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1.
The IPL gene on chromosome 11p15.5 is imprinted in humans and mice and is similar to TDAG51, implicated in Fas expression and apoptosis 总被引:4,自引:1,他引:4
Qian N; Frank D; O'Keefe D; Dao D; Zhao L; Yuan L; Wang Q; Keating M; Walsh C; Tycko B 《Human molecular genetics》1997,6(12):2021-2029
We searched for novel imprinted genes in a region of human chromosome
11p15.5, which contains several known imprinted genes. Here we describe the
cloning and characterization of the IPL ( I mprinted in P lacenta and L
iver) gene, which shows tissue-specific expression and functional
imprinting, with the maternal allele active and the paternal allele
relatively inactive, in many human and mouse tissues. Human IPL is highly
expressed in placenta and shows low but detectable expression in fetal and
adult liver and lung. Mouse Ipl maps to the region of chromosome 7 which is
syntenic with human 11p15.5 and this gene is expressed in placenta and at
higher levels in extraembryonic membranes (yolk sac), fetal liver and adult
kidney. Mouse and human IPL show sequence similarity to TDAG51 , a gene
which was shown to be essential for Fas expression and susceptibility to
apoptosis in a T lymphocyte cell line. Like several other imprinted genes,
mouse and human IPL genes are small and contain small introns. These data
expand the repertoire of known imprinted genes and will be helpful in
testing the mechanism of genomic imprinting and the role of imprinted genes
in growth regulation.
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2.
Retention of imprinting of the human apoptosis-related gene TSSC3 in human brain tumors 总被引:3,自引:0,他引:3
Müller S van den Boom D Zirkel D Köster H Berthold F Schwab M Westphal M Zumkeller W 《Human molecular genetics》2000,9(5):757-763
Genomic imprinting is the result of a gamete-specific modification leading to parental origin-specific gene expression in somatic cells of the offspring. Several embryonal tumors show loss of imprinting of genes clustered in human chromosome 11p15.5, an important tumor suppressor gene region, harboring several normally imprinted genes. TSSC3, a gene homologous to mouse TDAG51, implicated in Fas-mediated apoptosis, is also located in this region between hNAP2 and p57 (KIP2). TSSC3 is the first apoptosis-related gene found to be imprinted in placenta, liver and fetal tissues where it is expressed from the maternal allele in normal human development. This study investigated the imprinting status of TSSC3 in human normal, adult brain and in human neuroblastomas, medulloblastomas and glioblastomas. A polymorphism in exon 1 at position 54 was used to analyze the allelic expression of the TSSC3 gene by a primer oligo base extension (PROBE) assay using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). We found that the TSSC3 gene is not imprinted in human normal, adult brain and blood. In contrast, strong allelic bias resembling imprinting could be detected in most examined tumor specimens. The results demonstrate for the first time that the tumors under investigation are associated with a retention of imprinting of a potential growth inhibitory gene. 相似文献
3.
Expressed sequence tags (ESTs) in the human chromosome 7q21-q31 region were recently used to screen for allelic expression
bias in monochromosomal hybrids retaining a paternal or maternal human chromosome 7. Six candidate imprinted genes were identified.
In this study, we investigated parent-of-origin-specific expression profiles of their mouse homologues in the proximal region
of chromosome 6. An imprinting analysis, using F1 mice from reciprocal crosses between the B6 and JF strains, demonstrated
that the mouse calcitonin receptor gene (Calcr) was expressed preferentially from the maternal allele in brain, whereas no allelic bias was detected in other tissues. Our
results indicate that Calcr is imprinted in a tissue-specific manner, with a predominant expression from the maternal allele in the brain.
Electronic Publication 相似文献
4.
Chromosome 11p15.5 regional imprinting: comparative analysis of KIP2 and H19 in human tissues and Wilms' tumors 总被引:9,自引:1,他引:9
The imprinted H19 gene is frequently inactivated in Wilms' tumors (WTs)
either by chromosome 11p15.5 loss of heterozygosity (LOH) or by
hypermethylation of the maternal allele and it is possible that there might
be coordinate disruption of imprinting of multiple 11p15.5 genes in these
tumors. To test this we have characterized total and allele- specific mRNA
expression levels and DNA methylation of the 11p15.5 KIP2 gene in normal
human tissues, WTs and embryonal rhabdomyosarcoma (RMS). Both KIP2 alleles
are expressed but there is a bias with the maternal allele contributing
70-90% of mRNA. Tumors with LOH show moderate to marked reductions in KIP2
mRNA relative to control tissues and residual mRNA expression is from the
imprinted paternal allele. Among WTs without LOH most cases with H19
inactivation also have reduced KIP2 expression and most cases with
persistent H19 expression have high levels of KIP2 mRNA. In contrast to the
extensive hypermethylation of the imprinted H19 allele, both KIP2 alleles
are hypomethylated and WTs with biallelic H19 hypermethylation lack
comparable hypermethylation of KIP2 DNA. 5-aza-2'-deoxycytidine (aza-C)
increases H19 expression in RD RMS cells but does not activate KIP2
expression. These data indicate coordinately reduced expression of two
linked paternally imprinted genes in most WTs and also suggest mechanistic
differences in the maintenance of imprinting at these two loci.
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5.
Syntenic organization of the mouse distal chromosome 7 imprinting cluster and the Beckwith-Wiedemann syndrome region in chromosome 11p15.5 总被引:8,自引:2,他引:8
Paulsen M; Davies KR; Bowden LM; Villar AJ; Franck O; Fuermann M; Dean WL; Moore TF; Rodrigues N; Davies KE; Hu RJ; Feinberg AP; Maher ER; Reik W; Walter J 《Human molecular genetics》1998,7(7):1149-1159
In human and mouse, most imprinted genes are arranged in chromosomal
clusters. Their linked organization suggests co-ordinated mechanisms
controlling imprinting and gene expression. The identification of local and
regional elements responsible for the epigenetic control of imprinted gene
expression will be important in understanding the molecular basis of
diseases associated with imprinting such as Beckwith- Wiedemann syndrome.
We have established a complete contig of clones along the murine imprinting
cluster on distal chromosome 7 syntenic with the human imprinting region at
11p15.5 associated with Beckwith- Wiedemann syndrome. The cluster comprises
approximately 1 Mb of DNA, contains at least eight imprinted genes and is
demarcated by the two maternally expressed genes Tssc3 (Ipl) and H19 which
are directly flanked by the non-imprinted genes Nap1l4 (Nap2) and Rpl23l
(L23mrp), respectively. We also localized Kcnq1 (Kvlqt1) and Cd81 (Tapa-1)
between Cdkn1c (p57(Kip2)) and Mash2. The mouse Kcnq1 gene is maternally
expressed in most fetal but biallelically transcribed in most neonatal
tissues, suggesting relaxation of imprinting during development. Our
findings indicate conserved control mechanisms between mouse and human, but
also reveal some structural and functional differences. Our study opens the
way for a systematic analysis of the cluster by genetic manipulation in the
mouse which will lead to animal models of Beckwith-Wiedemann syndrome and
childhood tumours.
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6.
Identification and characterization of an imprinted antisense RNA (MESTIT1) in the human MEST locus on chromosome 7q32 总被引:2,自引:0,他引:2
Nakabayashi K Bentley L Hitchins MP Mitsuya K Meguro M Minagawa S Bamforth JS Stanier P Preece M Weksberg R Oshimura M Moore GE Scherer SW 《Human molecular genetics》2002,11(15):1743-1756
7.
Imprinting of mouse Kvlqt1 is developmentally regulated 总被引:4,自引:1,他引:4
8.
D Dao C P Walsh L Yuan D Gorelov L Feng T Hensle P Nisen D J Yamashiro T H Bestor B Tycko 《Human molecular genetics》1999,8(7):1337-1352
9.
Arnaud P Monk D Hitchins M Gordon E Dean W Beechey CV Peters J Craigen W Preece M Stanier P Moore GE Kelsey G 《Human molecular genetics》2003,12(9):1005-1019
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. 相似文献
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12.
A human p57(KIP2) transgene is not activated by passage through the maternal mouse germline. 总被引:5,自引:0,他引:5
Genomic imprinting results in expression of some autosomal genes from one parental allele only. Human chromosome 11p15, and the syntenic region on mouse distal chromosome 7, contain several imprinted genes, including p57 (KIP2) ( CDKN1C ) and IGF2. These two genes, which are separated by >700 kb, are both implicated in the pathogenesis of Beckwith-Wiedemann syndrome. We have shown previously that an Igf2/H19 transgene is expressed appropriately and can imprint at ectopic chromosomal locations. To investigate the p57 (KIP2) region, we similarly tested the imprinting and function of a 38 kb human genomic fragment containing the p57 (KIP2) gene in transgenic mice. This transgene showed appropriate tissue-specific expression and transgene copy number-dependent expression at ectopic sites. However, the levels of expression are reminiscent of that found for the paternal allele in humans (10%). There was no change in expression levels when the transgene was inherited from the maternal germline. These results suggest that the cis -elements required for enhanced expression of the maternally inherited p57 (KIP2) allele lie at a distance from the gene. This finding has important implications for the role of this gene in the human disease, in particular with respect to the translocation breakpoints identified in some patients. 相似文献
13.
Sequence conservation and variability of imprinting in the Beckwith-Wiedemann syndrome gene cluster in human and mouse 总被引:14,自引:0,他引:14
Paulsen M El-Maarri O Engemann S Strödicke M Franck O Davies K Reinhardt R Reik W Walter J 《Human molecular genetics》2000,9(12):1829-1841
In human and mouse most imprinted genes are arranged in chromosomal clusters. This linked organization suggests coordinated mechanisms controlling imprinted expression. We have sequenced 250 kb in the centre of the mouse imprinting cluster on distal chromosome 7 and compared it with the orthologous Beckwith-Wiedemann gene cluster on human chromosome 11p15.5. This first comparative imprinting cluster analysis revealed a high structural and functional conservation of the six orthologous genes identified. However, several striking differences were also discovered. First, compared with the mouse the human sequence is approximately 40% longer, mostly due to insertions of two large repetitive clusters. One of these clusters encompasses an additional gene coding for a homologue of the ribosomal protein L26. Second, pronounced blocks of unique direct repeats characteristic of imprinted genes were only found in the human sequence. Third, two of the orthologous gene pairs Tssc4/TSSC4 and Ltrpc5/LTRPC5 showed apparent differences in imprinting between human and mouse, whereas others like Tssc6/TSSC6 were not imprinted in either organism. Together these results suggest a significant functional and structural variability in the centre of the imprinting cluster. Some genes escape imprinting in both organisms whereas others exhibit tissue- and species-specific imprinting. Hence the control of imprinting in the cluster appears to be a highly dynamic process under fast evolutionary adaptation. Intriguingly, whereas imprinted genes within the cluster contain CpG islands the non-imprinted Ltrpc5 and Tssc6/TSSC6 do not. This and additional comparisons with other imprinted and non-imprinted regions suggest that CpG islands are key features of imprinted domains. 相似文献
14.
Identification of an imprinted gene, Meg3/Gtl2 and its human homologue MEG3, first mapped on mouse distal chromosome 12 and human chromosome 14q 总被引:7,自引:0,他引:7
Miyoshi N Wagatsuma H Wakana S Shiroishi T Nomura M Aisaka K Kohda T Surani MA Kaneko-Ishino T Ishino F 《Genes to cells : devoted to molecular & cellular mechanisms》2000,5(3):211-220
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. 相似文献
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K Mitsuya M Meguro M P Lee M Katoh T C Schulz H Kugoh M A Yoshida N Niikawa A P Feinberg M Oshimura 《Human molecular genetics》1999,8(7):1209-1217
17.
The necdin gene is deleted in Prader-Willi syndrome and is imprinted in human and mouse 总被引:9,自引:5,他引:9
Human chromosome 15q11-q13 contains genes that are imprinted and expressed
from only one parental allele. Prader-Willi syndrome (PWS) is due to the
loss of expression of one or more paternally expressed genes on proximal
human chromosome 15q, most often by deletion or maternal uniparental
disomy. Several candidate genes and a putative imprinting centre have been
identified in the deletion region. We report that the human necdin-encoding
gene (NDN) is within the centromeric portion of the PWS deletion region,
between the two imprinted genes ZNF127 and SNRPN. Murine necdin is a
nuclear protein expressed exclusively in differentiated neurons in the
brain. Necdin is postulated to govern the permanent arrest of cell growth
of post-mitotic neurons during murine nervous system development. We have
localized the mouse locus Ndn encoding necdin to chromosome 7 in a region
of conserved synteny with human chromosome 15q11-q13, by genetic mapping in
an interspecific backcross panel. Furthermore, we demonstrate that
expression of Ndn is limited to the paternal allele in RNA from newborn
mouse brain. Expression of NDN is detected in many human tissues, with
highest levels of expression in brain and placenta. NDN is expressed
exclusively from the paternally inherited allele in human fibroblasts. Loss
of necdin gene expression may contribute to the disorder of brain
development in individuals with PWS.
相似文献
18.
Parental origin effects in human trisomy for chromosome 14q: implications for genomic imprinting. 总被引:4,自引:0,他引:4 下载免费PDF全文
Parental origin specific congenital anomalies have been noted in patients with uniparental disomy of the long arm of human chromosome 14 (UPD14). This suggests the presence of imprinted genes, consistent with observations of imprinting in the region of syntenic homology in the mouse. It is not known whether the distinct defects reported for paternal and maternal UPD14 are the result of biallelic expression or absence of expression of imprinted genes. Furthermore, identification of the genes responsible would be facilitated by a higher resolution map of the imprinted region(s) involved. Subjects with partial trisomy for chromosome 14 (Ts14) have been reported and hence also have an alteration in the dosage of their parental chromosomes. In this study, we have carried out genotype-phenotype correlations considering the parental origin of the extra chromosome in previously reported cases of maternal and paternal partial Ts14. The analysis has provided evidence of a correlation between distal maternal Ts14 and anomalies including low birth weight, short philtrum, and small hands. The clinical features found in the maternal and paternal trisomies are compared with those associated with maternal and paternal UPD14 and their significance is discussed in relation to genomic imprinting on chromosome 14. 相似文献
19.
20.
Three genes on 11p15.5 are known to undergo genomic imprinting. The gene
for insulin-like growth factor II (IGF2) is normally expressed from the
paternal allele, while H19 and p57KIP2, a cyclin-dependent kinase
inhibitor, are expressed from the maternal allele. Five germline balanced
chromosomal rearrangement breakpoints from patients with Beckwith-Wiedemann
syndrome (BWS) have been mapped to 11p15.5 between p57KIP2 and IGF2, and
all are derived from the maternal chromosome. By positional cloning from
BWS breakpoints, we have isolated a gene 100 kb and 65 kb centromeric to
the proximal end of this BWS breakpoint cluster and p57KIP2, respectively.
This gene is homologous to yeast nucleosome assembly protein (NAP1) and to
a human homologue of NAP1, and we designate it hNAP2 (human nucleosome
assembly protein 2). hNAP2 diverges in its expression pattern from IGF2,
H19, and p57KIP2, and it shows biallelic expression in all tissues tested.
Thus, hNAP2 is functionally insulated from the imprinting domain of 11p15.
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