Genome-wide DNA methylation analysis of transient neonatal diabetes type 1 patients with mutations in ZFP57

BMC Medical Genetics

Research Article

Karen Grønskov¹  Johanne M. D. Hahnemann¹  Zeynep Tümer²  I. Karen Temple³  Deborah J. D. G. Mackay⁴  Christina Dahl⁵  Per Guldberg⁵  Mads Bak⁶  Niels Tommerup⁶  Susanne E. Boonen⁷ 

[1] Center for Applied Human Molecular Genetics, Kennedy Center, DK-2600, Glostrup, Denmark;Center for Applied Human Molecular Genetics, Kennedy Center, DK-2600, Glostrup, Denmark;Institute of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, DK-2200N, Copenhagen, Denmark;Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, SO16 6YD, Southampton, UK;Wessex Clinical Genetics Service, Southampton University Hospitals Trust, SO16 5YA, Southampton, UK;Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, SO16 6YD, Southampton, UK;Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury NHS Foundation Trust, SP2 8BJ, Salisbury, UK;Institute of Cancer Biology, Danish Cancer Society, DK-2100, Copenhagen Ø, Denmark;Wilhelm Johannsen Center for Functional Genome Research, Institute of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, DK-2200, Copenhagen N, Denmark;Wilhelm Johannsen Center for Functional Genome Research, Institute of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, DK-2200, Copenhagen N, Denmark;Center for Applied Human Molecular Genetics, Kennedy Center, DK-2600, Glostrup, Denmark;

关键词: Next-generation sequencing;    Imprinting disorder;    Transient neonatal diabetes;    DNA methylation;   

DOI  :  10.1186/s12881-016-0292-4

 received in 2015-08-15, accepted in 2016-04-08,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundTransient neonatal diabetes mellitus 1 (TNDM1) is a rare imprinting disorder characterized by intrautering growth retardation and diabetes mellitus usually presenting within the first six weeks of life and resolves by the age of 18 months. However, patients have an increased risk of developing diabetes mellitus type 2 later in life. Transient neonatal diabetes mellitus 1 is caused by overexpression of the maternally imprinted genes PLAGL1 and HYMAI on chromosome 6q24. One of the mechanisms leading to overexpression of the locus is hypomethylation of the maternal allele of PLAGL1 and HYMAI. A subset of patients with maternal hypomethylation at PLAGL1 have hypomethylation at additional imprinted loci throughout the genome, including GRB10, ZIM2 (PEG3), MEST (PEG1), KCNQ1OT1 and NESPAS (GNAS-AS1). About half of the TNDM1 patients carry mutations in ZFP57, a transcription factor involved in establishment and maintenance of methylation of imprinted loci. Our objective was to investigate whether additional regions are aberrantly methylated in ZFP57 mutation carriers.MethodsGenome-wide DNA methylation analysis was performed on four individuals with homozygous or compound heterozygous ZFP57 mutations, three relatives with heterozygous ZFP57 mutations and five controls. Methylation status of selected regions showing aberrant methylation in the patients was verified using bisulfite-sequencing.ResultsWe found large variability among the patients concerning the number and identity of the differentially methylated regions, but more than 60 regions were aberrantly methylated in two or more patients and a novel region within PPP1R13L was found to be hypomethylated in all the patients. The hypomethylated regions in common between the patients are enriched for the ZFP57 DNA binding motif.ConclusionsWe have expanded the epimutational spectrum of TNDM1 associated with ZFP57 mutations and found one novel region within PPP1R13L which is hypomethylated in all TNDM1 patients included in this study. Functional studies of the locus might provide further insight into the etiology of the disease.

【 授权许可】

CC BY   
© Bak et al. 2016