Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57

Mackay, Deborah J G; Callaway, Jonathan L A; Marks, Sophie; White, Helen; Acerini, Carlo L.; Boonen, Susanne E.; Dayanıklı, Pınar; Firth, Helen V.; Goodship, Judith A.; Haemers, Andreas P.; Hahnemann, Johanne M D; Kordonouri, Olga; Masoud, Ahmed F; Oestergaard, E; Storr, J.N.P.; Ellard, Sian; Hattersley, Andrew T.; Robinson, David; Temple, I. Karen

doi:10.1038/ng.187

Cited by 470 publications

(421 citation statements)

References 15 publications

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“…About 20% of patients with transient neonatal diabetes mellitus type 1 show loss of methylation at the PLAGL1/HYMAI ICR, which is normally maternally methylated (Figure 2 and Table 1). 54,55 Over 50% of these patients also show hypomethylation at other maternally methylated ICRs across the genome, which was recently found to be associated with ZFP57 mutations (Table 1). 54 The phenotype can be explained by defects in either establishment or maintenance of methylation imprints but, as noted above, studies on Zfp57 knock-out mice showed that its predominant role is in maintenance after fertilization.…”

Section: Childhood Diseases Associated With Imprint Establishment or mentioning

confidence: 89%

“…54,55 Over 50% of these patients also show hypomethylation at other maternally methylated ICRs across the genome, which was recently found to be associated with ZFP57 mutations (Table 1). 54 The phenotype can be explained by defects in either establishment or maintenance of methylation imprints but, as noted above, studies on Zfp57 knock-out mice showed that its predominant role is in maintenance after fertilization. 30 However, it is important to note that some individuals with hypomethylation at multiple ICRs carry no mutation in ZFP57, indicating the existence of other factors.…”

Section: Childhood Diseases Associated With Imprint Establishment or mentioning

confidence: 89%

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Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

Tomizawa

Sasaki

2012

J Hum Genet

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Genomic imprinting is an epigenetic gene-marking phenomenon that occurs in the germline, whereby genes are expressed from only one of the two parental copies in embryos and adults. Imprinting is essential for normal mammalian development and its disruption can cause various developmental defects and diseases. The process of imprinting in the germline involves DNA methylation of the imprint control regions (ICRs), and resulting parental-specific methylation imprints are maintained in the zygote and act as the marks controlling imprinted gene expression. Recent studies in mice have revealed new factors involved in imprint establishment during gametogenesis and maintenance during early development. Clinical studies have identified cases of imprinting disorders where involvement of factors shared by multiple ICRs for establishment or maintenance is suspected. These include Beckwith-Wiedemann syndrome, transient neonatal diabetes, Silver-Russell syndrome and others. More severe disruptions can lead to recurrent molar pregnancy, miscarriage or infertility. Imprinting defects may also occur during assisted reproductive technology or cell reprogramming. In this review, we summarize our current knowledge on the mechanisms of imprint establishment and maintenance, and discuss the relationship with various human disorders.

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Section: Childhood Diseases Associated With Imprint Establishment or mentioning

confidence: 89%

Section: Childhood Diseases Associated With Imprint Establishment or mentioning

confidence: 89%

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

Tomizawa

Sasaki

2012

J Hum Genet

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“…26,27,33 In addition, mutations in the ZFP57 gene result in transient neonatal diabetes mellitus type 1, possibly through Plagl1 overexpression. 34,35 The role of ZFP57 in tumorigenesis has not been elucidated yet.…”

Section: Discussionmentioning

confidence: 99%

The stem cell transcription factor ZFP57 induces IGF2 expression to promote anchorage-independent growth in cancer cells

et al. 2014

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Several common biological properties between cancer cells and embryonic stem (ES) cells suggest the possibility that some genes expressed in ES cells might play important roles in cancer cell growth. The transcription factor ZFP57 is expressed in self-renewing ES cells and its expression level decreases during ES cell differentiation.This study showed that ZFP57 is involved in the anchorage-independent growth of human fibrosarcoma HT1080 cells in soft agar. ZFP57 overexpression enhanced, while knockdown suppressed, HT1080 tumor formation in nude mice. Furthermore, ZFP57 regulates the expression of IGF2, which plays a critical role in ZFP57-induced anchorage-independent growth. ZFP57 also promotes anchorage-independent growth in ES cells and immortal fibroblasts. Finally, immunohistochemical analysis revealed that ZFP57 is overexpressed in human cancer clinical specimens. Taken together, these results suggest that the ES-specific transcription factor ZFP57 is a novel oncogene.

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“…Mutations in genes encoding members of the zinc-finger protein family have been considered good candidates as causative defects of MLID, given the well-established role of ZFP57 mutation in patients with transient neonatal diabetes mellitus and MLID [26,27]. However, no mutations have been found to date in other members of the protein family in MLID patients.…”

Section: Introductionmentioning

confidence: 99%

Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders

et al. 2018

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The identification of multilocus imprinting disturbances (MLID) appears fundamental to uncover molecular pathways underlying imprinting disorders (IDs) and to complete clinical diagnosis of patients. However, MLID genetic associated mechanisms remain largely unknown. To characterize MLID in Beckwith-Wiedemann (BWS) and Silver-Russell (SRS) syndromes, we profiled by MassARRAY the methylation of 12 imprinted differentially methylated regions (iDMRs) in 21 BWS and 7 SRS patients with chromosome 11p15.5 epimutations. MLID was identified in 50% of BWS and 29% of SRS patients as a maternal hypomethylation syndrome. By next-generation sequencing, we searched for putative MLID-causative mutations in genes involved in methylation establishment/maintenance and found two novel missense mutations possibly causative of MLID: one in NLRP2, affecting ADP binding and protein activity, and one in ZFP42, likely leading to loss of DNA binding specificity. Both variants were paternally inherited. In silico protein modelling allowed to define the functional effect of these mutations. We found that MLID is very frequent in BWS/SRS. In addition, since MLID-BWS patients in our cohort show a peculiar pattern of BWS-associated clinical signs, MLID test could be important for a comprehensive clinical assessment. Finally, we highlighted the possible involvement of ZFP42 variants in MLID development and confirmed NLRP2 as causative locus in BWS-MLID.

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Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57

Cited by 470 publications

References 15 publications

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

The stem cell transcription factor ZFP57 induces IGF2 expression to promote anchorage-independent growth in cancer cells

Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders

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