title: Identification and characterization of 5' CCG interruptions in complex DMPK expanded alleles.
abstract: Myotonic dystrophy type 1 is a multisystemic autosomal dominant disorder caused by the expansion of (CTG)ntriplets in the 3'UTR of the DMPK gene, on chromosome 19q13.3. In the last years, few DM1 patients with different patterns of CCG/CTC interruptions at the 3' end of the DMPK expanded tract have been described. However, the role of these interruptions in DM1 pathogenesis is still unclear. To study the frequency, stability and the structure of DMPK variant expanded alleles in the Italian population, we have re-evaluated 254 Italian DM1 patients using triplet-primed PCR (TP-PCR), at both the 3' and 5' ends of the CTG expansion. In addition, three DM1 families were also investigated in order to analyze the intergenerational stability of the interrupted DMPK alleles. Fourteen DM1 patients showed a TP-PCR electrophoretic profile indicating CCG/CTC interruptions within the CTG expansion. Interestingly, interruptions have been detected and, for the first time, sequenced at the 5' end of the CTG array. Analysis of five intergenerational transmissions revealed a substantial intrafamilial stability of the DM1 mutation among relatives. Our results support the hypothesis that CCG/CTC interruptions within the DMPK expanded alleles have a stabilizing effect on the mutational dynamics and can modulate the severity of symptoms in DM1 patients.
authors.affiliation: Department of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy.|Department of Laboratory Medicine, Tor Vergata Hospital, Rome, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Botta
authors.affiliation: Department of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Rossi
authors.affiliation: Department of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Marcaurelio
authors.affiliation: Department of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy.
authors.forename: Luana
authors.initials: L
authors.lastname: Fontana
authors.affiliation: Department of Laboratory Medicine, Tor Vergata Hospital, Rome, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: D'Apice
authors.affiliation: Department of Laboratory Medicine, Tor Vergata Hospital, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Brancati
authors.affiliation: Department of Neurosciences, Tor Vergata University of Rome, Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Massa
authors.affiliation: Institute of Molecular, Cell and System Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Darren
authors.initials: D
authors.lastname: G Monckton
authors.affiliation: Department of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy.|Department of Laboratory Medicine, Tor Vergata Hospital, Rome, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Sangiuolo
authors.affiliation: Department of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy.|Department of Laboratory Medicine, Tor Vergata Hospital, Rome, Italy.|Istitute Neuromed, IRCCS, Pozzilli, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Novelli
mesh_terms: D024506:5' Flanking Region; D000328:Adult; D000368:Aged; D000483:Alleles; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009223:Myotonic Dystrophy / Q000175:diagnosis / Q000235:genetics*; D065636:Myotonin-Protein Kinase / Q000235:genetics*; D010375:Pedigree; D019680:Trinucleotide Repeat Expansion
chemical_list: C585517:DMPK protein, human; D065636:Myotonin-Protein Kinase