title: Severe MDC1A congenital muscular dystrophy due to a splicing mutation in the LAMA2 gene resulting in exon skipping and significant decrease of mRNA level.
abstract: 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.
authors.affiliation: Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, 3029 Sfax, Tunisia.
authors.forename: Olfa
authors.initials: O
authors.lastname: Siala
authors.forename: Nacim
authors.initials: N
authors.lastname: Louhichi
authors.forename: Chahnez
authors.initials: C
authors.lastname: Triki
authors.forename: Madeleine
authors.initials: M
authors.lastname: Morinière
authors.forename: Ahmed
authors.initials: A
authors.lastname: Rebai
authors.forename: Pascale
authors.initials: P
authors.lastname: Richard
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
authors.forename: Faouzi
authors.initials: F
authors.lastname: Baklouti
authors.forename: Faiza
authors.initials: F
authors.lastname: Fakhfakh
mesh_terms: 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*
chemical_list: D018388:Codon, Terminator; D007797:Laminin; D022821:RNA Splice Sites; D012333:RNA, Messenger; C102645:laminin alpha 2