Myotonic dystrophy type 1 (DM1) clinical sub-types and CTCF site methylation status flanking the CTG expansion are mutant allele length-dependent

Morales, F., Corrales, E., Zhang, B., Vásquez, M., Santamaría-Ulloa, C., Quesada, H., Sirito, M., Estecio, M. R., Monckton, D. G. and Krahe, R. (2022) Myotonic dystrophy type 1 (DM1) clinical sub-types and CTCF site methylation status flanking the CTG expansion are mutant allele length-dependent. Human Molecular Genetics, 31(2), pp. 262-274. (doi: 10.1093/hmg/ddab243) (PMID:34432028)

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Abstract

Myotonic dystrophy type 1 (DM1) is a complex disease with a wide spectrum of symptoms. The exact relationship between mutant CTG repeat expansion size and clinical outcome remains unclear. DM1 congenital patients (CDM) inherit the largest expanded alleles, which are associated with abnormal and increased DNA methylation flanking the CTG repeat. However, DNA methylation at the DMPK locus remains understudied. Its relationship to DM1 clinical subtypes, expansion size and age-at-onset is not yet completely understood. Using pyrosequencing-based methylation analysis on 225 blood DNA samples from Costa Rican DM1 patients, we determined that the size of the estimated progenitor allele length (ePAL) is not only a good discriminator between CDM and non-CDM cases (with an estimated threshold at 653 CTG repeats), but also for all DM1 clinical subtypes. Secondly, increased methylation at both CTCF sites upstream and downstream of the expansion was almost exclusively present in CDM cases. Thirdly, levels of abnormal methylation were associated with clinical subtype, age and ePAL, with strong correlations between these variables. Fourthly, both ePAL and the intergenerational expansion size were significantly associated with methylation status. Finally, methylation status was associated with ePAL and maternal inheritance, with almost exclusively maternal transmission of CDM. In conclusion, increased DNA methylation at the CTCF sites flanking the DM1 expansion could be linked to ePAL, and both increased methylation and the ePAL could be considered biomarkers for the CDM phenotype.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Monckton, Professor Darren
Authors: Morales, F., Corrales, E., Zhang, B., Vásquez, M., Santamaría-Ulloa, C., Quesada, H., Sirito, M., Estecio, M. R., Monckton, D. G., and Krahe, R.
College/School:College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
Journal Name:Human Molecular Genetics
Publisher:Oxford University Press
ISSN:0964-6906
ISSN (Online):1460-2083
Published Online:25 August 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Human Molecular Genetics 31(2): 262-274
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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