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PubMed1997

Molecular genetics of Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder characterized by developmental anomalies, tissue and organ hyperplasia, and an increased risk of embryonal tumors. BWS is a multigenic disorder with dysregulation of the expression of imprinted genes involved in growth and cell cycle control in the 11p15 chromosomal region. The molecular genetics appear to involve either mutations of imprinted genes or chromosomal alterations of a putative imprinting center that controls gene expression across a large chromosomal domain. As the molecular genetics underlying BWS are unraveled, our knowledge of this imprinting disorder and its relationship to neoplasia and developmental anomalies will be expanded. Currently available diagnostic testing and follow-up protocols will evolve as our understanding of the molecular basis of this disease progresses.

Beckwith-Wiedemann Syndrome↗

PubMed2026

Convergent IGF2 overexpression in pheochromocytoma/paraganglioma: insights from Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized by overgrowth and tumor predisposition, caused by dysregulated expression of genes on chromosome 11p15.5. An association between BWS and pheochromocytoma/paraganglioma (PPGL) has been suggested in isolated case reports over the past fifty years, but the molecular basis for this link remains unclear. We identified four patients with BWS who developed metastatic PPGL and investigated IGF2 pathway activation in these tumors and in PPGL across various genotypes. Pan-cancer transcriptomic analysis of The Cancer Genome Atlas (TCGA) demonstrated that PPGL overexpresses IGF2, with pseudohypoxic tumors exhibiting higher expression compared to other molecular clusters. Loss of heterozygosity and loss of imprinting at 11p15.5 partially explain this overexpression, with PPGL additionally demonstrating globally elevated expression of imprinted genes compared to most other tumor types, suggesting a broader relaxation of genomic imprinting. Cognate receptor profiling revealed that PPGLs are equipped to respond to IGF2 signaling, with high expression of IGF1R and insulin receptor isoform A (IR-A). Immunohistochemistry confirmed IGF2 protein overexpression in both BWS-associated and genotypically diverse sporadic PPGLs. Our results indicate that IGF2 overexpression is a convergent molecular feature of PPGL across genotypes and suggest the IGF2 pathway as a potential diagnostic and therapeutic target.

Humans↗

PubMed2000

Epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is a model imprinting disorder resulting from mutations or epigenetic events involving imprinted genes at chromosome 11p15.5. Thus, germline mutations in CDKN1C, uniparental disomy (UPD), and loss of imprinting of IGF2 and other imprinted genes have been implicated. Many familial BWS cases have germline CDKN1C mutations. However, most BWS cases are sporadic and UPD or putative imprinting errors predominate in this group. We have identified previously a subgroup of sporadic cases with loss of imprinting (LOI) of IGF2 and epigenetic silencing of H19 proposed to be caused by a defect in a distal 11p15.5 imprinting control element (designated BWSIC1). However, many sporadic BWS patients show biallelic IGF2 expression in the presence of normal H19 methylation and expression patterns. This and other evidence suggested the existence of a further imprinting control element (BWSIC2) at 11p15. 5. Recently, we showed that a subgroup of BWS patients have loss of methylation (LOM) at a differentially methylated region (KvDMR1) within the KCNQ1 gene centromeric to the IGF2 and H19 genes. We have now analysed a large series of sporadic cases to define the frequency and phenotypic correlates of epigenetic abnormalities in BWS. LOM at KvDMR1 was detected by Southern analysis or a novel PCR based method in 35 of 69 (51%) sporadic BWS without UPD. LOM at KvDMR1 was often, but not invariably associated with LOI of IGF2. KvDMR1 LOM was not detected in BWS patients with putative BWSIC1 defects and cases with KvDMR1 LOM (that is, putative BWSIC2 defects) invariably had a normal H19 methylation pattern. The incidence of exomphalos in putative BWSIC2 defect patients was not significantly different from that in patients with germline CDKN1C mutations (20/29 and 13/15 respectively), but was significantly greater than that in patients with putative BWSIC1 defects (0/5, p=0.007) and UPD (0/22, p<0.0001). These findings are consistent with the hypothesis that LOM of KvDMR1 (BWSIC2 defect) results in epigenetic silencing of CDKN1C and variable LOI of IGF2. BWS patients with embryonal tumours have UPD or a BWSIC1 defect but not LOM of KvDMR1. This study has further shown how (1) variations in phenotypic expression of BWS may be linked to specific molecular subgroups and (2) molecular analysis of BWS can provide insights into mechanisms of imprinting regulation.

Beckwith-Wiedemann Syndrome↗

PubMed2004

Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3.

Autism is a common neurodevelopmental disorder of complex genetic etiology. Rett syndrome, an X-linked dominant disorder caused by MECP2 mutations, and Angelman syndrome, an imprinted disorder caused by maternal 15q11-q13 or UBE3A deficiency, have phenotypic and genetic overlap with autism. MECP2 encodes methyl-CpG-binding protein 2 that acts as a transcriptional repressor for methylated gene constructs but is surprisingly not required for maintaining imprinted gene expression. Here, we test the hypothesis that MECP2 deficiency may affect the level of expression of UBE3A and neighboring autism candidate gene GABRB3 without necessarily affecting imprinted expression. Multiple quantitative methods were used including automated quantitation of immunofluorescence and in situ hybridization by laser scanning cytometry on tissue microarrays, immunoblot and TaqMan PCR. The results demonstrated significant defects in UBE3A/E6AP expression in two different Mecp2 deficient mouse strains and human Rett, Angelman and autism brains compared with controls. Although no difference was observed in the allelic expression of several imprinted transcripts in Mecp2-null brain, Ube3a sense expression was significantly reduced, consistent with the decrease in protein. A non-imprinted gene from 15q11-q13, GABRB3, encoding the beta3 subunit of the GABAA receptor, also showed significantly reduced expression in multiple Rett, Angelman and autism brain samples, and Mecp2 deficient mice by quantitative immunoblot. These results suggest an overlapping pathway of gene dysregulation within 15q11-q13 in Rett, Angelman and autism and implicate MeCP2 in the regulation of UBE3A and GABRB3 expressions in the postnatal mammalian brain.

Angelman Syndrome↗

PubMed2005

Epigenetic deregulation of genomic imprinting in human disorders and following assisted reproduction.

Imprinted genes play important roles in the regulation of growth and development, and several have been shown to influence behavior. Their allele-specific expression depends on inheritance from either the mother or the father, and is regulated by "imprinting control regions" (ICRs). ICRs are controlled by DNA methylation, which is present on one of the two parental alleles only. These allelic methylation marks are established in either the female or the male germline, following the erasure of preexisting DNA methylation in the primordial germ cells. After fertilization, the allelic DNA methylation at ICRs is maintained in all somatic cells of the developing embryo. This epigenetic "life cycle" of imprinting (germline erasure, germline establishment, and somatic maintenance) can be disrupted in several human diseases, including Beckwith-Wiedemann syndrome (BWS), Prader-Willi syndrome (PWS), Angelman syndrome and Hydatidiform mole. In the neurodevelopmental Rett syndrome, the way the ICR mediates imprinted expression is perturbed. Recent studies indicate that assisted reproduction technologies (ART) can sometimes affect the epigenetic cycle of imprinting as well, and that this gives rise to imprinting disease syndromes. This finding warrants careful monitoring of the epigenetic effects, and absolute risks, of currently used and novel reproduction technologies.

Alleles↗

PubMed1995

Parents do matter: genomic imprinting and parental sex effects in neurological disorders.

Genomic imprinting is a recently recognized phenomenon of differential expression of genetic material depending upon whether the genetic material has come from the male or female parent. This process of differential phenotypic expression involves mammalian development both in the normal and abnormal situations, resulting in parental sex effects. However, some parental sex effects may be due to other mechanisms such as mitochondrial inheritance. In the following article, evidence for genomic imprinting in experimental animals and in diseases are summarized. Relevant human neurological disorders manifesting parental sex effects discussed here include myotonic dystrophy, Huntington's disease, fragile X syndrome, spinocerebellar ataxia type 1, and neurofibromatosis type 1 and 2. A possible mechanism of imprinting involves the processes of methylation imprint and replication imprint. The knowledge of imprinting is helpful in clinical practice particularly in the areas of genetic counseling, prenatal diagnosis, and possible future gene therapy.

Animals↗

PubMed2005

Epigenetic alteration at the DLK1-GTL2 imprinted domain in human neoplasia: analysis of neuroblastoma, phaeochromocytoma and Wilms' tumour.

Epigenetic alterations in the 11p15.5 imprinted gene cluster are frequent in human cancers and are associated with disordered imprinting of insulin-like growth factor (IGF)2 and H19. Recently, an imprinted gene cluster at 14q32 has been defined and includes two closely linked but reciprocally imprinted genes, DLK1 and GTL2, that have similarities to IGF2 and H19, respectively. Both GTL2 and H19 are maternally expressed RNAs with no protein product and display paternal allele promoter region methylation, and DLK1 and IGF2 are both paternally expressed. To determine whether methylation alterations within the 14q32 imprinted domain occur in human tumorigenesis, we investigated the status of the GTL2 promoter differentially methylated region (DMR) in 20 neuroblastoma tumours, 20 phaeochromocytomas and, 40 Wilms' tumours. Hypermethylation of the GTL2 promoter DMR was detected in 25% of neuroblastomas, 10% of phaeochromocytoma and 2.5% of Wilms' tumours. Tumours with GTL2 promoter DMR hypermethylation also demonstrated hypermethylation at an upstream intergenic DMR thought to represent a germline imprinting control element. Analysis of neuroblastoma cell lines revealed that GTL2 DMR hypermethylation was associated with transcriptional repression of GTL2. These epigenetic findings are similar to those reported in Wilms' tumours in which H19 repression and DMR hypermethylation is associated with loss of imprinting (LOI, biallelic expression) of IGF2. However, a neuroblastoma cell line with hypermethylation of the GTL2 promoter and intergenic DMR did not show LOI of DLK1 and although treatment with a demethylating agent restored GTL2 expression and reduced DLK1 expression. As described for IGF2/H19, epigenetic changes at DLK1/GTL2 occur in human cancers. However, these changes are not associated with DLK1 LOI highlighting differences in the imprinting control mechanisms operating in the IGF2-H19 and DLK1-GTL2 domains. GTL2 promoter and intergenic DMR hypermethylation is associated with the loss of GTL2 expression and this may contribute to tumorigenesis in a subset of human cancers.

Base Sequence↗

PubMed2006

Imprinted genes in placental growth and obstetric disorders.

Genomic imprinting has a special role in placental biology. Imprinted genes are often strongly expressed in the placenta, and the allelic expression bias due to imprinting is sometimes stronger in this extraembryonic organ than in the embryo and adult. Mutations, epimutations, and uniparental disomies affecting imprinted loci cause placental stunting or overgrowth in mice and humans, and placental neoplasms (complete hydatidiform moles) are androgenetic. Whether imprinted genes might also play a role in the more common medical conditions that affect the placenta, including preeclampsia and intrauterine growth restriction (IUGR), is an important question that is now receiving some attention. Here we review this area and describe recent data indicating altered expression of imprinted genes in the placental response to maternal vascular underperfusion associated with IUGR.

Female↗

PubMed1994

On the oncodevelopmental role of human imprinted genes.

Genome imprinting has an essential role in normal embryonal mammalian development. Starting early in differentiation, the transcripts of certain human genes, e.g. the paternally-H19 and the maternally-imprinted IGF2, are expressed in specific tissues and organs during fetal life. In several malignant disorders, imprinted genes are, again, unfolded. Characteristically, expression follows the same tissue presentation as during embryogenesis. Clinical paternal disomies, i.e. trophoblastic diseases, and their maternal counterpart, i.e. ovarian teratomas, are associated with apparent relaxation of imprinting once they turn malignant. Paediatric neoplasms, like Wilm's tumor (WT) and rhabdomyosarcoma, often express IGF2 and H19. Recently, we have found H19 expression in invasive urothelial cancer. Evidently, imprinted genes display an oncodevelopmental mode of expression, very much like the classical oncofetal proteins AFP and CEA. Based on available data, including tumor preferential paternal allele retention and chromosome 11 short arm physical linkage with oncogenes like H-ras, we hypothesize that imprinted genes not only accompany cancer but may play a causative role as well.

Antigens, Neoplasm↗

PubMed2001

Imprinting status of 11p15 genes in Beckwith-Wiedemann syndrome patients with CDKN1C mutations.

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized by somatic overgrowth, congenital malformations, and predisposition to childhood tumors. Aberrant expression of multiple imprinted genes, including H19, IGF2, KCNQ1OT1, and CDKN1C, has been observed in BWS patients. It has been estimated that mutations in CDKN1C occur in 12-17% of BWS patients. We have screened 10 autosomal dominant pedigrees and 65 sporadic BWS cases by PCR/heteroduplex analysis and DNA sequencing and have identified four mutations, two of which were associated with biallelic IGF2 expression and normal H19 and KCNQ1OT1 imprinting. One patient demonstrated phenotypic expression of paternally transmitted mutation in this maternally expressed gene, a second proband is the child of one of a pair of monozygotic twin females who carry the mutation de novo, and a third patient exhibited unusual skeletal changes more commonly found in other overgrowth syndromes. When considered with other studies published to date, this work reveals the frequency of CDKN1C mutations in BWS to be only 4.9%. This is the first report of an analysis of the imprinting status of genes in the 11p15 region where CDKN1C mutations were associated with loss of IGF2 imprinting and maintenance of H19 and KCNQ1OT1 imprinting.

Amino Acid Sequence↗

PubMed2006

Familial molar tissues due to mutations in the inflammatory gene, NALP7, have normal postzygotic DNA methylation.

An imprinting disorder has been believed to underlie the etiology of familial biparental hydatidiform moles (HMs) based on the abnormal methylation or expression of imprinted genes in molar tissues. However, the extent of the epigenetic defect in these tissues and the developmental stage at which the disorder begins have been poorly defined. In this study, we assessed the extent of abnormal DNA methylation in two HMs caused by mutations in the recently identified 19q13.4 gene, NALP7. We demonstrate normal postzygotic DNA methylation patterns at major repetitive and long interspersed nuclear elements (LINEs), genes on the inactive X-chromosome, three-cancer related genes, and CpG rich regions surrounding the PEG3 differentially methylated region (DMR). Our data provide a comprehensive assessment of DNA methylation in familial molar tissues and indicate that abnormal DNA methylation in these tissues is restricted to imprinted DMRs. The known role of NALP7 in apoptosis and inflammation pinpoints previously unrecognized pathways that could directly or indirectly underlie the abnormal methylation of imprinted genes in molar tissues.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Imprinting defects in mouse embryos: stochastic errors or polymorphic phenotype?

Defects in expression of imprinted genes are believed to cause developmental abnormalities and play a role in carcinogenesis. To determine whether spontaneous imprinting defects may occur in mouse embryos, we studied the expression of two imprinted genes H19 and Igf2 in individual postimplantation 7.5 d.p.c. and 8.5 d.p.c. embryos. Biallelic expression of H19 was found in 1.6% of the embryos, whereas biallelic expression of Igf2 was found in 0.5% of the embryos. The loss of H19 imprinting (LOI) observed in a small fraction of early postimplantation embryos may be purely stochastic. Alternatively, since we never observed it in an inbred background, it may depend on genetic factors acting in trans. Either mechanism could explain the occurrence of polymorphic imprinting as well as the genesis of sporadic imprinting defects, including cancer. The frequency of LOI of H19 was higher than the incidence of sporadic imprinting disorders in humans (about 1 in 20,000). This contradiction may be explained by different incidence of imprinting errors in different imprinted regions of the genome, in different species, or by loss of the majority of nonmosaic embryos with imprinting defects before birth.

Alleles↗

PubMedDate not supplied

Potential significance of genomic imprinting defects for reproduction and assisted reproductive technology.

Recent studies suggest a possible link between human assisted reproductive technology and genomic imprinting disorders. Assisted reproductive technology includes the isolation, handling and culture of gametes and early embryos at times when imprinted genes are likely to be particularly vulnerable to external influences. Evidence of sex-specific differences in imprint acquisition suggests that male and female germ cells may be susceptible to perturbations in imprinted genes at specific prenatal and postnatal stages. Imprints acquired first during gametogenesis must be maintained during preimplantation development when reprogramming of the overall genome occurs. In this review, we will discuss both new developments in our understanding of genomic imprinting including the mechanisms and timing of imprint erasure, acquisition and maintenance during germ cell development and early embryogenesis as well as the implications of this research for future epigenetic studies in reproduction and assisted reproductive technology.

Angelman Syndrome↗

PubMed1997

Imprint switch mechanism indicated by mutations in Prader-Willi and Angelman syndromes.

Genomic imprinting is an epigenetic mechanism resulting in the preferential expression of the maternal or paternal alleles of a specific subset of genes in the mammalian genome. A key but relatively unexplored question is how imprints are established in the germline. New observations on two classical imprinting disorders, the Prader-Willi (PWS) and Angelman (AS) syndromes, offer the first genetic insight into this process. Molecular analysis of imprinting mutations that interfere with the appropriate establishment of the maternal and paternal epigenotypes has led to the identification of imprinted transcripts that could be involved in switching imprints in the germlines.

Angelman Syndrome↗

PubMed2005

Gametes and embryo epigenetic reprogramming affect developmental outcome: implication for assisted reproductive technologies.

There is concern about the health of children who are conceived with the use assisted reproductive technologies (ART). In addition to reports of low birth weight and chromosomal anomalies, there is evidence that ART may be associated with increased epigenetic disorders in the infants who are conceived using these procedures. Epigenetic reprogramming is critical during gametogenesis and at preimplantation stage and involves DNA methylation, imprinting, RNA silencing, covalent modifications of histones, and remodeling by other chromatin-associated complexes. Epigenetic regulation is involved in early embryo development, fetal growth, and birth weight. Disturbances in epigenetic reprogramming may lead to developmental problems and early mortality. Recent reports suggest the increased incidence of imprinting disorders such as Beckwith-Wiedemann syndrome, Angelman syndrome, and retinoblastoma in children who are conceived with the use of ART. These may result from an accumulation of epigenetic alterations during embryo culture and/or by altered embryonic developmental timing. Further research is urgently needed to determine whether a causal relationship between ART and epigenetic disorders exists. Until then, cautious review of both short-term and long-term ART outcomes at a national level is recommended.

Embryo, Mammalian↗

PubMed2006

Aberrant DNA methylation of imprinted loci in superovulated oocytes.

BACKGROUND: There is an increased incidence of rare imprinting disorders associated with assisted reproduction technologies (ARTs). The sex-specific epigenetic modifications that are imposed during gametogenesis act as a primary imprint to distinguish maternal and paternal alleles. The most likely candidate for the gametic mark is DNA methylation. However, the timing of DNA methylation acquisition in adult oocytogenesis and the effects of superovulation are unknown. METHODS: We examined the maternal methylation of PEG1(MEST), LIT1(KCNQ1OT1) and ZAC(PLAGL1) and the paternal methylation of H19 in adult growing oocytes of humans and mice and compared them with the methylation status of mouse neonatal growing oocytes by using bisulphite sequencing. Furthermore, we examined the effects of superovulation in the human and mouse. RESULTS: Maternal methylation of these genes has already been initiated to some extent in adult human and mouse non-growing oocytes but not in mouse neonates. In addition, the methylation dynamics during adult human and mouse oocyte development changed more gradually than those during neonatal oocyte development. Furthermore, we found the demethylation of PEG1 in growing oocytes from some ART-treated infertile women and a gain in the methylation of H19. We also detected methylation changes in superovulated mice. CONCLUSION: Our studies in the human and mouse suggest that superovulation can lead to the production of oocytes without their correct primary imprint and highlight the need for more research into ARTs.

Adult↗

PubMed2001

Genetic conflict, genomic imprinting and establishment of the epigenotype in relation to growth.

Genomic imprinting is the process that differentially modifies the parental alleles at certain genetic loci in the parental germlines. Such modifications of DNA and chromatin are somatically heritable and cause unequal expression of the parental alleles during subsequent development. In mammals, imprinted genes encode a relatively small number of functionally heterogeneous proteins. Nevertheless, imprinted genes exert important effects, primarily on fetal development, and their deregulation is implicated in a variety of pathologies including sporadic, inherited and induced growth disorders. Imprinted loci show several unusual structural and functional characteristics that may be related to mechanistic aspects of mono-allelic expression or to modes of evolution of imprinted genetic loci. Typically, imprinted genes are clustered in certain genomic regions and have relatively reduced intronic DNA content relative to non-imprinted genes. In addition, their regulatory regions frequently contain a combination of features including tandem repeats associated with differentially methylated CpG islands and overlapping transcription of coding or non-coding RNAs. The evolution of imprinting can be understood as the stable outcome of sexual selection acting differently on the parental alleles of genes that influence parental investment in offspring. Consistent with this explanation, imprinted genes are expressed predominantly during embryonic and postnatal development in mammals and in the developing endosperm of plants, and maternal or paternal expression at imprinted loci is associated with reduced or increased parental investment, respectively. Such selective forces have implications for understanding mechanistic aspects of genome reprogramming in the early mammalian embryo.

Animals↗

PubMed1998

Prader-Willi and Angelman syndromes. Disorders of genomic imprinting.

Prader-Willi and Angelman syndromes are 2 clinically distinct disorders associated with multiple anomalies and mental retardation. They are only discussed together because they share a similar and uncommon genetic basis: they involve genes that are located in the same region in the genome and are characterized by genetic imprinting. This normal process has contributed to these 2 complex and severe conditions through inactivation of 1 copy of the genes relevant to each disorder: the maternally derived copy of genes for Prader-Willi syndrome in proximal 15q are normally silent, and a paternally derived copy of 1 gene for Angelman syndrome in 15q is normally silent. For both disorders, when the normally active copy of the gene or genes is missing, abnormality results. Since the genes for these 2 disorders are located very close together, and since the center involved in inactivating the genes involved in imprinting may be the same, both these disorders usually result from the same chromosomal deletion; which disorder results depends on the parent of origin of the chromosome 15 that becomes deleted. Both Prader-Willi and Angelman syndrome can also occur as a result of having both members of the chromosome 15 pair derived from 1 parent, a condition known as uniparental disomy. Both can also result from a structural abnormality of the imprinting center, known as an imprinting mutation. In addition, Angelman syndrome can be caused by a mutation in the gene that causes it; a comparable cause is not present in Prader-Willi syndrome since it results from abnormality in more than 1 gene. Finally, despite the complexity of possible causes, all but the single gene mutation of the Angelman syndrome gene can be detected through methylation-sensitive DNA probes, since DNA methylation is the process by which the genes for these 2 disorders are imprinted. This unusual property of specific areas of the DNA holds promise for future treatment of these and other disorders related to imprinting through reversal of the imprinting process.

Adult↗