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PubMed2006

Imbalanced genomic imprinting in brain development: an evolutionary basis for the aetiology of autism.

We describe a new hypothesis for the development of autism, that it is driven by imbalances in brain development involving enhanced effects of paternally expressed imprinted genes, deficits of effects from maternally expressed genes, or both. This hypothesis is supported by: (1) the strong genomic-imprinting component to the genetic and developmental mechanisms of autism, Angelman syndrome, Rett syndrome and Turner syndrome; (2) the core behavioural features of autism, such as self-focused behaviour, altered social interactions and language, and enhanced spatial and mechanistic cognition and abilities, and (3) the degree to which relevant brain functions and structures are altered in autism and related disorders. The imprinted brain theory of autism has important implications for understanding the genetic, epigenetic, neurological and cognitive bases of autism, as ultimately due to imbalances in the outcomes of intragenomic conflict between effects of maternally vs. paternally expressed genes.

Autistic Disorder↗
PubMed2003

Conserved methylation imprints in the human and mouse GRB10 genes with divergent allelic expression suggests differential reading of the same mark.

Grb10/GRB10 encodes a cytoplasmic adapter protein which modulates coupling of a number of cell surface receptor tyrosine kinases with specific signalling pathways. Mouse Grb10 is an imprinted gene with maternal-specific expression. In contrast, human GRB10 is expressed biallelically in most tissues, except for maternal-specific expression of one isoform in muscle and paternal expression in fetal brain. Owing to its location in 7p11.2-p12, GRB10 has been considered a candidate gene for the imprinted growth disorder, the Silver-Russell syndrome (SRS), but its predominantly biallelic expression argues against involvement in the syndrome. To investigate the discrepant imprinting between mouse and human, we compared the sequence organization of their upstream regions, and examined their allelic methylation patterns and the splice variant organization of the mouse locus. Contrary to expectation, we detected both maternal and paternal expression of mouse Grb10. Expression of the paternal allele arises from a different promoter region than the maternal and, as in human, is restricted to the brain. The upstream regions are well conserved, especially the presence of two CpG islands. Surprisingly, both genes have a similar imprinted methylation pattern, the second CpG island is a differentially methylated region (DMR) with maternal methylation in both species. Analysis of 24 SRS patients did not reveal methylation anomalies in the DMR. In the mouse this DMR is a gametic methylation mark. Our results suggest that the difference in imprinted expression in mouse and human is not due to acquisition of an imprint mark but in differences in the reading of this mark.

Animals↗
PubMed2001

Tumor development in the Beckwith-Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of KCNQ1OT1.

Dysregulation of imprinted genes on human chromosome 11p15 has been implicated in Beckwith-Wiedemann syndrome (BWS), an overgrowth syndrome associated with congenital malformations and tumor predisposition. The molecular basis of BWS is complex and heterogeneous. The syndrome is associated with alterations in two distinct imprinting domains on 11p15: a telomeric domain containing the H19 and IGF2 genes and a centromeric domain including the KCNQ1OT1 and CDKNIC genes. It has been postulated that disorders of imprinting in the telomeric domain are associated with overgrowth and cancer predisposition, whereas those in the centromeric domain involve malformations but not tumor development. In this study of 125 BWS cases, we confirm the association of tumors with constitutional defects in the 11p15 telomeric domain; six of 21 BWS cases with uniparental disomy (UPD) of 11p15 developed tumors and one of three of the rare BWS subtype with hypermethylation of the H19 gene developed tumors. Most importantly, we find that five of 32 individuals with BWS and imprinting defects in the centromeric domain developed embryonal tumors. Furthermore, the type of tumors observed in BWS cases with telomeric defects are different from those seen in BWS cases with defects limited to the centromeric domain. Whereas Wilms' tumor was the most frequent tumor seen in BWS cases with UPD for 11p15 or H19 hypermethylation, none of the embryonal tumors with imprinting defects at KCNQ1OT1 was a Wilms' tumor. This suggests that distinct tumor predisposition profiles result from dysregulation of the telomeric domain versus the centromeric domain and that these imprinting defects activate distinct genetic pathways for embryonal tumorigenesis.

Beckwith-Wiedemann Syndrome↗
PubMed1997

Roles of the imprinted gene Igf2 and paternal duplication of distal chromosome 7 in the perinatal abnormalities of androgenetic mouse chimeras.

Mouse chimeras made with androgenetic (two paternal genomes) ova or embryonic stem cells frequently die at the perinatal stage and exhibit a range of defects, the most noticeable being a pronounced overgrowth of rib cartilage. Excess concentrations of IGFII, a potent mitogen, has been suggested to play a major role in these defects, as androgenetic cells possess two active paternal copies of the imprinted Igf2 gene, rather than one inactive maternal and one active paternal copy as in normal cells. Here, we show that chimeras made with androgenetic embryonic stem cells, homozygous for an Igf2 null mutation, do not develop rib cartilage hyperplasia, demonstrating the dependence of this defect on Igf2 activity produced by androgenetic cells. In contrast, in these same chimeras, many other defects, including whole body overgrowth and perinatal death, are still prevalent, indicating that the abnormal expression of one or more imprinted genes, other than Igf2, is also capable of inducing most of the defects of androgenetic chimeras. Many of these genes may reside on distal chromosome 7, as we also show that perinatal chimeras made with embryonic stem cells possessing paternal duplication of distal chromosome 7 exhibit a range of defects similar to those of androgenetic chimeras. The relevance of these findings for the human imprinting-related disorder, Beckwith-Wiedemann syndrome, is discussed.

Animals↗
PubMed2000

Partial paternal uniparental disomy of chromosome 6 in an infant with neonatal diabetes, macroglossia, and craniofacial abnormalities.

Neonatal diabetes, which can be transient or permanent, is defined as hyperglycemia that presents within the first month of life and requires insulin therapy. Transient neonatal diabetes mellitus has been associated with abnormalities of the paternally inherited copy of chromosome 6, including duplications of a portion of the long arm of chromosome 6 and uniparental disomy, implicating overexpression of an imprinted gene in this disorder. To date, all patients with transient neonatal diabetes mellitus and uniparental disomy have had complete paternal isodisomy. We describe a patient with neonatal diabetes, macroglossia, and craniofacial abnormalities, with partial paternal uniparental disomy of chromosome 6 involving the distal portion of 6q, from 6q24-qter. This observation demonstrates that mitotic recombination of chromosome 6 can also give rise to uniparental disomy and neonatal diabetes, a situation similar to that observed in Beckwith-Wiedemann syndrome, another imprinted disorder. This finding has clinical implications, since somatic mosaicism for uniparental disomy of chromosome 6 should also be considered in patients with transient neonatal diabetes mellitus.

Aneuploidy↗
PubMed1996

Role of genomic imprinting in Wilms' tumour and overgrowth disorders.

Activation of the silent maternal IGF2 allele has recently been found in approximately half of Wilms' tumour (WTs) examined. This process of imprint relaxation leads to biallelic expression of IGF2 and it has been suggested that this is a key event in the onset of some WTs. Although it has previously been proposed that the 11p15 chromosome region contains a growth-promoting gene and a tumour suppressor gene, the simplest explanation is that increased expression of the IGF2 gene is responsible for somatic overgrowth in the BWS and predisposition to tumours. This model explains overgrowth in BWS cases with unbalanced translocations with paternal dup(11p), and cases with balanced maternal translocations which are physically close to the IGF2 gene. Maternal translocations are envisaged to disrupt the maternal IGF2 imprint by a mechanism similar to the position-effect variegation mechanism in Drosophila. Relaxation of IGF2 imprinting has also been detected in several patients with the BWS syndrome and a patient with gigantism and Wilms' tumour. Recent gene disruption experiments have shown that inactivation of the mouse h19 gene leads to biallelic lgf2 expression and extensive proportional overgrowth. This mouse model has parallels with the BWS and WT where it has been found that biallelic IGF2 expression is accompanied by an epigenetic modification of the H19 gene. From these data it is possible to speculate that an epigenetic modification of the H19 gene may be the primary event leading to the relaxation of IGF2 imprinting.

Alleles↗
PubMed2006

Hormonal regulation of fetal growth.

Fetal growth is a complex process depending on the genetics of the fetus, the availability of nutrients and oxygen to the fetus, maternal nutrition and various growth factors and hormones of maternal, fetal and placental origin. Hormones play a central role in regulating fetal growth and development. They act as maturational and nutritional signals in utero and control tissue development and differentiation according to the prevailing environmental conditions in the fetus. The insulin-like growth factor (IGF) system, and IGF-I and IGF-II in particular, plays a critical role in fetal and placental growth throughout gestation. Disruption of the IGF1, IGF2 or IGF1R gene retards fetal growth, whereas disruption of IGF2R or overexpression of IGF2 enhances fetal growth. IGF-I stimulates fetal growth when nutrients are available, thereby ensuring that fetal growth is appropriate for the nutrient supply. The production of IGF-I is particularly sensitive to undernutrition. IGF-II plays a key role in placental growth and nutrient transfer. Several key hormone genes involved in embryonic and fetal growth are imprinted. Disruption of this imprinting causes disorders involving growth defects, such as Beckwith-Wiedemann syndrome, which is associated with fetal overgrowth, or Silver-Russell syndrome, which is associated with intrauterine growth retardation. Optimal fetal growth is essential for perinatal survival and has long-term consequences extending into adulthood. Given the high incidence of intrauterine growth retardation and the high risk of metabolic and cardiovascular complications in later life, further clinical and basic research is needed to develop accurate early diagnosis of aberrant fetal growth and novel therapeutic strategies.

Animals↗
PubMed2004

Investigation of UBE3A and MECP2 in Angelman syndrome (AS) and patients with features of AS.

Angelman syndrome (AS) is an imprinted neurobehavioral disorder characterized by mental retardation, absent speech, excessive laughter, seizures, ataxia, and a characteristic EEG pattern. Classical lesions, including deletion, paternal disomy, or epigenetic mutation, are confirmatory of AS diagnoses in 80% of cases. Loss-of-function mutations of the UBE3A gene have been identified in approximately 8% of AS cases, failing to account for the remaining patient population, and there appears to be a higher prevalence of mutations in familial than sporadic cases. We screened UBE3A in 45 index cases of AS without obvious 15q11-13 abnormalities. Pathological mutations were identified in 3/6 (50%) familial and 4/39 (>10%) sporadic cases. By combining our data with those of the literature, we demonstrate statistically that the frequency of UBE3A mutations is significantly higher in the familial than sporadic subsets of AS. This indicates that an independent molecular mechanism or 'phenocopy' exists for the sporadic group. Rett syndrome (RS), caused by mutations of the MECP2 gene, and patients with deletions of 22q13.3 --> qter, have overlapping clinical features with AS. We screened 24 of the sporadic AS cases without detectable UBE3A mutations for mutations of MECP2, but found none. A separate cohort of 43 atypical patients with features common to AS and RS, in whom 15q11-13 lesions and 22q13.3 --> qter deletion had been ruled out, were also screened for MECP2 mutations. One male patient was mosaic for a frameshift mutation of this gene (previously reported). While MECP2 mutations can cause a phenotype reminiscent of AS in rare cases, they fail to account for the excess of sporadic patients with a definitive clinical diagnosis of AS.

Angelman Syndrome↗
PubMed2000

Genetic aspects of miscarriage.

Fetal chromosome abnormalities account for about 50% of first-trimester pregnancy losses. Most of these abnormalities are numerical abnormalities (86%) and a low percentage is caused by structural abnormalities (6%) or other genetic mechanisms, including chromosome mosaicism (8%). The recurrence risk of numerical abnormalities is low, so karyotyping of fetal material in case of a miscarriage does not seem worthwhile in daily practice. Half of the structural abnormalities may be inherited from a parent carrying a balanced chromosome translocation or inversion. Parental carriership is found in 4-6% of the couples with recurrent miscarriage. In case of parental carriership of a balanced structural chromosome abnormality, a next pregnancy may result in a child with an unbalanced structural chromosome abnormality. This child can have multiple congenital malformations and/or a mental handicap. Prenatal diagnosis is therefore recommended. Conventional laboratory techniques, such as tissue culturing and karyotyping, or (semi-)direct chromosome technique of chorionic villi, and the recently developed laboratory techniques such as fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH), are described successively. Until now, not enough evidence has been available about the role of other genetic mechanisms, such as single-gene abnormalities, uniparental disomy, genomic imprinting, multifactorial disorders and skewed X chromosome, in the occurrence of miscarriages.

Abortion, Spontaneous↗
PubMed2026

Beckwith-Wiedemann spectrum exhibiting a 46,XY karyotype caused by genome-wide paternal uniparental heterodisomy: a case report.

BACKGROUNDS: Patients with genome-wide paternal uniparental disomy (GWpUPD) usually exhibit clinical features of Beckwith-Wiedemann syndrome (BWS) and a 46,XX karyotype, with all chromosomes showing isodisomy. To date, male patients with GWpUPD and a complete 46,XY karyotype, specifically involving heterodisomy, have not been described. RESULTS: We report a male infant exhibiting classical BWS clinical features. DNA methylation analyses showed paternal-specific methylation across multiple imprinted loci, suggesting GWpUPD. Genetic analysis of autosomes and sex chromosomes indicated two distinct paternal genomes in peripheral blood leukocytes, whereas a normal biparental genome was detected in other tissues under chimeric conditions. These findings indicated that the patient had genome-wide paternal uniparental heterodisomy (GWpUPhD). The SNP array revealed the presence of one copy of the X chromosome and one copy of the Y chromosome, the patient is a chimera composed of 46,XY biparental cells (with maternal X) and 46,XY GWpUPhD cells (with paternal X). CONCLUSIONS: This is the first report of a male patient with a GWpUPhD chimera. We propose a potential mechanism of GWpUPhD formation. Our findings expand the molecular spectrum of GWpUPD and provide valuable insights into its pathogenesis in chimeric conditions. Furthermore, the potential for clinical manifestations unique to 46,XY heterodisomy warrants careful long-term follow-up.

Humans↗
PubMed1993

A strong promoter element is located between alternative exons of a gene encoding the human gamma-aminobutyric acid-type A receptor beta 3 subunit (GABRB3).

The gene that encodes the beta 3 subunit of the gamma-aminobutyrate-Type A (GABAA) receptor is widely expressed in brain tissue and has been associated with imprinted genetic disorders. Here, the 5' regions of the human and rat genes were characterized and found to be highly conserved in both coding and non-coding sequences. A novel transcript of the human gene revealed the existence of an alternative exon 1 (exon 1a) that encodes a variant signal sequence. Relative levels of the alternative transcripts were found to vary between fetal and adult brain, and between different brain regions. Endogenous beta 3 subunit transcripts were also detected in several immortalized cell lines, including human kidney 293 cells. Transcription of exon 1 is initiated from multiple sites within a pyrimidine-rich region of the gene. This region of the human gene also exhibits strong promoter activity and binds nuclear factors at a site which overlaps the transcriptional start sites. The promoter element was shown to bind Sp1 and at least one other unidentified nuclear factor.

Amino Acid Sequence↗
PubMed2006

Modes of imprinted gene action in learning disability.

BACKGROUND: It is now widely acknowledged that there may be a genetic contribution to learning disability and neuropsychiatric disorders, stemming from evidence provided by family, twin and adoption studies, and from explicit syndromic conditions. Recently it has been recognized that in some cases the presentation of genetic syndromes (or discrete aspects of disorders) is dependent on the sex of the transmitting parent. Such 'parent-of-origin effects' can be explained by a number of genetic mechanisms, a predominant one of which is genomic imprinting. Genomic imprinting refers to the parent of origin-specific epigenetic marking of an allele of a gene, such that for some genes it is mainly the maternally inherited allele only that is expressed, whereas for others expression occurs mainly from the paternal copy. METHODS: Here we discuss the contribution of imprinted genes to mental dysfunction and learning disability, using clinical examples of association studies and explicit imprinting disorders (with particular emphasis to Angelman and Prader-Willi syndromes), and evidence from animal work. RESULTS: Clinical and animal studies strongly suggest that imprinted genes contribute to brain functioning, and when the genes or epigenetic processes are disrupted, this can give rise to neuropsychiatric problems. Another system to which imprinted genes provide a large contribute is the placenta and foetal development. Epidemiological studies suggest that this is also a key area in which dysregulation can give rise to learning difficulties. CONCLUSIONS: Disruption of imprinted genes, or the epigenetic processes controlling them, can contribute to learning disability. These effects can be divided into two types: direct effects, such as those seen in explicit imprinting disorders such as Angelman and Prader-Willi syndromes, and indirect effects as manifest via changes in foetal programming.

Animals↗
PubMed1996

Parental imprinting and human disease.

Parental imprinting is a process that results in allele-specific differences in transcription, DNA methylation, and DNA replication timing. Imprinting plays an important role in development, and its deregulation can cause certain defined disease states. Absence of a paternal contribution to chromosome 15q11-q13, due to hemizygous deletion or uniparental disomy, results in the Prader-Willi syndrome. The absence of a normal maternal copy of the same region causes Angelman syndrome. The Beckwith-Wiedemann syndrome is associated with the failure of normal biparental inheritance of chromosome 11p15, and loss of imprinting is observed in several cancers including Wilms' tumor. The study of the molecular basis of abnormal imprinting in these disorders will facilitate the identification and characterization of other imprinted human disease loci.

Angelman Syndrome↗
PubMedDate not supplied

Differential diagnosis of malignant lymphomas by imprint cytology.

The results of a study of 214 touch imprints of benign and malignant lymphoid disorders are presented. The diagnostic criteria, including the results of special stains, are described for both benign proliferative disorders and malignant lymphomas. Imprint cytology achieved an accuracy of 99% in diagnosing both benign and malignant conditions. Specific subtyping of malignant disorders was correctly made in 83% of non-Hodgkin's lymphomas and in 66% of Hodgkin's lymphomas. It is concluded that imprint cytology is a useful adjunct to the histopathologic diagnosis of lymphoid disease.

Cytodiagnosis↗
PubMed2003

[Prader-Willi syndrome and genomic imprinting].

OBJECTIVE: Prader-Willi syndrome (PWS) is an example of a human genetic disorder that involves imprinting genes on the proximal long arm of chromosome 15 and SNRPN gene as a candidate gene for this syndrome. The purpose of this study was to show the molecular genetic defects and genomic imprinting basis in Chinese PWS patients and to evaluate the clinical applications of a differential diagnostic test for PWS. METHODS: Fluorescence in situ hybridization (FISH) and methylation-specific PCR (MSPCR) techniques were applied for 4 clinically suspected PWS patients. Using three probes, including SNRPN probe for identification of the critical locus in PWS region, D15Z1 and PML control probes for identification of the 15p arm and 15q arm, the authors detected the deletions 15q in PWS. MSPCR was based on sodium bisulfite treatment of DNA and PCR primers specific for the maternal and paternal allele. RESULTS: When hybridized with mixed probes, it was found in 2 patients that the central specific signal was absent, but both the flanking control signals were retained, indicating SNRPN gene deletion of chromosome 15q11-13. Bisulfite-modified DNA from all PWS children amplified with methylated allele-specific primer pair showed only maternal 131bp PCR product, indicating the maternal uniparental disomy (UPD15). CONCLUSION: Genomic imprinting plays an important role in the molecular pathogenesis of PWS that caused by paternal microdeletions of 15q11-q13 or maternal UPD of chromosome 15. The basic defect seemed to be an absence of function of PWS genes that are normally expressed only from the paternal chromosome 15. MSPCR is a rapid and simple PCR-based assay compared with other cyto-molecular tests and its results were consistent with the clinical diagnosis of PWS, so it seems to be a reliable diagnostic method for PWS patients who show abnormal methylation at SNRPN. The genetic differential tests for PWS are important in determining familial recurrence risk.

Adolescent↗
PubMed2005

Genomic imprinting and reproduction.

Genomic imprinting is the parent-of-origin specific gene expression which is a vital mechanism through both development and adult life. One of the key elements of the imprinting mechanism is DNA methylation, controlled by DNA methyltransferase enzymes. Germ cells undergo reprogramming to ensure that sex-specific genomic imprinting is initiated, thus allowing normal embryo development to progress after fertilisation. In some cases, errors in genomic imprinting are embryo lethal while in others they lead to developmental disorders and disease. Recent studies have suggested a link between the use of assisted reproductive techniques and an increase in normally rare imprinting disorders. A greater understanding of the mechanisms of genomic imprinting and the factors that influence them are important in assessing the safety of these techniques.

Adult↗