Primary constitutional MLH1 epimutations: a focal epigenetic event

BACKGROUND: Constitutional MLH1 epimutations are characterised by monoallelic methylation of the MLH1 promoter throughout normal tissues, accompanied by allele-specific silencing. The mechanism underlying primary MLH1 epimutations is currently unknown. The aim of this study was to perform an in-dept...

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Detalles Bibliográficos
Autores: Dámaso, Estela, Castillejo, Adela, Arias, María del Mar, Canet Hermida, Júlia, Navarro, Matilde, Valle Domínguez, Jesús del, Campos, Olga, Fernández, Anna, Marín, Fátima, Turchetti, Daniela, García Díaz, Juan de Dios, Lázaro García, Conxi, Genuardi, Maurizio, Rueda, Daniel, Alonso, Ángel, Soto, José Luis, Hitchins, Megan, Pineda Riu, Marta, Capellá, G. (Gabriel)
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/172157
Acceso en línea:https://hdl.handle.net/2445/172157
Access Level:acceso abierto
Palabra clave:Epigènesi
Mutació (Biologia)
Epigenesis
Mutation (Biology)
Descripción
Sumario:BACKGROUND: Constitutional MLH1 epimutations are characterised by monoallelic methylation of the MLH1 promoter throughout normal tissues, accompanied by allele-specific silencing. The mechanism underlying primary MLH1 epimutations is currently unknown. The aim of this study was to perform an in-depth characterisation of constitutional MLH1 epimutations targeting the aberrantly methylated region around MLH1 and other genomic loci. METHODS: Twelve MLH1 epimutation carriers, 61 Lynch syndrome patients, and 41 healthy controls, were analysed by Infinium 450 K array. Targeted molecular techniques were used to characterise the MLH1 epimutation carriers and their inheritance pattern. RESULTS: No nucleotide or structural variants were identified in-cis on the epimutated allele in 10 carriers, in which inter- generational methylation erasure was demonstrated in two, suggesting primary type of epimutation. CNVs outside the MLH1 locus were found in two cases. EPM2AIP1-MLH1 CpG island was identified as the sole differentially methylated region in MLH1 epimutation carriers compared to controls. CONCLUSION: Primary constitutional MLH1 epimutations arise as a focal epigenetic event at the EPM2AIP1-MLH1 CpG island in the absence of cis-acting genetic variants. Further molecular characterisation is needed to elucidate the mechanistic basis of MLH1 epimutations and their heritability/reversibility.

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