The University of Southampton
University of Southampton Institutional Repository

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

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

Transient 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.

Methods

Genome-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.

Results

We 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.

Conclusions

We 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.
1471-2350
1-8
Bak, M.
bc291a35-9203-45e0-b674-d518aa1cce2b
Boonen, S.E.
d1c63e8f-4d38-4ff3-a6fd-f29db9a05e3b
Dahl, C.
94cdd87d-469f-4afe-8da9-0e6a9489c799
Hahnemann, J.M.D.
5977bf56-16ed-4c53-8f23-9b2dd7737fd6
Mackay, D.J.D.G.
588a653e-9785-4a00-be71-4e547850ee4a
Tumer, Z.
9d85cfd9-6677-49ef-ba83-b7d95866053d
Gronskov, K.
c14b8b4f-2cec-4954-9033-acf0a3e03ed4
Temple, I.K.
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Guldberg, P.
b3291719-dee1-4f60-94bd-66e19300d757
Tommerup, N.
02736ac3-b066-4b90-8c6d-91babd0be663
Bak, M.
bc291a35-9203-45e0-b674-d518aa1cce2b
Boonen, S.E.
d1c63e8f-4d38-4ff3-a6fd-f29db9a05e3b
Dahl, C.
94cdd87d-469f-4afe-8da9-0e6a9489c799
Hahnemann, J.M.D.
5977bf56-16ed-4c53-8f23-9b2dd7737fd6
Mackay, D.J.D.G.
588a653e-9785-4a00-be71-4e547850ee4a
Tumer, Z.
9d85cfd9-6677-49ef-ba83-b7d95866053d
Gronskov, K.
c14b8b4f-2cec-4954-9033-acf0a3e03ed4
Temple, I.K.
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Guldberg, P.
b3291719-dee1-4f60-94bd-66e19300d757
Tommerup, N.
02736ac3-b066-4b90-8c6d-91babd0be663

Bak, M., Boonen, S.E., Dahl, C., Hahnemann, J.M.D., Mackay, D.J.D.G., Tumer, Z., Gronskov, K., Temple, I.K., Guldberg, P. and Tommerup, N. (2016) Genome-wide DNA methylation analysis of transient neonatal diabetes type 1 patients with mutations in ZFP57. BMC Medical Genetics, 17 (29), 1-8. (doi:10.1186/s12881-016-0292-4). (PMID:27075368)

Record type: Article

Abstract

Background

Transient 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.

Methods

Genome-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.

Results

We 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.

Conclusions

We 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.

Text
ZFP57_manuscript_with_figures.pdf - Accepted Manuscript
Available under License Creative Commons Attribution.
Download (950kB)
Text
art%3A10.1186%2Fs12881-016-0292-4.pdf - Version of Record
Available under License Creative Commons Attribution.
Download (1MB)

More information

Accepted/In Press date: 8 April 2016
e-pub ahead of print date: 14 April 2016
Published date: 2016
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 391976
URI: http://eprints.soton.ac.uk/id/eprint/391976
ISSN: 1471-2350
PURE UUID: c983a89c-9cd0-4b52-83c2-233c0e7fbe2e
ORCID for D.J.D.G. Mackay: ORCID iD orcid.org/0000-0003-3088-4401
ORCID for I.K. Temple: ORCID iD orcid.org/0000-0002-6045-1781

Catalogue record

Date deposited: 12 Apr 2016 15:56
Last modified: 17 Dec 2019 01:54

Export record

Altmetrics

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×