LAMA2 mRNA processing alterations generate a complete deficiency of laminin-alpha2 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-alpha2 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 7nt 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.
Siala
Olfa
O
Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, Avenue Majida Baklouti-Boulila 3029 Sfax, Tunisia.
Louhichi
Nacim
N
Triki
Chahnez
C
Morinière
Madeleine
M
Fakhfakh
Faiza
F
Baklouti
Faouzi
F
D002648:Child; D017809:Fatal Outcome; D005260:Female; D017353:Gene Deletion; D008040:Genetic Linkage; D006367:HeLa Cells; D006801:Humans; D007438:Introns / Q000235:genetics; D007797:Laminin / Q000172:deficiency / Q000235:genetics*; D008297:Male; D009136:Muscular Dystrophies / Q000151:congenital / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics; D012720:Severity of Illness Index; D014162:Transfection
D007797:Laminin; D012333:RNA, Messenger; C102645:laminin alpha 2