Phenotypic clustering of lamin A/C mutations in neuromuscular patients

Neurology. 2007 Sep 18;69(12):1285-92. doi: 10.1212/01.wnl.0000261254.87181.80. Epub 2007 Mar 21.

Abstract

Background: Mutations in the LMNA gene, encoding human lamin A/C, have been associated with an increasing number of disorders often involving skeletal and cardiac muscle, but no clear genotype/phenotype correlation could be established to date.

Methods: We analyzed the LMNA gene in a large cohort of patients mainly affected by neuromuscular or cardiac disease and clustered mutated patients in two groups to unravel possible correlations.

Results: We identified 28 variants, 9 of which reported for the first time. The two groups of patients were characterized by clinical and genetic differences: 1) patients with childhood onset displayed skeletal muscle involvement with predominant scapuloperoneal and facial weakness associated with missense mutations; 2) patients with adult onset mainly showed cardiac disorders or myopathy with limb girdle distribution, often associated with frameshift mutations presumably leading to a truncated protein.

Conclusions: Our findings, supported by meta-analysis of previous literature, suggest the presence of two different pathogenetic mechanisms: late onset phenotypes may arise through loss of function secondary to haploinsufficiency, while dominant negative or toxic gain of function mechanisms may explain the severity of early phenotypes. This model of patient stratification may help patient management and facilitate future studies aimed at deciphering lamin A/C pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Child
  • Child, Preschool
  • Cluster Analysis
  • Cohort Studies
  • DNA Mutational Analysis
  • Disease Progression
  • Frameshift Mutation / genetics
  • Genetic Markers / genetics
  • Genetic Predisposition to Disease / genetics*
  • Haplotypes / genetics
  • Heart Diseases / genetics*
  • Heart Diseases / metabolism
  • Heart Diseases / physiopathology
  • Humans
  • Lamin Type A / genetics
  • Lamins / genetics*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / physiopathology
  • Mutation / genetics*
  • Mutation, Missense / genetics
  • Myocardium / metabolism
  • Myocardium / pathology
  • Neuromuscular Diseases / genetics*
  • Neuromuscular Diseases / metabolism
  • Neuromuscular Diseases / physiopathology
  • Phenotype

Substances

  • Genetic Markers
  • Lamin Type A
  • Lamins
  • lamin C