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PubMed2004

Genomic imprinting and assisted reproduction.

Imprinted genes exhibit a parent-of-origin specific pattern of expression. Such genes have been shown to be targets of molecular defects in particular genetic syndromes such as Beckwith-Wiedemann and Angelman syndromes. Recent reports have raised concern about the possibility that assisted reproduction techniques, such as in vitro fertilization or intracytoplasmic sperm injection, might cause genomic imprinting disorders. The number of reported cases of those disorders is still too small to draw firm conclusions and the safety of these widely used assisted reproduction techniques needs to be further evaluated.

Journal Article↗
PubMedDate not supplied

[Diagnosis of Prader-Willi syndrome. Considerations on a case of erroneous diagnosis].

Prader-Willi syndrome is a genetic disease, which is clinically characterized by neonatal hypotonia, feeding problems in the first year of life, excessive eating with severe obesity from the second year of life, developmental delay, hypogonadism, typical facial features, short stature, behaviour problems, mental retardation. It is caused by a genomic imprinting disorder, i.e., lacking expression of paternally derived genes located on the long arm of chromosome 15. We present a case of a child with a neonatal diagnosis of Prader-Willi syndrome, founded on some facial dysmorphic features and a partial deletion of 15q, which we belied thanks to an anamnestic and clinical revaluation, and a metilation test. We also present main topics about Prader-Willi syndrome diagnosis, including clinical and endocrinological features, scoring system, and genetics.

Child↗
PubMed2001

[Gene abnormality associated with resistance to parathyroid hormone].

Pseudohypoparathyroidism (PHP) is characterized by PTH-resistant hypocalcemia and hyperphosphatemia. Patients with PHP-Ia exhibit Albright osteodystrophy and resistance to TSH and other hormones in addition to PTH. PHP-Ia is caused by heterozygous inactivating mutations in the GNAS1 gene which encodes Gsalpha protein. In PHP-Ib, resistance to PTH is confined to the renal tubules. Recent reports describe a paternally imprinted disorder in a region including the GNAS1 gene as the cause of PHP-Ib.

English Abstract↗
PubMedDate not supplied

[Health of children born after the infertility treatment with Assisted Reproduction Technology].

Since the birth of Louise Brown in July 1978 and the birth of the first intracytoplasmic sperm injection (ICSI) child in January 1992 many couples with female-factor or male-factor infertility can be helped to overcome their infertility resulting in a delivery and birth of a child. Over a million children have been born from assisted conception worldwide. Newer techniques being introduced appear less and less 'natural', such as intracytoplasmic sperm injection (ICSI), but there is little information on these children beyond the neonatal period. This risk varied according to the patient's age, the type of ART procedure performed, the number of embryos transferred, and embryo availability. ART is associated with low increase risk of congenital malformations, major birth defects and genetic and imprinting disorders.

Child↗
PubMed1989

Genomic imprinting and genetic disorders in man.

In a considerable number of genetic disorders in the human, the phenotypic expression of the disease can depend on maternal or paternal inheritance of the mutation. It is suggested that genomic imprinting, an epigenetic process that marks maternal and paternal chromosomes in mammals, is involved in such parental effects.

Animals↗
PubMed1996

Minimal definition of the imprinting center and fixation of chromosome 15q11-q13 epigenotype by imprinting mutations.

Patients with disorders involving imprinted genes such as Angelman syndrome (AS) and Prader-Willi syndrome (PWS) can have a mutation in the imprinting mechanism. Previously, we identified an imprinting center (IC) within chromosome 15q11-ql3 and proposed that IC mutations block resetting of the imprint, fixing on that chromosome the parental imprint (epigenotype) on which the mutation arose. We now describe four new microdeletions of the IC, the smallest (6 kb) of which currently defines the minimal region sufficient to confer an AS imprinting mutation. The AS deletions all overlap this minimal region, centromeric to the PWS microdeletions, which include the first exon of the SNRPN gene. None of five genes or transcripts in the 1.0 Mb vicinity of the IC (ZNF127, SNRPN, PAR-5, IPW, and PAR-1), each normally expressed only from the paternal allele, was expressed in cells from PWS imprinting mutation patients. In contrast, AS imprinting mutation patients show biparental expression of SNRPN and IPW but must lack expression of the putative AS gene 250-1000 kb distal of the IC. These data strongly support a model in which the paternal chromosome of these PWS patients carries an ancestral maternal epigenotype, and the maternal chromosome of these AS patients carries an ancestral paternal epigenotype. The IC therefore functions to reset the maternal and paternal imprints throughout a 2-Mb imprinted domain within human chromosome 15q11-q13 during gametogenesis.

Angelman Syndrome↗
PubMed1995

Clinical evidence for genomic imprinting in bipolar I disorder.

The phenotypic indicators of the genomic imprinting model were applied to clinical psychopathology data on 100 bipolar (BP) I probands and their families. The paternal transmission was associated with a significantly younger age of onset of the BP illness in probands and a higher rate of affective disorders in first- and second-degree relatives. The effect of the sex of the transmitting parent on age of onset in probands decreased but remained significant when controlling for the effect of the probands' age at investigation. Probands' sex had no significant influence on their age of onset. The severity of the BP illness in probands in terms of number of illness episodes and annual frequency was not influenced by the sex of the transmitting parent.

Adolescent↗
PubMed2005

Genomic imprinting and assisted reproductive technology: connections and potential risks.

Assisted reproductive technology (ART) has become the standard of care for the treatment of many types of infertility. As a result, the numbers of children born after ART worldwide has escalated dramatically, and attention has turned to the potential risks of these procedures to the health and development of the children. In addition to the well-established risks of multiple gestations, recent reports have suggested a link between ART and rare disorders of imprinting including Beckwith-Wiedemann syndrome and Angelman syndrome. Here we review molecular mechanisms of genomic imprinting, consider how ART procedures could influence imprinting of gametes and embryos, and review the reports connecting imprinting disorders to ART. We highlight the importance of long-term follow-up of children born after ART, and emphasize the need for an improved understanding of the mechanisms of imprinting at the molecular level so that methods to prevent disruption of this critical epigenetic process can be developed.

Angelman Syndrome↗
PubMed2001

No association between 5HT-2A and bipolar disorder irrespective of genomic imprinting.

Recent evidence that 5HT-2A may be subjected to genomic imprinting prompted us to examine a collection of Irish family trios (an affected individual and both parents) for evidence of an association between 5HT-2A and bipolar disorder. Family trios offer an advantage over case control studies in regard to genomic imprinting since with family trios it is possible to trace the path of alleles from the parents to the offspring. Using haplotype-based haplotype relative risk (HHRR) and transmission/disequilibrium (TDT) analyses, no evidence was found for an association of 5HT-2A with bipolar affective disorder under the assumption of no imprinting and of imprinting.

Alleles↗
PubMed1998

Anticipation and imprinting in Japanese familial mood disorders.

Several reports have suggested the presence of anticipation and imprinting in Caucasian families with either unipolar or bipolar affective disorders. In practice, families consisting of subjects with bipolar and unipolar affective disorders are common, whereas unipolar cases were not included in the analysis because of their uncertain diagnostic status. The purpose of this study is to determine if anticipation and imprinting are associated with Japanese familial mood disorders. The age of onset, clinical course rating, single/recurrent disease episodes, number of hospitalizations, and number of suicide attempts were compared between two generations in 26 Japanese families with mood disorders [offspring/parental: unipolar (U/U), 14; bipolar/unipolar (B/U), 12]. A significantly lower age of onset and more recurrent episodes were observed in the offspring generation than in the parental generation in both U/U and B/U families. Our results suggest the presence of anticipation in both Japanese U/U and B/U families with mood disorders.

Adult↗
PubMed2001

The role of genomic imprinting in human developmental disorders: lessons from Prader-Willi syndrome.

Normal human development involves a delicate interplay of gene expression in specific tissues at narrow windows of time. Temporally and spatially regulated gene expression is controlled both by gene-specific factors and chromatin-specific factors. Genomic imprinting is the expression of specific genes primarily from only one allele at particular times during development, and is one mechanism implicated in the intricate control of gene expression. Two human genetic disorders, Prader-Willi syndrome (PWS, MIM 176270) and Angelman syndrome (AS, MIM 105830), result from rearrangements of chromosome 15q11-q13, an imprinted region of the human genome. Despite their rarity, disorders such as PWS and AS can give focused insight into the role of genomic imprinting and imprinted genes in human development.

Alleles↗
PubMed2006

Genetic imprinting during impaired spermatogenesis.

Disorders in genetic imprinting are discussed as potential genetic risk in assisted reproduction technology (ART), where most of the natural selection mechanisms are bypassed. As currently only limited information about genomic imprinting in disruptive spermatogenesis is available, we analysed the imprinting state of the paternally methylated gene H19 in various germ cell populations derived from seminiferous tubules exhibiting impaired spermatogenesis. Different germ cell types were isolated by laser microdissection from human testicular paraffin sections. Although the methylation state of the maternally imprinted gene SNRPN was investigated by methylation-specific PCR (M-PCR) to establish the isolation method, methylation of H19 was analysed by a single-strand conformation-based method. Contamination by somatic Sertoli cells was excluded because of Sertoli cell-specific vimentin immunohistochemistry before germ cell laser microdissection. We demonstrate correct genetic imprints for H19 even in spermatogonia selected from seminiferous tubules exhibiting spermatogenic arrest at the level of spermatogonia, providing no evidence for incorrect genomic imprinting in spermatozoa from infertile men used for ICSI.

Autoantigens↗
PubMed2005

Imprinting and assisted reproductive technology.

In the past 25 years, the frequency of assisted reproductive technology (ART) births has increased rapidly to account for 1-2% of all births in many developed countries. ART procedures such as in vitro fertilization and intracytoplasmic sperm injection are generally considered to be safe, but recent studies suggest a small excess of birth defects and low-birth weight in ART children. In addition, several clinical studies have reported an increased frequency of ART conceptions among children with Beckwith-Wiedemann syndrome or Angelman syndrome caused by an imprinting defect. Although these studies require further confirmation, they are consistent with animal studies reporting disordered expression and epigenetic changes in imprinted genes following in vitro embryo culture. The absolute risk of an imprinting disorder after ART appears to be very small, but further data are required to determine whether the association between ART and human imprinting disorders reflects the effect of embryo culture (or some other aspect of ART) and/or a common mechanism for infertility and imprinting disorders. Retinoblastoma and neurodevelopmental defects have been only tentatively linked to ART, but in view of the role of epigenetic processes in the regulation of gene expression in development and cancer, further research is required into long-term health outcomes for ART children and the epigenetic consequences of ART protocols.

Angelman Syndrome↗
PubMed2026

Loss of maternal PADI6 disrupts DNA methylation and genomic imprinting maintenance in late preimplantation mouse embryos.

BACKGROUND: The maternal-effect protein PADI6, which is part of the subcortical maternal complex, is involved in proper spindle assembly, organelle distribution, ribosome storage, and cytoplasmic lattice organization in mouse oocytes. In humans, variants of PADI6 are associated with female infertility and multilocus imprinting disturbance in offspring. Recently, it was demonstrated that PADI6 plays a role in the storage and cytoplasmic localization of epigenetic factors, including UHRF1 and DNMT1. Moreover, maternal PADI6 depletion leads to defective epigenetic reprogramming and zygotic genome activation but not to an imprinting defect in two-cell mouse embryos. These findings raise the possibility that imprinting disturbances arise later in development. RESULTS: By employing combined single-blastocyst RNA-seq/BS-seq and immunostaining validation in the embryos derived from Padi6P620A-mutant oocytes, we investigated the role of Padi6 in late preimplantation development. We demonstrated that embryos that overcame the two-cell stage block had a dramatic reduction in UHRF1 and DNMT1 protein levels, a decrease in H3K9me3, and whole-genome hypomethylation, including most imprinted loci and repetitive elements, at the blastocyst stage. Furthermore, these maternal mutant embryos showed deregulation of inner cell mass markers and defective blastocyst implantation, but no effect on trophoblast differentiation. CONCLUSION: Our results demonstrate that maternal PADI6 is a key regulator of the stability of epigenetic factors required to maintain repressive marks in late preimplantation mouse embryos. Its deficiency results in genomic imprinting defects that closely resemble those found in human patients and provide a mechanistic explanation for MLID caused by maternal PADI6 variants. Furthermore, the impairment of blastocyst implantation capacity, likely due to dysregulation of inner cell mass differentiation, provides new mechanistic insights into the control of female fertility and embryo development exerted by PADI6.

DNA Methylation↗
PubMed2003

Imprinted methylation profiles for proximal mouse chromosomes 11 and 7 as revealed by methylation-sensitive representational difference analysis.

Proximal mouse Chromosome (Chr) 11 shares regions of orthology with the candidate gene region for the imprinting growth disorder Silver-Russell syndrome (SRS) on human Chr 7p. It has previously been shown that mice with two maternal or two paternal copies (duplications, Dp) of proximal Chr 11 exhibit reciprocal growth phenotypes. Those with two paternal copies show fetal and placental overgrowth, while those with two maternal copies are growth retarded. The growth retardation observed in the latter is reminiscent of the intrauterine growth restriction (IUGR) observed in SRS patients with maternal uniparental disomy for Chr 7 (mUPD7). We have carried out a methylation-sensitive representational difference analysis (Me-RDA) screen to look for regions of differential methylation (DMRs) associated with imprinted genes. For these experiments, we have used mouse embryos with uniparental duplications of Chrs 11 and 7 proximal to the breakpoint of the reciprocal translocation T(7;11)40Ad. Two previously known imprinted loci associated with paternal allele hypomethylation were recovered on proximal mouse Chr 11, U2af1-rs1 and Meg1/Grb10. These two genes map 15 cM apart, so it seems likely that they are within separate imprinted domains that do not contain additional DMRs. The known imprinted gene Peg3, located on mouse proximal Chr 7, was also detected in our screen. The finding that Peg3 was differentially methylated in embryos with uniparental inheritance of proximal Chr 7 confirms that Peg3 is located proximal to the breakpoint of T40Ad in G-band 7A2. Because GRB10 has previously been reported to be a candidate gene for SRS, we analysed 22 patients for epimutations of the GRB10 differentially methylated region that could lead to the altered expression of this gene. No such mutations were found.

Aneuploidy↗