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

From the Departments of Neurological and Psychiatric Sciences (Drs. Pegoraro, Trevisan, and Angelini, and M. Fanin), University of Padova, Italy; and the Center for Genetic Medicine (Dr. Hoffman), Children’s Research Hospital, Washington, DC.

Address correspondence and reprint requests to Dr. Elena Pegoraro, Department of Neurological and Psychiatric Sciences, University of Padova, via Giustiniani 5, 35128 Padova, Italy; e-mail: elenap{at}ux1.unipd.it

OBJECTIVES: Laminin 2 deficiency presents at birth with muscle weakness, hypotonia, and usually asymptomatic white matter signal on MRI. Few patients with laminin 2 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 2 deficiency is not known.

METHODS: A patient with CMD with partial laminin 2 presenting with brain structural abnormalities and untreatable generalized and partial complex seizure was studied. Alternative laminin 2 splicing was studied by single-strand conformational polymorphism/sequencing analysis.

RESULTS: A novel laminin 2 isoform was identified. Nonsense laminin 2 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 2 corresponding to this isoform. Laminin 2 immunofluorescence showed that this isoform was not evenly distributed at the muscle fiber basal lamina, but preferentially localized in discrete areas. Laminin 5, ß1, 1, 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 2 isoform. Exon 31 lies in the IIIA domain of the laminin 2 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.

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