A novel laminin alpha 2 isoform in severe laminin alpha 2 deficient congenital muscular dystrophy

Objectives: Laminin alpha2 deficiency presents at birth with muscle weaknes s, hypotonia, and usually asymptomatic white matter signal on MRI. Few pati ents with laminin alpha2 deficiency have been described with seizures and s tructural brain abnormalities. The reason for the variation in the severity of the clinical phenotype in congenital muscular dystrophy (CMD) with lami nin alpha2 deficiency is not known. Methods: A patient with CMD with partia l laminin alpha2 presenting with brain structural abnormalities and untreat able generalized and partial complex seizure was studied. Alternative lamin in alpha2 splicing was studied by since-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 lamin in alpha2 corresponding to this isoform. Laminin alpha2 immunofluorescence showed that this isoform was not evenly distributed at the muscle fiber bas al lamina, but preferentially localized in discrete areas. Laminin alpha5, beta1, gamma1, and nidogen showed decreased expression by immunofluorescenc e. Conclusions: The severity of this patient's phenotype may be due to over expression of the exon 31-spliced laminin alpha2 isoform. Exon 31 lies in t he IIIA domain of the laminin alpha2 protein, just proximal to the triple c oil-coiled region. It is possible that chain assembly is impaired by this i soform, resulting in a loss of possible rescue mechanisms.