title: Dystrophin nonsense mutation induces different levels of exon 29 skipping and leads to variable phenotypes within one BMD family.
abstract: Within one X-linked muscular dystrophy family, different phenotypes for three males occurred: (1) a severely affected Becker patient with cardiomyopathy, (2) a mildly affected Becker patient, and (3) an apparently healthy male with elevated serum CK levels. In the muscle biopsy specimen of patient2 one out of four antibodies (NCL-DYS1) showed absence of dystrophin. The protein truncation test detected a truncated dystrophin for both muscle tissue and lymphocytes of this patient next to an additional near normal size fragment in muscle. Genomic sequence analysis revealed a nonsense mutation in exon 29 (4148C > T) of the dystrophin gene. Sequence analysis of the mRNA fragment of the larger peptide showed skipping of exon 29, restoring an open reading frame. Consequently, the epitope of the antibody NCL-DYS1 is mapped to exon 29. The variable clinical features of the three relatives from healthy to severely affected therefore seems to be related to the level of skipping of exon 29. This finding underscores the future potential of gene therapeutic strategies aimed at inducing exon skipping in Duchenne muscular dystrophy, to generate a much milder disease.
authors.affiliation: Department of Human and Clinical Genetics, Leiden University Medical Center, The Netherlands. H.B.Ginjaar@kgc.azl.nl
authors.forename: I B
authors.initials: IB
authors.lastname: Ginjaar
authors.forename: A L
authors.initials: AL
authors.lastname: Kneppers
authors.forename: J D
authors.initials: JD
authors.lastname: v d Meulen
authors.forename: L V
authors.initials: LV
authors.lastname: Anderson
authors.forename: M
authors.initials: M
authors.lastname: Bremmer-Bout
authors.forename: J C
authors.initials: JC
authors.lastname: van Deutekom
authors.forename: J
authors.initials: J
authors.lastname: Weegenaar
authors.forename: J T
authors.initials: JT
authors.lastname: den Dunnen
authors.forename: E
authors.initials: E
authors.lastname: Bakker
mesh_terms: D000328:Adult; D001706:Biopsy; D018389:Codon, Nonsense / Q000235:genetics*; D004252:DNA Mutational Analysis; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005091:Exons / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000502:physiology; D006801:Humans; D007124:Immunoenzyme Techniques; D008214:Lymphocytes / Q000502:physiology; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology; D009136:Muscular Dystrophies / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012326:RNA Splicing
chemical_list: D018389:Codon, Nonsense; D016189:Dystrophin