Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Uniparental Disomy”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 577 records · Page 32Linked to original sources
PubMed2001

Evidence from skewed X inactivation for trisomy mosaicism in Silver-Russell syndrome.

The finding of maternal uniparental disomy for chromosome 7 (matUPD7) in approximately 7% of Silver-Russell syndrome (SRS) cases has lead to the assumption that imprinted gene(s) on chromosome 7 are responsible for at least some cases. However, the observation in a familial case that both maternal and paternal inheritance of proximal 7p results in an SRS-like phenotype suggests that the causative genes may not be imprinted, and that an extra copy of genes within this region cause SRS. As all cases of complete matUPD7 could have arisen by trisomy rescue, it is possible that undetected trisomy 7 mosaicism contributes towards the phenotype of SRS, and that the matUPD7 seen in some cases is a consequence of trisomy rescue. Previous studies in cases of trisomy rescue for a number of autosomes have shown a strong association with skewed X inactivation in diploid tissues. Thus, we hypothesised that if trisomy mosaicism was involved in SRS, the frequency of skewed X inactivation should be increased in a population of non-matUPD7 SRS patients. Consistent with this hypothesis, results showed a significant increase in the frequency of completely skewed X inactivation in SRS patients (three of 29) when compared to controls (three of 270), suggesting the possible presence of undetected trisomy 7 in SRS patients and/or their placentas.

Aged↗
PubMed2003

The epsilon-sarcoglycan gene (SGCE), mutated in myoclonus-dystonia syndrome, is maternally imprinted.

Myoclonus-dystonia syndrome (MDS) is a non-degenerative neurological disorder that has been described to be inherited in an autosomal dominant mode with incomplete penetrance. MDS is caused by loss of function mutations in the epsilon-sarcoglycan gene. Reinvestigation of MDS pedigrees provided evidence for a maternal imprinting mechanism. As differential methylated regions (DMRs) are a characteristic feature of imprinted genes, we studied the methylation pattern of CpG dinucleotides within the CpG island containing the promoter region and the first exon of the SGCE gene by bisulphite genomic sequencing. Our findings revealed that in peripheral blood leukocytes the maternal allele is methylated, while the paternal allele is unmethylated. We also showed that most likely the maternal allele is completely methylated in brain tissue. Furthermore, CpG dinucleotides in maternal and paternal uniparental disomy 7 (UPD7) lymphoblastoid cell lines show a corresponding parent-of-origin specific methylation pattern. The effect of differential methylation on the expression of the SGCE gene was tested in UPD7 cell lines with only a weak RT-PCR signal observed in matUPD7 and a strong signal in patUPD7. These results provide strong evidence for a maternal imprinting of the SGCE gene. The inheritance pattern in MDS families is in agreement with such an imprinting mechanism with the exception of a few cases. We investigated one affected female that inherited the mutated allele from her mother. Surprisingly, we found the paternal wild type allele expressed whereas the mutated maternal allele was not detectable in peripheral blood cDNA.

5-Methylcytosine↗
PubMed2004

Difficulties of genetic counseling and prenatal diagnosis in a consanguineous couple segregating for the same translocation (14;15) (q11;q13) and at risk for Prader-Willi and Angelman syndromes.

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are associated with a loss of function of imprinted genes in the 15q11-q13 region mostly due to deletions or uniparental disomies (UPD). These anomalies usually occur de novo with a very low recurrence risk. However, in rare cases, familial translocations are observed, giving rise to a high recurrence risk. We report on the difficulties of genetic counseling and prenatal diagnosis in a family segregating for a translocation (14;15)(q11;q13) where two consanguineous parents carry the same familial translocation in this chromosome 15 imprinting region. Both children of the couple inherited a chromosomal anomaly leading to PWS. However, a paternal 15q11-q13 deletion was responsible for PWS in the first child, whereas prenatal diagnosis demonstrated that PWS was associated with a maternal 15q11-q13 UPD in the fetus. This report demonstrates that both conventional and molecular cytogenetic parental analyses have to be performed when a deletion is responsible for PWS or AS in order not to overlook a familial translocation and to insure reliable diagnosis and genetic counseling.

Angelman Syndrome↗
PubMed2004

Inverted duplications: how many of them are mosaic?

The best-known situation indissolubly linked to mosaicism is the uniparental disomy where a trisomic or monosomic zygote develops at least one cell line with 46 chromosomes. The mosaicism normal/abnormal cell lines may remain confined to placenta or persist in the embryo. Here, we describe a second situation that might also be indissolubly linked to a mosaic condition or at least to a confined placental mosaicism. We analysed the case of a mosaicism del(8p)/inv dup(8p) found in prenatal diagnosis. We had already demonstrated that the first product of the abnormal meiotic recombination at the basis of the inv dup rearrangements is a dicentric chromosome. Its breakage leads to the formation of a deleted and an inv dup chromosome. Although we had previously assumed that the dicentric underwent a breakage at meiosis II so that the zygote inherited the inv dup chromosome, our findings and those of others indeed indicate that the dicentric may be inherited in the zygote and that it might persist as such in early postzygotic stages, then undergoing different breakages in different cells leading to different abnormal chromosomes, either deleted or duplicated. Selection versus the most viable cell line(s) results either in a confined placental mosaicism with the inv dup cell line as the only one present in the embryo or in children with both the deleted and the inv dup cell lines. Phenotype/karyotype relationships in inv dup rearrangements must also take into account the influence of the other abnormal cell line during embryogenesis.

Aborted Fetus↗
PubMed2006

Molecular karyotyping of human hepatocellular carcinoma using single-nucleotide polymorphism arrays.

Genomic amplification of oncogenes and inactivation of suppressor genes are critical in the pathogenesis of human cancer. To identify chromosomal alterations associated with hepatocarcinogenesis, we performed allelic gene dosage analysis on 36 hepatocellular carcinomas (HCCs). Data from high-density single-nucleotide polymorphism arrays were analysed using the Genome Imbalance Map (GIM) algorithm, which simultaneously detects DNA copy number alterations and loss of heterozygosity (LOH) events. Genome Imbalance Map analysis identified allelic imbalance regions, including uniparental disomy, and predicted the coexistence of a heterozygous population of cancer cells. We observed that gains of 1q, 5p, 5q, 6p, 7q, 8q, 17q and 20q, and LOH of 1p, 4q, 6q, 8p, 10q, 13q, 16p, 16q and 17p were significantly associated with HCC. On 6q24-25, which contains imprinting gene clusters, we observed reduced levels of PLAGL1 expression owing to loss of the unmethylated allele. Finally, we integrated the copy number data with gene expression intensity, and found that genome dosage is correlated with alteration in gene expression. These observations indicated that high-resolution GIM analysis can accurately determine the localizations of genomic regions with allelic imbalance, and when integrated with epigenetic information, a mechanistic basis for inactivation of a tumor suppressor gene in HCC was elucidated.

Algorithms↗
PubMed2000

Identification of an imprinted gene, Meg3/Gtl2 and its human homologue MEG3, first mapped on mouse distal chromosome 12 and human chromosome 14q.

BACKGROUND: The paternal duplication of mouse distal chromosome 12 leads to late embryonal/neonatal lethality and growth promotion, whereas maternal duplication leads to late embryonal lethality and growth retardation. Human paternal or maternal uniparental disomies of chromosome 14q that are syntenic to mouse distal chromosome 12 have also been reported to show some imprinting effects on growth, mental activity and musculoskeletal morphology. For the isolation of imprinted genes in this region, a systematic screen of maternally expressed genes (Megs) was carried out by our subtraction-hybridization method using androgenetic and normally fertilized embryos. RESULTS: We have isolated seven candidate clones of the mouse Meg gene. Among them, we identified a novel maternally expressed imprinted gene, Meg3, on mouse distal chromosome 12 and showed that it was identical to the Gtl2 gene. We also found that the human homologue MEG3 on chromosome 14q was also monoallelically expressed. CONCLUSIONS: This is the first identification of the imprinting gene, both on mouse distal chromosome 12 and on human chromosome 14q, respectively. Because there are no obvious open reading frames in either the mouse Meg3/Gtl2 or human MEG3, the function of these genes remains unclear. However, this result will provide a good basis for the further investigation of several important imprinted genes in this chromosomal region.

Animals↗
PubMed2000

Mouse Peg9/Dlk1 and human PEG9/DLK1 are paternally expressed imprinted genes closely located to the maternally expressed imprinted genes: mouse Meg3/Gtl2 and human MEG3.

BACKGROUND: Genomic imprinting significantly influences development, growth and behaviour in mammals. Systematic screening of imprinted genes has been extensively carried out to identify the genes responsible for imprinted phenotypes and to elucidate the biological significance of this phenomenon. In this study, we applied DNA chip technology for isolating paternally expressed imprinted genes (Pegs). We compared the resulting expression profiles of parthenogenetic and fertilized control embryos to identify novel imprinted genes. RESULTS: A novel paternally expressed mouse imprinted gene, Peg9/Dlk1, was identified. Consistent with this finding, the paternal expression of its human homologue, PEG9/DLK1, was also confirmed. These two genes form imprinted gene clusters with the reciprocally imprinted mouse Meg3/Gtl2 and human MEG3 genes that we first identified on distal chromosome 12 and chromosome 14q32, respectively. CONCLUSIONS: As DNA chip technology allows us to quickly screen a large number of genes, using this technology to search for imprinted genes could accelerate the identification of genes responsible for human and mouse genetic diseases. Dlk1 and DLK1, which encode transmembrane proteins, have six EGF-like repeats and show homology to the Delta gene in Drosophila melanogaster. Because of its homology to mammalian Delta homologues, PEG9/DLK1 may contribute to the scoliosis phenotype observed in maternal uniparental disomy 14 (mUPD14) patients.

Animals↗
PubMed1998

Prader-Willi syndrome and psychotic symptoms: 1. Case descriptions and genetic studies.

Six people with Prader-Willi syndrome (PWS) who developed psychoses are described. Along with other literature reviewed in the present paper, the results imply an association between PWS and psychotic symptoms. Genetic studies were possible in five cases and SNRPN expression was examined in three cases. Maternal uniparental disomy and 15q11q13 deletions were found, demonstrating that psychotic symptoms are not associated with a single type of genetic abnormality.

Adolescent↗
PubMed2000

Intellectual characteristics of Prader-Willi syndrome: comparison of genetic subtypes.

Advances in genetics have led to an increased understanding of the role of the genotype on behavioural functioning. The purpose of the present study was to examine differences in intellectual functioning in individuals with Prader-Willi syndrome (PWS) with a paternal 15q11-q13 deletion versus maternal uniparental disomy (UPD) of chromosome 15. Measures of intelligence and academic achievement were administered to 38 individuals with PWS (24 with deletion and 14 with UPD). The subjects with UPD had significantly higher verbal IQ scores than those with deletion (P< 0.01). The magnitude of the difference in verbal IQ was 9.1 points (69.9 versus 60.8 for UPD and deletion PWS subjects, respectively). Only 17% of subjects with the 15q11-q13 deletion had a verbal IQ > or = 70, while 50% of those with UPD had a verbal IQ > or = 70. Performance IQ scores did not differ between the two PWS genetic subtype groups. This is the first report to document the difference between verbal and performance IQ score patterns among subjects with PWS of the deletion versus the UPD subtype.

Adolescent↗
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↗
PubMed2005

Invasive prenatal diagnostic techniques.

As aneuploid screening evolves to the first trimester a complimentary diagnostic procedure becomes increasingly important. Chorionic villus (CVS) sampling has emerged as the only safe invasive prenatal diagnostic procedure prior to the 14(th) week of gestation. Over 2 decades of experience have demonstrated the accuracy, efficacy and safety of CVS. The karyotype is identical to that of the fetus in over 98% of cases. In the remaining 1 to 2% confined placental mosaicism (CPM) occurs. Current knowledge of the etiology of CPM allows accurate clinical interpretation, the recognition of cases of fetal uniparental disomy, and identification of pregnancies at risk for poor perinatal outcome. Prospective comparative studies have demonstrated that with equally experienced operators, CVS and second trimester amniocentesis have similar procedure induced miscarriage rates. When CVS procedures are performed after 10 weeks gestation, no increased risk of fetal anomalies has been demonstrated.

Aneuploidy↗
PubMed2002

Mutations in the DNAH11 (axonemal heavy chain dynein type 11) gene cause one form of situs inversus totalis and most likely primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD; MIM 242650) is an autosomal recessive disorder of ciliary dysfunction with extensive genetic heterogeneity. PCD is characterized by bronchiectasis and upper respiratory tract infections, and half of the patients with PCD have situs inversus (Kartagener syndrome). We characterized the transcript and the genomic organization of the axonemal heavy chain dynein type 11 (DNAH11) gene, the human homologue of murine Dnah11 or lrd, which is mutated in the iv/iv mouse model with situs inversus. To assess the role of DNAH11, which maps on chromosome 7p21, we searched for mutations in the 82 exons of this gene in a patient with situs inversus totalis, and probable Kartagener syndrome associated with paternal uniparental disomy of chromosome 7 (patUPD7). We identified a homozygous nonsense mutation (R2852X) in the DNAH11 gene. This patient is remarkable because he is also homozygous for the F508del allele of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Sequence analysis of the DNAH11 gene in an additional 6 selected PCD sibships that shared DNAH11 alleles revealed polymorphic variants and an R3004Q substitution in a conserved position that might be pathogenic. We conclude that mutations in the coding region of DNAH11 account for situs inversus totalis and probably a minority of cases of PCD.

Axonemal Dyneins↗
PubMed1998

Identification of the Meg1/Grb10 imprinted gene on mouse proximal chromosome 11, a candidate for the Silver-Russell syndrome gene.

In a systematic screen for maternally expressed imprinted genes using subtraction hybridization with androgenetic and normal fertilized mouse embryos, seven candidate maternally expressed genes (Megs) have been isolated, including the H19 and p57(Kip2) genes that are known to be maternally expressed. Herein, we demonstrate that an imprinted gene, Meg1, is apparently identical to Grb10 (growth factor receptor-bound protein 10), which is located on mouse proximal chromosome 11. Grb10 protein was reported to bind to the insulin receptor and/or the insulin-like growth factor (IGF) I receptor via its src homology 2 domain and to inhibit the associated tyrosine kinase activity that is involved in the growth promoting activities of insulin and IGFs (IGF-I and -II). Thus, it is probable that Meg1/Grb10 is responsible for the imprinted effects of prenatal growth retardation or growth promotion caused by maternal or paternal duplication of proximal chromosome 11 with reciprocal deficiencies (MatDp.prox11 or PatDp.prox11), respectively. In the human, it has been reported that the maternal uniparental disomy 7 is responsible for the Silver-Russell syndrome (SRS) whose effects include pre- and postnatal growth retardation and other dysmorphologies. The human homologue GRB10 on chromosome 7q11.2-12 is a candidate gene for Silver-Russell syndrome.

Animals↗
PubMed2000

Patched target Igf2 is indispensable for the formation of medulloblastoma and rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children (Dagher, R., and Helman, L. (1999) Oncologist 4, 34-44), whereas medulloblastoma, a highly malignant tumor of the cerebellum, accounts for 20% of childhood brain tumors (Goodrich, L. V., and Scott, M. P. (1998) Neuron 21, 1243-1257). Both tumors are associated with a deficiency in the tumor suppressor Patched (PTCH) in Gorlin syndrome (Gorlin, R. J. (1987) Medicine (Baltimore) 66, 98-113), and they are present in the corresponding murine models. RMS in Ptch mutant mice consistently contain elevated levels of the tumor growth-promoting insulin-like growth factor 2 (Igf2). We have investigated the mechanism of Igf2 overexpression and its significance in medulloblastoma and RMS tumorigenesis. Here we report that Igf2 is indispensable for the formation of medulloblastoma and RMS in Ptch mutants. Overexpression of Igf2 in RMS in these mice does not involve loss of imprinting, uniparental disomy, amplification of the Igf2 locus, or polyploidy. Since Igf2 is also overexpressed in non-tumor tissue deficient in Ptch, these observations suggest that Ptch regulates Igf2 levels through a transcriptional mechanism. They also identify Igf2 as a potential target for medulloblastoma and RMS.

Animals↗
PubMed1997

Skewed X-chromosome inactivation is common in fetuses or newborns associated with confined placental mosaicism.

The inactivation of one X chromosome in females is normally random with regard to which X is inactivated. However, exclusive or almost-exclusive inactivation of one X may be observed in association with some X-autosomal rearrangements, mutations of the XIST gene, certain X-linked diseases, and MZ twinning. In the present study, a methylation difference near a polymorphism in the X-linked androgen-receptor gene was used to investigate the possibility that nonrandom X inactivation is increases in fetuses and newborns that are associated with confined placental mosaicism (CPM) involving an autosomal trisomy. Extreme skewing was observed in 7 (58%) of 12 cases with a meiotic origin of the trisomy, but in none of 10 cases examined with a somatic origin of the trisomy, and in only 1 (4%) of 27 control adult females. In addition, an extremely skewed X-inactivation pattern was observed in 3 of 10 informative cases of female uniparental disomy (UPD) of chromosome 15. This may reflect the fact that a proportion of UPD cases arise by "rescue" of a chromosomally abnormal conceptus and are therefore associated with CPM. A skewed pattern of X inactivation in CPM cases is hypothesized to result from a reduction in the size of the early-embryonic cell pool, because of either poor early growth or subsequent selection against the trisomic cells. Since approximately 2% of pregnancies detected by chorionic villus sampling are associated with CPM, this is likely a significant contributor to both skewed X inactivation observed in the newborn population and the expression of recessive X-linked diseases in females.

Adult↗
PubMed1998

Mutation analysis of UBE3A in Angelman syndrome patients.

Angelman syndrome (AS) is caused by chromosome 15q11-q13 deletions of maternal origin, by paternal uniparental disomy (UPD) 15, by imprinting defects, and by mutations in the UBE3A gene. UBE3A encodes a ubiquitin-protein ligase and shows brain-specific imprinting. Here we describe UBE3A coding-region mutations detected by SSCP analysis in 13 AS individuals or families. Two identical de novo 5-bp duplications in exon 16 were found. Among the other 11 unique mutations, 8 were small deletions or insertions predicted to cause frameshifts, 1 was a mutation to a stop codon, 1 was a missense mutation, and 1 was predicted to cause insertion of an isoleucine in the hect domain of the UBE3A protein, which functions in E2 binding and ubiquitin transfer. Eight of the cases were familial, and five were sporadic. In two familial cases and one sporadic case, mosaicism for UBE3A mutations was detected: in the mother of three AS sons, in the maternal grandfather of two AS first cousins, and in the mother of an AS daughter. The frequencies with which we detected mutations were 5 (14%) of 35 in sporadic cases and 8 (80%) of 10 in familial cases.

Angelman Syndrome↗
PubMed1999

Prader-Willi syndrome is caused by disruption of the SNRPN gene.

A Prader-Willi syndrome patient is described who has a de novo balanced translocation, (4;15)(q27;q11.2)pat, with breakpoints lying between SNRPN exons 2 and 3. Parental-origin studies indicate that there is no uniparental disomy and no apparent deletion. This patient expresses ZNF127, SNRPN exons 1 and 2, IPW, and D15S227E (PAR1) but does not express either SNRPN exons 3 and 4 or D15S226E (PAR5), as assayed by reverse transcription-PCR, of peripheral blood cells. Methylation studies showed normal biparental patterns of inheritance of loci DN34/ZNF127, D15S63, and SNRPN exon 1. Results for this patient and that reported by Sun et al. support the contention that an intact genomic region and/or transcription of SNRPN exons 2 and 3 play a pivotal role in the manifestations of the major clinical phenotype in Prader-Willi syndrome.

Autoantigens↗
PubMed2000

Duplication of 7p11.2-p13, including GRB10, in Silver-Russell syndrome.

Silver-Russell syndrome (SRS) is characterized by pre- and postnatal growth failure and other dysmorphic features. The syndrome is genetically heterogeneous, but maternal uniparental disomy of chromosome 7 has been demonstrated in approximately 7% of cases. This suggests that at least one gene on chromosome 7 is imprinted and involved in the pathogenesis of SRS. We have identified a de novo duplication of 7p11.2-p13 in a proband with features characteristic of SRS. FISH confirmed the presence of a tandem duplication encompassing the genes for growth factor receptor-binding protein 10 (GRB10) and insulin-like growth factor-binding proteins 1 and 3 (IGFBP1 and -3) but not that for epidermal growth factor-receptor (EGFR). Microsatellite markers showed that the duplication was of maternal origin. These findings provide the first evidence that SRS may result from overexpression of a maternally expressed imprinted gene, rather than from absent expression of a paternally expressed gene. GRB10 lies within the duplicated region and is a strong candidate, since it is a known growth suppressor. Furthermore, the mouse homologue (Grb10/Meg1) is reported to be maternally expressed and maps to the imprinted region of proximal mouse chromosome 11 that demonstrates prenatal growth failure when it is maternally disomic. We have demonstrated that the GRB10 genomic interval replicates asynchronously in human lymphocytes, suggestive of imprinting. An additional 36 SRS probands were investigated for duplication of GRB10, but none were found. However, it remains possible that GRB10 and/or other genes within 7p11.2-p13 are responsible for some cases of SRS.

Abnormalities, Multiple↗