LAMA2 mRNA processing alterations generate a complete deficiency of laminin-α2 protein and a severe congenital muscular dystrophy

An increasing number of genomic variations are no more regarded as harmless changes in protein coding sequences or as genetic polymorphisms. Studying the impact of these variations on mRNA metabolism became a central issue to better understand the biological significance of disease. We describe here a severe congenital muscular dystrophy (CMD) with lumbar scoliosis and respiratory complications in a patient, who died at the age of 10. Despite a poor linkage to any form of CMD, total deficiency of laminin-α2 rather suggested the occurrence of an MDC1A form. Extensive analysis of LAMA2 gene revealed two novel mutations: a (8007delT) frameshift deletion in exon 57, and a de novo 7 nt deletion in intron 17. Using an ex vivo approach, we provided strong evidence that the intron mutation is responsible for complete exon 17 skipping. The mutations are in trans and they each generate a nonsense mRNA potentially elicited to degradation by NMD. We further discuss the impact of mRNA alterations on the subtle phenotypic discrepancies.