Mild muscular dystrophy due to a nonsense mutation in the LAMA2 gene resulting in exon skipping.
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 alpha2 (LAMA2) gene. Two siblings from a consanguineous family had altered expression of the laminin alpha2 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 alpha2 chain in atypical dystrophic adults as well as children.
Di Blasi
C
C
Department of Neuromuscular Diseases, Istituto Nazionale Neurologico C. Besta, Milano, Italy.
He
Y
Y
Morandi
L
L
Cornelio
F
F
Guicheney
P
P
Mora
M
M
D000328:Adult; D017398:Alternative Splicing / Q000235:genetics; D018389:Codon, Nonsense; D003241:Consanguinity; D003286:Contracture / Q000209:etiology; D004252:DNA Mutational Analysis; D004576:Electromyography; D005091:Exons / Q000235:genetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007797:Laminin / Q000235:genetics*; D008297:Male; D018908:Muscle Weakness / Q000209:etiology; D018482:Muscle, Skeletal / Q000473:pathology; D009136:Muscular Dystrophies / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics
D018389:Codon, Nonsense; D007797:Laminin; D012333:RNA, Messenger; C102645:laminin alpha 2