Expansion size and presence of CCG/CTC/CGG sequence interruptions in the expanded CTG array are independently associated to hypermethylation at the DMPK locus in myotonic dystrophy type 1 (DM1)

Massimo Santoro, Luana Fontana, Marcella Masciullo, Maria Laura Ester Bianchi, Salvatore Rossi, Emanuele Leoncini, Giuseppe Novelli, Annalisa Botta, Gabriella Silvestri

Research output: Contribution to journalArticle

Abstract

A differential CpGmethylation profile upstreamof the expanded CTG array at the DMPK locus has been reported in patientswithmyotonic dystrophy type 1 (DM1), suggesting that hypermethylationmightmodulate DM1 phenotype, possibly affecting expression levels of DMPK and/or flanking genes. To clarify this issue,we characterized by methylation sensitive high resolution melting (MS-HRM) the CpG methylation pattern of DNA sequences flanking the pathological CTG expansion in 13 childhood-onset, 37 juvenile/adult-onset, 7 congenital DM1 pa- tients carrying uninterrupted CTG expansions and in 9 DM1 patients carrying variant expansions vs 30 controls. Association of methylation status with disease features (nCTG, age, sex, MIRS, disease duration) was also assessed. Finally, DMPK and SIX5 expression levels were evaluated in leukocytes from controls, methylated and unmethylated DM1 patients. We found hypermethylation involving upstreamsequences of DM1 locus in patientswith uninterrupted CTG ex- pansions N1000 CTG and affected by a congenital or childhood onset form. Besides the n(CTG) and early disease onset, hypermethylation was also significantly associated with maternal transmission. On the other hand, hypermethylation involved the 3' of the CTG array in DM1 patients carrying variant expan-sions. DMPK and SIX5 expression did not significantly differ in methylated vs unmethylated DM1 patients. Our results suggest that either the inherited size of the expanded allele and the presence of interruptions at the 3' end are associated with a highly polarized pattern of CpGmethylation at the DM1 locus and that, at least in leukocytes, DM1 locus hypermethylation would not significantly affect DMPK or SIX5 expression.

Original languageEnglish
Pages (from-to)2645-2652
Number of pages8
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1852
Issue number12
DOIs
Publication statusPublished - Dec 1 2015

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Myotonic Dystrophy
Methylation
Leukocytes
Freezing
Alleles
Mothers
Phenotype
Genes

Keywords

  • DMPK
  • High resolution melting
  • Methylation
  • Myotonic dystrophy type 1
  • SIX5
  • Variant expansions

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine

Cite this

Expansion size and presence of CCG/CTC/CGG sequence interruptions in the expanded CTG array are independently associated to hypermethylation at the DMPK locus in myotonic dystrophy type 1 (DM1). / Santoro, Massimo; Fontana, Luana; Masciullo, Marcella; Bianchi, Maria Laura Ester; Rossi, Salvatore; Leoncini, Emanuele; Novelli, Giuseppe; Botta, Annalisa; Silvestri, Gabriella.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1852, No. 12, 01.12.2015, p. 2645-2652.

Research output: Contribution to journalArticle

Santoro, Massimo ; Fontana, Luana ; Masciullo, Marcella ; Bianchi, Maria Laura Ester ; Rossi, Salvatore ; Leoncini, Emanuele ; Novelli, Giuseppe ; Botta, Annalisa ; Silvestri, Gabriella. / Expansion size and presence of CCG/CTC/CGG sequence interruptions in the expanded CTG array are independently associated to hypermethylation at the DMPK locus in myotonic dystrophy type 1 (DM1). In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2015 ; Vol. 1852, No. 12. pp. 2645-2652.
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T1 - Expansion size and presence of CCG/CTC/CGG sequence interruptions in the expanded CTG array are independently associated to hypermethylation at the DMPK locus in myotonic dystrophy type 1 (DM1)

AU - Santoro, Massimo

AU - Fontana, Luana

AU - Masciullo, Marcella

AU - Bianchi, Maria Laura Ester

AU - Rossi, Salvatore

AU - Leoncini, Emanuele

AU - Novelli, Giuseppe

AU - Botta, Annalisa

AU - Silvestri, Gabriella

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