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Brain, Vol. 124, No. 4, 698-704, April 2001
© 2001 Oxford University Press

Mild muscular dystrophy due to a nonsense mutation in the LAMA2 gene resulting in exon skipping

Claudia Di Blasi1, Yi He2, Lucia Morandi1, Ferdinando Cornelio1, Pascale Guicheney2 and Marina Mora1

1 Department of Neuromuscular Diseases, Istituto Nazionale Neurologico C. Besta, Milano, Italy and 2 Unité INSERM U523, Institut de Myologie, IFR ‘Coeur, Muscle et Vaisseaux’ N.14, Groupe Hospitalier Pitié-Salpêtrière, Paris, France

Correspondence to: Marina Mora, Department of Neuromuscular Diseases, Istituto Nazionale Neurologico ‘C. Besta’, Via Celoria 11, 20133 Milano, Italy Email: mmora{at}tin.it

Nonsense mutations outside the splicing consensus sequence have been reported to cause skipping of the nonsense-containing exon in several human diseases. We describe, for the first time, nonsense-mediated exon skipping in the laminin {alpha}2 (LAMA2) gene. Two siblings from a consanguineous family had altered expression of the laminin {alpha}2 chain and moderate clinical manifestations. In both we identified the new nonsense mutation Arg744Stop, which we expected to result in a totally non-functional polypeptide. However, analysis of the transcript revealed skipping of exon 15, containing the mutation, even though the consensus sequences for splicing at both ends of the exon and the beginning of intron 15 were unaltered. Exon skipping restored the open reading frame of the mutant transcript and resulted in a truncated protein. In cases where the genetic findings do not elucidate the phenotype, mRNA analysis is necessary to clarify the primary effect of mutations. Our findings also point to the necessity of immunochemical screening for expression of laminin {alpha}2 chain in atypical dystrophic adults as well as children.


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