1. The position of nonsense mutations can predict the phenotype severity: A survey on the DMD gene
- Author
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Annalaura Torella, Arcomaria Garofalo, Marco Savarese, Mariateresa Zanobio, Roberta Zeuli, Francesca Del Vecchio Blanco, Teresa Giugliano, Vincenzo Nigro, Giulio Piluso, Luisa Politano, Medicum, University of Helsinki, Department of Medical and Clinical Genetics, Torella, A., Zanobio, M., Zeuli, R., Del Vecchio Blanco, F., Savarese, M., Giugliano, T., Garofalo, A., Piluso, G., Politano, L., and Nigro, V.
- Subjects
0301 basic medicine ,Heredity ,Genetic Linkage ,Duchenne muscular dystrophy ,Gene Expression ,Duchenne Muscular Dystrophy ,ALTERNATIVELY SPLICED ISOFORMS ,POINT MUTATIONS ,medicine.disease_cause ,Biochemistry ,Muscular Dystrophies ,Dystrophin ,Database and Informatics Methods ,Medical Conditions ,0302 clinical medicine ,Surveys and Questionnaires ,Medicine and Health Sciences ,CHINESE PATIENTS ,media_common ,Genetics ,Mutation ,Multidisciplinary ,biology ,Nucleotides ,Messenger RNA ,Translational readthrough ,1184 Genetics, developmental biology, physiology ,Nonsense Mutation ,EXON ,Exons ,Null allele ,Nucleic acids ,Phenotype ,Neurology ,Codon, Nonsense ,X-Linked Traits ,Sex Linkage ,Medicine ,Research Article ,musculoskeletal diseases ,media_common.quotation_subject ,Science ,Nonsense mutation ,Nonsense ,Research and Analysis Methods ,DIAGNOSIS ,SEQUENCE ,DUCHENNE MUSCULAR-DYSTROPHY ,ENHANCER ,03 medical and health sciences ,medicine ,Humans ,Amino Acid Sequence ,Clinical Genetics ,SPECTRUM ,Base Sequence ,Point mutation ,Biology and Life Sciences ,Proteins ,medicine.disease ,Muscular Dystrophy, Duchenne ,DELETIONS ,Cytoskeletal Proteins ,Biological Databases ,030104 developmental biology ,Mutation Databases ,biology.protein ,RNA ,Protein Translation ,3111 Biomedicine ,030217 neurology & neurosurgery - Abstract
A nonsense mutation adds a premature stop signal that hinders any further translation of a protein-coding gene, usually resulting in a null allele. To investigate the possible exceptions, we used theDMDgene as an ideal model. First, because dystrophin absence causes Duchenne muscular dystrophy (DMD), while its reduction causes Becker muscular dystrophy (BMD). Second, theDMDgene is X-linked and there is no second allele that can interfere in males. Third, databases are accumulating reports on many mutations and phenotypic data. Finally, becauseDMDmutations may have important therapeutic implications. For our study, we analyzed large databases (LOVD, HGMD and ClinVar) and literature and revised critically all data, together with data from our internal patients. We totally collected 2593 patients. Positioning these mutations along the dystrophin transcript, we observed a nonrandom distribution of BMD-associated mutations within selected exons and concluded that the position can be predictive of the phenotype. Nonsense mutations always cause DMD when occurring at any point in fifty-one exons. In the remaining exons, we found milder BMD cases due to early 5' nonsense mutations, if reinitiation can occur, or due to late 3' nonsense when the shortened product retains functionality. In the central part of the gene, all mutations in some in-frame exons, such as in exons 25, 31, 37 and 38 cause BMD, while mutations in exons 30, 32, 34 and 36 cause DMD. This may have important implication in predicting the natural history and the efficacy of therapeutic use of drug-stimulated translational readthrough of premature termination codons, also considering the action of internal natural rescuers. More in general, our survey confirm that a nonsense mutation should be not necessarily classified as a null allele and this should be considered in genetic counselling.
- Published
- 2020