, Are Associated with Childhood-Onset, Slowly Progressive Nemaline Myopathy. / Miyatake, Satoko; Mitsuhashi, Satomi; Hayashi, Yukiko K.; Purevjav, Enkhsaikhan; Nishikawa, Atsuko; Koshimizu, Eriko; Suzuki, Mikiya; Yatabe, Kana; Tanaka, Yuzo; Ogata, Katsuhisa; Kuru, Satoshi; Shiina, Masaaki; Tsurusaki, Yoshinori; Nakashima, Mitsuko; Mizuguchi, Takeshi; Miyake, Noriko; Saitsu, Hirotomo; Ogata, Kazuhiro; Kawai, Mitsuru; Towbin, Jeffrey; Nonaka, Ikuya; Nishino, Ichizo; Matsumoto, Naomichi.

In: American Journal of Human Genetics, Vol. 100, No. 1, 05.01.2017, p. 169-178.

Research output: Contribution to journalArticle

Miyatake, S, Mitsuhashi, S, Hayashi, YK, Purevjav, E, Nishikawa, A, Koshimizu, E, Suzuki, M, Yatabe, K, Tanaka, Y, Ogata, K, Kuru, S, Shiina, M, Tsurusaki, Y, Nakashima, M, Mizuguchi, T, Miyake, N, Saitsu, H, Ogata, K, Kawai, M, Towbin, J, Nonaka, I, Nishino, I & Matsumoto, N 2017, 'Biallelic Mutations in MYPN, Encoding Myopalladin, Are Associated with Childhood-Onset, Slowly Progressive Nemaline Myopathy', American Journal of Human Genetics, vol. 100, no. 1, pp. 169-178. https://doi.org/10.1016/j.ajhg.2016.11.017
Miyatake, Satoko ; Mitsuhashi, Satomi ; Hayashi, Yukiko K. ; Purevjav, Enkhsaikhan ; Nishikawa, Atsuko ; Koshimizu, Eriko ; Suzuki, Mikiya ; Yatabe, Kana ; Tanaka, Yuzo ; Ogata, Katsuhisa ; Kuru, Satoshi ; Shiina, Masaaki ; Tsurusaki, Yoshinori ; Nakashima, Mitsuko ; Mizuguchi, Takeshi ; Miyake, Noriko ; Saitsu, Hirotomo ; Ogata, Kazuhiro ; Kawai, Mitsuru ; Towbin, Jeffrey ; Nonaka, Ikuya ; Nishino, Ichizo ; Matsumoto, Naomichi. / Biallelic Mutations in MYPN, Encoding Myopalladin, Are Associated with Childhood-Onset, Slowly Progressive Nemaline Myopathy. In: American Journal of Human Genetics. 2017 ; Vol. 100, No. 1. pp. 169-178.
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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.",
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AU - Mitsuhashi, Satomi

AU - Hayashi, Yukiko K.

AU - Purevjav, Enkhsaikhan

AU - Nishikawa, Atsuko

AU - Koshimizu, Eriko

AU - Suzuki, Mikiya

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AU - Tanaka, Yuzo

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AU - Miyake, Noriko

AU - Saitsu, Hirotomo

AU - Ogata, Kazuhiro

AU - Kawai, Mitsuru

AU - Towbin, Jeffrey

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N2 - 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.

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