Identification of 45 novel mutations in the nebulin gene associated with autosomal recessive nemaline myopathy

Vilma Lotta Lehtokari, Katarina Pelin, Maria Sandbacka, Salla Ranta, Kati Donner, Francesco Muntoni, Caroline Sewry, Corrado Angelini, Kate Bushby, Peter Van Den Bergh, Susan Iannaccone, Nigel G. Laing, Carina Wallgren-Pettersson

Research output: Contribution to journalArticlepeer-review

107 Scopus citations


Nemaline myopathy (NM) is a clinically and genetically heterogeneous disorder of skeletal muscle caused by mutations in at least five different genes encoding thin filament proteins of the striated muscle sarcomere. We have previously described 18 different mutations in the last 42 exons of the nebulin gene (NEB) in 18 families with NM. Here we report 45 novel NEB mutations detected by denaturing high-performance liquid chromatography (dHPLC) and sequence analysis of all 183 NEB exons in NM patients from 44 families. Altogether we have identified, including the deletion of exon 55 identified in the Ashkenazi Jewish population, 64 different mutations in NEB segregating with autosomal recessive NM in 55 families. The majority (55%) of the mutations in NEB are frameshift or nonsense mutations predicted to cause premature truncation of nebulin. Point mutations (25%) or deletions (3%) affecting conserved splice signals are predicted in the majority of cases to cause in-frame exon skipping, possibly leading to impaired nebulin-tropomyosin interaction along the thin filament. Patients in 18 families had one of nine missense mutations (14%) affecting conserved amino acids at or in the vicinity of actin or tropomyosin binding sites. In addition, we found the exon 55 deletion in four families. The majority of the patients (in 49/55 families) were shown to be compound heterozygous for two different mutations. The mutations were found in both constitutively and alternatively expressed exons throughout the NEB gene, and there were no obvious mutational hotspots. Patients with more severe clinical pictures tended to have mutations predicted to be more disruptive than patients with milder forms.

Original languageEnglish (US)
Pages (from-to)946-956
Number of pages11
JournalHuman mutation
Issue number9
StatePublished - Sep 2006


  • NEB
  • Nebulin
  • Nemaline (rod) myopathy
  • dHPLC

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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