Novel mutations in NEB cause abnormal nebulin expression and markedly impaired muscle force generation in severe nemaline myopathy

Michael W. Lawlor, Coen A. Ottenheijm, Vilma Lotta Lehtokari, Kiyomi Cho, Katarina Pelin, Carina Wallgren-Pettersson, Hendrikus "Henk" Granzier, Alan H. Beggs

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Background: Nemaline myopathy (NM) is a congenital muscle disease associated with weakness and the presence of nemaline bodies (rods) in muscle fibers. Mutations in seven genes have been associated with NM, but the most commonly mutated gene is nebulin (NEB), which is thought to account for roughly 50% of cases.Results: We describe two siblings with severe NM, arthrogryposis and neonatal death caused by two novel NEB mutations: a point mutation in intron 13 and a frameshift mutation in exon 81. Levels of detectable nebulin protein were significantly lower than those in normal control muscle biopsies or those from patients with less severe NM due to deletion of NEB exon 55. Mechanical studies of skinned myofibers revealed marked impairment of force development, with an increase in tension cost.Conclusions: Our findings demonstrate that the mechanical phenotype of severe NM is the consequence of mutations that severely reduce nebulin protein levels and suggest that the level of nebulin expression may correlate with the severity of disease.

Original languageEnglish (US)
Article number23
JournalSkeletal Muscle
Volume1
Issue number1
DOIs
StatePublished - Jun 20 2011

Fingerprint

Nemaline Myopathies
Muscles
Mutation
Exons
Arthrogryposis
Frameshift Mutation
Point Mutation
Introns
Genes
nebulin
Siblings
Proteins
Phenotype
Biopsy
Costs and Cost Analysis

Keywords

  • Congenital myopathy
  • Nebulin
  • Nemaline myopathy
  • Nemaline rod (body)
  • Thin filament

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology
  • Orthopedics and Sports Medicine

Cite this

Lawlor, M. W., Ottenheijm, C. A., Lehtokari, V. L., Cho, K., Pelin, K., Wallgren-Pettersson, C., ... Beggs, A. H. (2011). Novel mutations in NEB cause abnormal nebulin expression and markedly impaired muscle force generation in severe nemaline myopathy. Skeletal Muscle, 1(1), [23]. https://doi.org/10.1186/2044-5040-1-23

Novel mutations in NEB cause abnormal nebulin expression and markedly impaired muscle force generation in severe nemaline myopathy. / Lawlor, Michael W.; Ottenheijm, Coen A.; Lehtokari, Vilma Lotta; Cho, Kiyomi; Pelin, Katarina; Wallgren-Pettersson, Carina; Granzier, Hendrikus "Henk"; Beggs, Alan H.

In: Skeletal Muscle, Vol. 1, No. 1, 23, 20.06.2011.

Research output: Contribution to journalArticle

Lawlor, Michael W. ; Ottenheijm, Coen A. ; Lehtokari, Vilma Lotta ; Cho, Kiyomi ; Pelin, Katarina ; Wallgren-Pettersson, Carina ; Granzier, Hendrikus "Henk" ; Beggs, Alan H. / Novel mutations in NEB cause abnormal nebulin expression and markedly impaired muscle force generation in severe nemaline myopathy. In: Skeletal Muscle. 2011 ; Vol. 1, No. 1.
@article{c47cd9aec7534cf999ce6e1acc8bd0bc,
title = "Novel mutations in NEB cause abnormal nebulin expression and markedly impaired muscle force generation in severe nemaline myopathy",
abstract = "Background: Nemaline myopathy (NM) is a congenital muscle disease associated with weakness and the presence of nemaline bodies (rods) in muscle fibers. Mutations in seven genes have been associated with NM, but the most commonly mutated gene is nebulin (NEB), which is thought to account for roughly 50{\%} of cases.Results: We describe two siblings with severe NM, arthrogryposis and neonatal death caused by two novel NEB mutations: a point mutation in intron 13 and a frameshift mutation in exon 81. Levels of detectable nebulin protein were significantly lower than those in normal control muscle biopsies or those from patients with less severe NM due to deletion of NEB exon 55. Mechanical studies of skinned myofibers revealed marked impairment of force development, with an increase in tension cost.Conclusions: Our findings demonstrate that the mechanical phenotype of severe NM is the consequence of mutations that severely reduce nebulin protein levels and suggest that the level of nebulin expression may correlate with the severity of disease.",
keywords = "Congenital myopathy, Nebulin, Nemaline myopathy, Nemaline rod (body), Thin filament",
author = "Lawlor, {Michael W.} and Ottenheijm, {Coen A.} and Lehtokari, {Vilma Lotta} and Kiyomi Cho and Katarina Pelin and Carina Wallgren-Pettersson and Granzier, {Hendrikus {"}Henk{"}} and Beggs, {Alan H.}",
year = "2011",
month = "6",
day = "20",
doi = "10.1186/2044-5040-1-23",
language = "English (US)",
volume = "1",
journal = "Skeletal Muscle",
issn = "2044-5040",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Novel mutations in NEB cause abnormal nebulin expression and markedly impaired muscle force generation in severe nemaline myopathy

AU - Lawlor, Michael W.

AU - Ottenheijm, Coen A.

AU - Lehtokari, Vilma Lotta

AU - Cho, Kiyomi

AU - Pelin, Katarina

AU - Wallgren-Pettersson, Carina

AU - Granzier, Hendrikus "Henk"

AU - Beggs, Alan H.

PY - 2011/6/20

Y1 - 2011/6/20

N2 - Background: Nemaline myopathy (NM) is a congenital muscle disease associated with weakness and the presence of nemaline bodies (rods) in muscle fibers. Mutations in seven genes have been associated with NM, but the most commonly mutated gene is nebulin (NEB), which is thought to account for roughly 50% of cases.Results: We describe two siblings with severe NM, arthrogryposis and neonatal death caused by two novel NEB mutations: a point mutation in intron 13 and a frameshift mutation in exon 81. Levels of detectable nebulin protein were significantly lower than those in normal control muscle biopsies or those from patients with less severe NM due to deletion of NEB exon 55. Mechanical studies of skinned myofibers revealed marked impairment of force development, with an increase in tension cost.Conclusions: Our findings demonstrate that the mechanical phenotype of severe NM is the consequence of mutations that severely reduce nebulin protein levels and suggest that the level of nebulin expression may correlate with the severity of disease.

AB - Background: Nemaline myopathy (NM) is a congenital muscle disease associated with weakness and the presence of nemaline bodies (rods) in muscle fibers. Mutations in seven genes have been associated with NM, but the most commonly mutated gene is nebulin (NEB), which is thought to account for roughly 50% of cases.Results: We describe two siblings with severe NM, arthrogryposis and neonatal death caused by two novel NEB mutations: a point mutation in intron 13 and a frameshift mutation in exon 81. Levels of detectable nebulin protein were significantly lower than those in normal control muscle biopsies or those from patients with less severe NM due to deletion of NEB exon 55. Mechanical studies of skinned myofibers revealed marked impairment of force development, with an increase in tension cost.Conclusions: Our findings demonstrate that the mechanical phenotype of severe NM is the consequence of mutations that severely reduce nebulin protein levels and suggest that the level of nebulin expression may correlate with the severity of disease.

KW - Congenital myopathy

KW - Nebulin

KW - Nemaline myopathy

KW - Nemaline rod (body)

KW - Thin filament

UR - http://www.scopus.com/inward/record.url?scp=84861231735&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861231735&partnerID=8YFLogxK

U2 - 10.1186/2044-5040-1-23

DO - 10.1186/2044-5040-1-23

M3 - Article

C2 - 21798101

AN - SCOPUS:84861231735

VL - 1

JO - Skeletal Muscle

JF - Skeletal Muscle

SN - 2044-5040

IS - 1

M1 - 23

ER -