Severe MDC1A congenital muscular dystrophy due to a splicing mutation in the LAMA2 gene resulting in exon skipping and significant decrease of mRNA level.
Congenital muscular dystrophies (CMDs) are a clinically and genetically heterogeneous group of neuromuscular disorders, with autosomal recessive inheritance. We report a patient with severe congenital muscular dystrophy and total deficiency in the laminin alpha2 chain. Genetic analyses showed a linkage to the MDC1A locus for the patient's family, and DNA sequencing revealed in the propositus of a new homozygous mutation in the donor splice site of intron 58 of the LAMA2 gene. RT-PCR experiments performed on total RNA from a patient's muscle biopsy showed a complete skipping of exon 58 in LAMA2 cDNA and a significant decrease in the LAMA2 mRNA level. This exon skipping altered the open reading frame of the mutant transcript and generated a premature termination codon (PTC) within exon 59, which potentially elicits the nonsense mRNA to degradation by NMD (nonsense-mediated mRNA decay). However, the residual exon 58-lacking mRNA could potentially be translated, and the resulting truncated alpha2 chain would lack its LG4 and LG5 domains that are involved in binding with alpha-dystroglycan. These results demonstrate the utility of mRNA analysis to understand the mutation primary impact and the disease phenotype in the patients.
Siala
Olfa
O
Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, 3029 Sfax, Tunisia.
Louhichi
Nacim
N
Triki
Chahnez
C
Morinière
Madeleine
M
Rebai
Ahmed
A
Richard
Pascale
P
Guicheney
Pascale
P
Baklouti
Faouzi
F
Fakhfakh
Faiza
F
D001483:Base Sequence; D002675:Child, Preschool; D018388:Codon, Terminator; D005091:Exons; D008040:Genetic Linkage; D006801:Humans; D007797:Laminin / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009136:Muscular Dystrophies / Q000151:congenital* / Q000235:genetics*; D009154:Mutation; D022821:RNA Splice Sites; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism*
D018388:Codon, Terminator; D007797:Laminin; D022821:RNA Splice Sites; D012333:RNA, Messenger; C102645:laminin alpha 2