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Transient neonatal diabetes mellitus and hypomethylation at additional imprinted loci: novel ZFP57 mutation and review on the literature

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Abstract

Aim

6q24-related transient neonatal diabetes mellitus (6q24-TNDM) is a rare imprinting disorder characterized by uncontrolled hyperglycemia during the first 6 months of life. The molecular etiology of 6q24-TNDM is attributable to overexpression of the paternally inherited PLAGL1 and HYMAI genes located on the 6q24 locus. One of these major defects is maternal loss of methylation (LOM) at 6q24. In addition, approximately 50% of TNDM patients that present LOM at 6q24 can also display hypomethylation at additional imprinted loci (multilocus imprinting disturbances, MLID). Interestingly, the majority of these patients carry mutations in the ZFP57 gene, a transcription factor required for the adequate maintenance of methylation during early embryonic development.

Methods

Methylation analysis of 6q24 and additional imprinted loci was carried out by MS-MLPA in a Tunisian male patient with clinical diagnosis of TNMD. For the same patient, mutation analysis of the ZFP57 gene was conducted by direct Sanger sequencing.

Results

We report a novel nonsense mutation (c.373C > T; p.R125*; ENST00000376883.1) at the ZFP57 gene causing TNDM-MLID and describe detailed phenotype/epigenotype analysis of TNMD patients carrying ZFP57 mutations.

Conclusion

We provide additional support to the role of ZFP57 as a genetic determinant cause of MLID in patients with TNMD.

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Authors and Affiliations

  1. Department of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat HACHED University Hospital, 4000, Sousse, Tunisia

    Ameni Touati, Yosra Halleb, Ali Saad & Dorra H’mida ben brahim

  2. High Institute of Biotechnology, Monastir University, Monastir, Tunisia

    Ameni Touati

  3. Molecular (Epi)Genetic Lab, BioAraba National Health Institute, OSI Araba University Hospital, 01009, Vitoria-Gasteiz, Alava, Spain

    Javier Errea-Dorronsoro, Arrate Pereda & Guiomar Perez de Nanclares

  4. Department of Neonatology, Farhat HACHED University Hospital, 4000, Sousse, Tunisia

    Sonia Nouri, Nabiha Mahdhaoui & Aida Ghith

  5. Faculty of Medicine, Sousse University, Sousse, Tunisia

    Sonia Nouri, Yosra Halleb, Nabiha Mahdhaoui, Aida Ghith, Ali Saad & Dorra H’mida ben brahim

Authors
  1. Ameni Touati
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  2. Javier Errea-Dorronsoro
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  3. Sonia Nouri
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  4. Yosra Halleb
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  6. Nabiha Mahdhaoui
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  7. Aida Ghith
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  8. Ali Saad
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  9. Guiomar Perez de Nanclares
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  10. Dorra H’mida ben brahim
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Corresponding author

Correspondence to Dorra H’mida ben brahim.

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Conflict of interest

The authors declare that they have no competing interest.

Ethical approval

Ethical procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national, local ethics committee: Comitato Etico Centrale IRCCS Lazion, Sezione IFO/Fondazione Bietti, Rome, Italy) and with the Helsinki Declaration of 1975, as revised in 2008.

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Informed consent was obtained from the patient included in the study.

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Managed by Massimo Porta.

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Touati, A., Errea-Dorronsoro, J., Nouri, S. et al. Transient neonatal diabetes mellitus and hypomethylation at additional imprinted loci: novel ZFP57 mutation and review on the literature. Acta Diabetol 56, 301–307 (2019). https://doi.org/10.1007/s00592-018-1239-3

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  • DOI: https://doi.org/10.1007/s00592-018-1239-3

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