title: A novel laminin alpha2 isoform in severe laminin alpha2 deficient congenital muscular dystrophy.
abstract: OBJECTIVE
  Laminin alpha2 deficiency presents at birth with muscle weakness, hypotonia, and usually asymptomatic white matter signal on MRI. Few patients with laminin alpha2 deficiency have been described with seizures and structural brain abnormalities. The reason for the variation in the severity of the clinical phenotype in congenital muscular dystrophy (CMD) with laminin alpha2 deficiency is not known.
  
  
  METHODS
  A patient with CMD with partial laminin alpha2 presenting with brain structural abnormalities and untreatable generalized and partial complex seizure was studied. Alternative laminin alpha2 splicing was studied by single-strand conformational polymorphism/sequencing analysis.
  
  
  RESULTS
  A novel laminin alpha2 isoform was identified. Nonsense laminin alpha2 mutations (stop codons) were inherited from both parents; however, one of the nonsense mutations was in a region of exon 31, which is alternatively spliced. The alternatively spliced isoform excluded one of the stop codon mutations, and was thus able to produce normal laminin alpha2 corresponding to this isoform. Laminin alpha2 immunofluorescence showed that this isoform was not evenly distributed at the muscle fiber basal lamina, but preferentially localized in discrete areas. Laminin alpha5, beta1, gamma1, and nidogen showed decreased expression by immunofluorescence.
  
  
  CONCLUSIONS
  The severity of this patient's phenotype may be due to overexpression of the exon 31-spliced laminin alpha2 isoform. Exon 31 lies in the IIIA domain of the laminin alpha2 protein, just proximal to the triple coil-coiled region. It is possible that chain assembly is impaired by this isoform, resulting in a loss of possible rescue mechanisms.
authors.affiliation: Department of Neurological and Psychiatric Sciences, University of Padova, Italy. elenap@ux1.unipd.it
authors.forename: E
authors.initials: E
authors.lastname: Pegoraro
authors.forename: M
authors.initials: M
authors.lastname: Fanin
authors.forename: C P
authors.initials: CP
authors.lastname: Trevisan
authors.forename: C
authors.initials: C
authors.lastname: Angelini
authors.forename: E P
authors.initials: EP
authors.lastname: Hoffman
mesh_terms: D000293:Adolescent; D017398:Alternative Splicing; D005091:Exons; D005260:Female; D006801:Humans; D007797:Laminin / Q000032:analysis / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D009132:Muscles / Q000737:chemistry / Q000473:pathology*; D009136:Muscular Dystrophies / Q000151:congenital / Q000235:genetics* / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics*
chemical_list: D007797:Laminin; D020033:Protein Isoforms; C102645:laminin alpha 2