title: Phenotypic clustering of lamin A/C mutations in neuromuscular patients.
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.
authors: Laboratory of Clinical Molecular Biology DIBIT 2, Diagnostics and Research San Raffaele, Milan, Italy. benedetti.sara@hsr.it
authors: S
authors: S
authors: Benedetti
authors: I
authors: I
authors: Menditto
authors: M
authors: M
authors: Degano
authors: C
authors: C
authors: Rodolico
authors: L
authors: L
authors: Merlini
authors: A
authors: A
authors: D'Amico
authors: L
authors: L
authors: Palmucci
authors: A
authors: A
authors: Berardinelli
authors: E
authors: E
authors: Pegoraro
authors: C P
authors: CP
authors: Trevisan
authors: L
authors: L
authors: Morandi
authors: I
authors: I
authors: Moroni
authors: G
authors: G
authors: Galluzzi
authors: E
authors: E
authors: Bertini
authors: A
authors: A
authors: Toscano
authors: M
authors: M
authors: Olivè
authors: G
authors: G
authors: Bonne
authors: F
authors: F
authors: Mari
authors: R
authors: R
authors: Caldara
authors: R
authors: R
authors: Fazio
authors: I
authors: I
authors: Mammì
authors: P
authors: P
authors: Carrera
authors: D
authors: D
authors: Toniolo
authors: G
authors: G
authors: Comi
authors: A
authors: A
authors: Quattrini
authors: M
authors: M
authors: Ferrari
authors: S C
authors: SC
authors: Previtali
mesh_terms: D000328:Adult; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D018450:Disease Progression; D016368:Frameshift Mutation / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006331:Heart Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D034904:Lamin Type A / Q000235:genetics; D034882:Lamins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009468:Neuromuscular Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D010641:Phenotype
chemical_list: D005819:Genetic Markers; D034904:Lamin Type A; D034882:Lamins; C440308:lamin C