Mackay DJ, Callaway JL, Marks SM, White HE, Acerini CL, Boonen SE et al.. Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nat Genet 40: 949-951

Division of Human Genetics, University of Southampton, Southampton SO16 6YD, UK.
Nature Genetics (Impact Factor: 29.65). 08/2008; 40(8):949-51. DOI: 10.1038/ng.187
Source: PubMed

ABSTRACT We have previously described individuals presenting with transient neonatal diabetes and showing a variable pattern of DNA hypomethylation at imprinted loci throughout the genome. We now report mutations in ZFP57, which encodes a zinc-finger transcription factor expressed in early development, in seven pedigrees with a shared pattern of mosaic hypomethylation and a conserved range of clinical features. This is the first description of a heritable global imprinting disorder that is compatible with life.

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    • "Intriguingly, human ZFP57 functionally replaces mouse Zfp57 in embryonic stem cells and mutation in human ZFP57 affect DNA methylation at a subset of imprinted loci in individuals suffering transient neonatal diabetes (Mackay et al., 2008; Takikawa et al., 2013). Altogether these studies suggested a conserved role for Zfp57 in the maintenance of DNA methylation pattern at imprinted loci in mammals, despite clear differences in early embryonic developmental processes. "
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    ABSTRACT: DNA methylation in mammals is a key epigenetic modification essential to normal genome regulation and development. DNA methylation patterns are established during early embryonic development, and subsequently maintained during cell divisions. Yet, discrete site-specific de novo DNA methylation or DNA demethylation events play a fundamental role in a number of physiological and pathological contexts, leading to critical changes in the transcriptional status of genes such as differentiation, tumor suppressor or imprinted genes. How the DNA methylation machinery targets specific regions of the genome during early embryogenesis and in adult tissues remains poorly understood. Here, we report advances being made in the field with a particular emphasis on the implication of transcription factors in establishing and in editing DNA methylation profiles. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
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    • "However, STELLA's global binding and protection of the whole maternal genome from active demethylation makes it an unlikely candidate for DNA methylation maintenance at specific loci. ZFP57, a Krueppel-associated box (KRAB) domain zinc finger protein, has also been associated with imprinting maintenance (Fig. 4C; Li et al. 2008; Mackay et al. 2008). "
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    ABSTRACT: Methylation of DNA is an essential epigenetic control mechanism in mammals. During embryonic development, cells are directed toward their future lineages, and DNA methylation poses a fundamental epigenetic barrier that guides and restricts differentiation and prevents regression into an undifferentiated state. DNA methylation also plays an important role in sex chromosome dosage compensation, the repression of retrotransposons that threaten genome integrity, the maintenance of genome stability, and the coordinated expression of imprinted genes. However, DNA methylation marks must be globally removed to allow for sexual reproduction and the adoption of the specialized, hypomethylated epigenome of the primordial germ cell and the preimplantation embryo. Recent technological advances in genome-wide DNA methylation analysis and the functional description of novel enzymatic DNA demethylation pathways have provided significant insights into the molecular processes that prepare the mammalian embryo for normal development.
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    • "Our findings are consistent with the hypothesis put forward by Fernandez-Rebollo et al. (2010) that PHP-1b is an autosomal recessive genetic disorder in some patients. The initial discovery of maternal hypomethylation syndrome led to the identification of mutations in the ZFP57 and NLRP2 genes in patients with TNDM and BWS, respectively, presenting multilocus imprinting defects [Mackay et al., 2008; Meyer et al., 2009]. Court et al. (2013) and Perez-Nanclares et al. (2012) failed to identify mutations in Figure 4. PTH and TSH resistance in patients with Spor-PHP-1b, including the patients with multilocus imprinting defects. "
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    ABSTRACT: Most patients with pseudohypoparathyroidism type 1b (PHP-1b) display a loss of imprinting (LOI) encompassing the GNAS locus resulting in PTH resistance. In other imprinting disorders, such as Russell Silver or Beckwith Wiedemann syndrome, we and others have shown that the LOI is not restricted to one imprinted locus yet may affect other imprinted loci for some patients. Therefore we hypothesized that patients with PHP-1b might present multilocus imprinting defects. We investigated, in 63 patients with PHP-1b, the methylation pattern of eight imprinted loci: GNAS, ZAC1, PEG1/MEST, ICR1 and ICR2 on chromosome 11p15, SNRPN, DLK1/GTL2 IG-DMR and L3MBTL1. We found multilocus imprinting defects in four PHP-1b patients carrying broad LOI at the GNAS locus i- simultaneous hypermethylation at L3MBTL1 differentially methylated region 3 (DMR3), and hypomethylation at PEG1/MEST DMR (n = 1), ii- hypermethylation at the L3MBTL1 (DMR3) (n = 1) and at the DLK1/GTL2 IG-DMR (n = 1) and iii- hypomethylation at the L3MBTL1 DMR3 (n = 1). We suggest that mechanisms underlying multilocus imprinting defects in PHP-1b differ from those of other imprinting disorders having only multilocus loss of methylation. Furthermore, our results favor the hypothesis of "epidominance", i.e. the phenotype is controlled by the most severely affected imprinted locus.
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