共查询到20条相似文献,搜索用时 31 毫秒
1.
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
2.
Weksberg R.; Teshima I.; Williams B.R.G.; Greenberg C.R.; Pueschel S.M.; Chernos J.E.; Fowlow S.B.; Hoyme E.; Anderson I.J.; Whiteman D.A.H.; Fisher N.; Squire J. 《Human molecular genetics》1993,2(5):549-556
To define the region of 11p15 involved in BeckwlthWiedemannsyndrome (BWS), we have carried out a molecular genetic analysisof six patients with features of BWS and constitutional cytogeneticabnormalities involving chromosome band 11pl5. Molecular analysisconfirmed the 11p origin of the duplicated material and definedthe smallest region of overlap for such duplications, withinwhich a gene involved in BWS must be located. This region encompassesthe ß-globin gene complex (HBB) to 11pter. In bothof our informative cases, the 11p duplication was found to beof paternal origin. Two BWS associated balanced traitslocatioasof 11p15 were studied to localize the breakpoints on 11p15.Somatic cell hybrids, Southern blotting and fluorescent in situhybridization (FISH) showed that both breakpoints were betweenD11S12 and the insulin-like growth factor 2 (IGF2) gene. A non-BWStranslocation breakpoint was more proximal, between HBB andcalcitonin-A (CALCA). Pedigree analysis showed that both BWSassociated 11p15 translocations were transmitted by phenotypicallynormal mothers. The data are compatible with the hypothesisthat the BWS gene is imprinted and that the maternally inheritedBWS gene is normally suppressed whereas the paternally inheritedallele is active. Thus, duplications of paternal origin wouldlead to increased dosage of the BWS gene. Similarly increaseddosage of the BWS gene could account for the findings in maternallyinherited 11p15 translocations by altering normal imprinting,so that the translocated maternal allele remains active. Thisstudy defines one or more gene loci for BWS on 11p15.5 in thegenomic region from D11512
[GenBank] to IGF2. 相似文献
3.
Acute lymphocytic leukaemia in a child with Beckwith–Wiedemann syndrome harbouring a CDKN1C mutation
C. Abadie F. Bernard I. Netchine D. Sanlaville A. Roque S. Rossignol I. Coupier 《European journal of medical genetics》2010,53(6):400-403
Beckwith–Wiedemann syndrome (BWS) is a rare overgrowth syndrome associated with an increased risk in childhood tumours. The phenotypic variability in BWS reflects its molecular heterogeneity. This syndrome is a multigenic disorder caused by dysregulation of imprinted growth regulatory genes in the 11p15.5 region. The most commonly reported tumours in this syndrome are tumours of embryologic origin such as Wilms tumours, hepatoblastomas, neuroblastomas, rhabdomyosarcomas and adrenocortical carcinomas.We report the case of a 10-year-old patient diagnosed with BWS, harbouring a CDKN1C (p57KIP2) mutation, who developed a T-type acute lymphoblastic leukaemia.To our knowledge it is the first report of an acute lymphoblastic leukaemia of T-type in a child with BWS. We discuss the possibility of a link between BWS and leukaemia via one of the few known negative regulator of hematopoiesis, the transforming growth factor beta pathway, depending upon the up-regulation of CDKN1C. 相似文献
4.
Analysis of the methylation status of the KCNQ1OT and H19 genes in leukocyte DNA for the diagnosis and prognosis of Beckwith-Wiedemann syndrome. 总被引:1,自引:0,他引:1
V Gaston Y Le Bouc V Soupre L Burglen J Donadieu H Oro G Audry M P Vazquez C Gicquel 《European journal of human genetics : EJHG》2001,9(6):409-418
5.
Hatada I; Inazawa J; Abe T; Nakayama M; Kaneko Y; Jinno Y; Niikawa N; Ohashi H; Fukushima Y; Iida K; Yutani C; Takahashi S; Chiba Y; Ohishi S; Mukai T 《Human molecular genetics》1996,5(6):783-788
p57KIP2 is a potent tight-binding inhibitor of several G1 cyclin complexes,
and is a negative regulator of cell proliferation. The gene encoding human
p57KIP2 is located on chromosome 11p15.5, a region implicated in both
sporadic cancers and Beckwith-Wiedemann syndrome (BWS), a cancer syndrome,
making it a tumor suppressor candidate. Several types of childhood tumors
including Wilms' tumor, adrenocortical carcinoma and rhabdomyosarcoma
display a specific loss of maternal 11p15 alleles, suggesting that genomic
imprinting plays an important part. Genetic analysis of the familial BWS
has indicated maternal carriers and suggested a role in genomic imprinting.
Previously, we demonstrated that p57KIP2 is imprinted in the mouse. Here we
describe the genomic imprinting of human p57KIP2 and the reduction of its
expression in Wilms' tumors. High resolution mapping locates p57KIP2 in the
region responsible for both tumor suppressivity and BWS.
相似文献
6.
IMPT1, an imprinted gene similar to polyspecific transporter and multi- drug resistance genes 总被引:5,自引:1,他引:5
Dao D; Frank D; Qian N; O'Keefe D; Vosatka RJ; Walsh CP; Tycko B 《Human molecular genetics》1998,7(4):597-608
Human chromosome 11p15.5 and distal mouse chromosome 7 include a
megabase-scale chromosomal domain with multiple genes subject to parental
imprinting. Here we describe mouse and human versions of a novel imprinted
gene, IMPT1 , which lies between IPL and p57 KIP2 and which encodes a
predicted multi-membrane-spanning protein similar to bacterial and
eukaryotic polyspecific metabolite transporter and multi- drug resistance
pumps. Mouse Impt1 and human IMPT1 mRNAs are highly expressed in tissues
with metabolite transport functions, including liver, kidney, intestine,
extra-embryonic membranes and placenta, and there is strongly preferential
expression of the maternal allele in various mouse tissues at fetal stages.
In post-natal tissues there is persistent expression, but the allelic bias
attenuates. An allelic expression bias is also observed in human fetal and
post-natal tissues, but there is significant interindividual variation and
rare somatic allele switching. The fact that Impt1 is relatively repressed
on the paternal allele, together with data from other imprinted genes,
allows a statistical conclusion that the primary effect of human chromosome
11p15.5/mouse distal chromosome 7 imprinting is domain-wide relative
repression of genes on the paternal homolog. Dosage regulation of the
metabolite transporter gene(s) by imprinting might regulate placental and
fetal growth.
相似文献
7.
Demars J Rossignol S Netchine I Lee KS Shmela M Faivre L Weill J Odent S Azzi S Callier P Lucas J Dubourg C Andrieux J Le Bouc Y El-Osta A Gicquel C 《Human mutation》2011,32(10):1171-1182
The imprinted 11p15 region is organized in two domains, each of them under the control of its own imprinting control region (ICR1 for the IGF2/H19 domain and ICR2 for the KCNQ1OT1/CDKN1C domain). Disruption of 11p15 imprinting results in two fetal growth disorders with opposite phenotypes: the Beckwith-Wiedemann (BWS) and the Silver-Russell (SRS) syndromes. Various 11p15 genetic and epigenetic defects have been demonstrated in BWS and SRS. Among them, isolated DNA methylation defects account for approximately 60% of patients. To investigate whether cryptic copy number variations (CNVs) involving only part of one of the two imprinted domains account for 11p15 isolated DNA methylation defects, we designed a single nucleotide polymorphism array covering the whole 11p15 imprinted region and genotyped 185 SRS or BWS cases with loss or gain of DNA methylation at either ICR1 or ICR2. We describe herein novel small gain and loss CNVs in six BWS or SRS patients, including maternally inherited cis-duplications involving only part of one of the two imprinted domains. We also show that ICR2 deletions do not account for BWS with ICR2 loss of methylation and that uniparental isodisomy involving only one of the two imprinted domains is not a mechanism for SRS or BWS. 相似文献
8.
9.
Gardiner K Chitayat D Choufani S Shuman C Blaser S Terespolsky D Farrell S Reiss R Wodak S Pu S Ray PN Baskin B Weksberg R 《American journal of medical genetics. Part A》2012,(6):1388-1394
Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder with variability in clinical manifestations and molecular causes. In most cases, patients with BWS have normal development. Cases with developmental delay are usually attributed to neonatal hypoglycemia or chromosome abnormalities involving copy number variation for genes beyond the critical BWS region at 11p15.5. Brain abnormalities have not previously been recognized within the BWS phenotypic spectrum. We report on seven cases of BWS associated with posterior fossa abnormalities. Of these, two cases presented with Blake's pouch cyst, two with Dandy-Walker variant (DWV; hypoplasia of the inferior part of the vermis), one with Dandy-Walker malformation (DWM) and one with a complex of DWM, dysgenesis of the corpus callosum and brain stem abnormality. In all these cases, molecular findings involved the centromeric imprinted domain on chromosome locus 11p15.5, which includes imprinting center 2 (IC2) and the imprinted growth suppressor gene, CDKN1C. Three cases had loss of methylation at IC2, two had CDKN1C mutations, and one had loss of methylation at IC2 and a microdeletion. In one case no mutation/methylation abnormality was detected. These findings together with previously reported correlations suggest that genes in imprinted domain 2 at 11p15.5 are involved in normal midline development of several organs including the brain. Our data suggest that brain malformations may present as a finding within the BWS phenotype when the molecular etiology involves imprinted domain 2. Brain imaging may be useful in identifying such malformations in individuals with BWS and neurodevelopmental issues. 相似文献
10.
Smith AC Shuman C Chitayat D Steele L Ray PN Bourgeois J Weksberg R 《American journal of medical genetics. Part A》2007,(24):3010-3015
Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by macrosomia, macroglossia, omphalocele, hemihyperplasia, and increased tumor risk. BWS can be associated with genetic and/or epigenetic alterations that modify imprinted gene expression on chromosome 11p15.5. Somatic mosaicism for paternal uniparental disomy (UPD) of chromosome 11p15, found in 20% of BWS patients, is associated with specific features of BWS including hemihyperplasia, Wilms tumor, and hepatoblastoma. The highly variable phenotypic spectrum of BWS associated with UPD may well reflect the level of UPD 11 cells in specific organs and tissues such that very high levels of UPD might produce a more severe phenotypic expression of BWS. In this regard we report on two patients with severe presentations of BWS and extremely high levels of UPD in DNA from lymphocytes. Clinically, both patients demonstrated extreme macroglossia, persistent hypoglycemia, cardiomyopathy, hemihyperplasia, renal abnormalities, abdominal organomegaly, hepatoblastoma and died in the first 6 months of life. These two patients support the hypothesis that high levels of UPD define high expressivity in BWS. 相似文献
11.
South ST Whitby H Maxwell T Aston E Brothman AR Carey JC 《American journal of medical genetics. Part A》2008,(20):2691-2697
Paternal duplications of chromosome region 11p15 can result in Beckwith-Weidemann syndrome (BWS), whereas maternal duplications of the same region on 11p15 can result in Russell-Silver syndrome (RSS). These two syndromes have numerous opposing phenotypes, especially with regards to growth parameters. The differences in the phenotype are proposed to be due to altered dosage of imprinted genes that control growth within this region of 11p15. Wolf-Hirschhorn syndrome (WHS) is due to deletions of a region in 4p16.3 and there is no known parent-of-origin effect for deletions of the WHS critical region, and no genes are known to be imprinted in this region. We report on three individuals with very similar unbalanced translocations resulting in a derivative chromosome 4 with both a deletion of 4p16.3 and a duplication of 11p15. Two of these individuals are family members with one inheriting the derivative 4 from her balanced mother and the other inheriting the derivative 4 from his balanced father. The third individual is unrelated and inherited his derivative 4 from his balanced father. While the findings of these individuals included some features of WHS and RSS or BWS, the phenotypes as an aggregate are distinct from these syndromes. The genomic and phenotypic characterization of these three individuals demonstrates how unbalanced translocations can result in the modification of chromosome duplication and deletion syndromes and identifies genomic architecture that may be responsible for mediating a recurrent translocation between 4p and 11p. 相似文献
12.
13.
Lirussi F Jonard L Gaston V Sanlaville D Kooy RF Winnepenninckx B Maher ER Fitzpatrick DR Gicquel C Portnoï MF Couderc R Vazquez MP Bahuau M 《American journal of medical genetics. Part A》2007,(23):2796-2803
Beckwith-Wiedemann syndrome (BWS) is an overgrowth condition with tumor proclivity linked to a genetic imbalance of a complex imprinted region in 11p15.5. A female child with features fitting in with the BWS diagnostic framework and an apparent loss of imprinting (LOI) of the IGF2 gene in 11p15.5 was also reported to have a de novo chromosome 18q segmental deletion (Patient 1), thus pointing at the location of a possible trans-activating regulator element for maintenance of IGF2 imprinting and providing one of the few examples of locus heterogeneity of BWS. A second child with de novo 18q23 deletion and features of macroglossia, naevus flammeus, bilateral inguinal hernia and transient neonatal hypoglycemia, thus also fitting in with the BWS diagnostic framework, is here fully reported (Patient 2). In this child, an analysis of the BWS1 locus precluded any paternal isodisomy and showed a normal imprinting pattern (mono-allelic expression of IGF2 and normal H19 and CDKN1OT1/LIT1 methylation index). In Patients 1 and 2, deletions were shown to overlap, defining a minimal region of haplo-insufficiency of 3.8-5.6 Mb in 18q23. We conclude that this region provides a candidate location for an original macroglossia condition with strong overlap with BWS, but without obvious upstream functional relationship with the BWS1 locus in 11p15.5. Because this minimal region of haplo-insufficiency falls into a common region of deletion in 18q- syndrome, we inferred that this macroglossia condition would follow a recessive pattern of inheritance. 相似文献
14.
15.
Boonen SE Hahnemann JM Mackay D Tommerup N Brøndum-Nielsen K Tümer Z Grønskov K 《European journal of human genetics : EJHG》2012,20(1):119-121
Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome, which, in 50-60% of sporadic cases, is caused by hypomethylation of KCNQ1OT1 differentially methylated region (DMR) at chromosome 11p15.5. The underlying defect of this hypomethylation is largely unknown. Recently, recessive mutations of the ZFP57 gene were reported in patients with transient neonatal diabetes mellitus type 1, showing hypomethylation at multiple imprinted loci, including KCNQ1OT1 DMR in some. The aim of our study was to determine whether ZFP57 alterations were a genetic cause of the hypomethylation at KCNQ1OT1 DMR in patients with BWS. We sequenced ZFP57 in 27 BWS probands and in 23 available mothers to test for a maternal effect. We identified three novel, presumably benign sequence variants in ZFP57; thus, we found no evidence for ZFP57 alterations as a major cause in sporadic BWS cases. 相似文献
16.
Sex dependent transmission of Beckwith-Wiedemann syndrome associated with a reciprocal translocation t(9;11)(p11.2;p15.5). 总被引:1,自引:2,他引:1
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Beckwith-Wiedemann syndrome (BWS), a disorder associated with neonatal hypoglycaemia, increased growth potential, and predisposition to Wilms's tumour (WT) and other malignancies, has been mapped to 11p15. The association with 11p15 duplications of paternal origin, of balanced translocations and inversions with breakpoints within 11p15.4-p15.5 of maternal origin, and the demonstration of uniparental paternal 11p15 isodisomy in some sporadic cases point towards the involvement of genomic imprinting. In agreement with this, we show the paternal origin of a de novo 9;11 translocation in a phenotypically normal mother, whose carrier daughter developed BWS. This supports the fact that BWS associated with balanced chromosome mutations is transmitted in the same sex dependent pattern as non-cytogenetic forms of familial BWS. 相似文献
17.
De Crescenzo A Coppola F Falco P Bernardo I Ausanio G Cerrato F Falco L Riccio A 《European journal of medical genetics》2011,54(4):e451-e454
The overgrowth disorder Beckwith-Wiedemann syndrome (BWS) is associated with dysregulation of imprinted genes at chromosome 11p15.5. The molecular defects are heterogeneous but most of the cases are associated with defective DNA methylation at either one of two Imprinting Control Regions (IC1 and IC2) or Uniparental paternal Disomy (UPD) at 11p15.5. In rare cases, the BWS phenotype has been found associated with maternal transmission of IC1 microdeletions. We describe a family with a novel 1.8 kb deletion that is associated with hypermethylation at IC1. The mutation results from recombination between highly homologous sequences containing target sites for the zinc-finger protein CTCF (CTSs). This finding supports the hypothesis that the function of IC1 and the penetrance of the clinical phenotype depend on the spacing of the CTSs resulting from recombination in the mutant allele. 相似文献
18.
Pathophysiological mechanisms of dominant and recessive KVLQT1 K+ channel mutations found in inherited cardiac arrhythmias 总被引:9,自引:0,他引:9
Wollnik B; Schroeder BC; Kubisch C; Esperer HD; Wieacker P; Jentsch TJ 《Human molecular genetics》1997,6(11):1943-1949
The inherited long QT syndrome (LQTS), characterized by a prolonged QT
interval in the electrocardiogram and cardiac arrhythmia, is caused by
mutations in at least four different genes, three of which have been
identified and encode cardiac ion channels. The most common form of LQTS is
due to mutations in the potassium channel gene KVLQT1, but their effects on
associated currents are still unknown. Different mutations in KVLQT1 cause
the dominant Romano-Ward (RW) syndrome and the recessive Jervell and
Lange-Nielsen (JLN) syndrome, which, in addition to cardiac abnormalities,
includes congenital deafness. Co- expression of KvLQT1 with the IsK protein
elicits slowly activating potassium currents resembling the cardiac Iks
current. We now show that IsK not only changes the kinetics of KvLQT1
currents, but also its ion selectivity. Several mutations found in RW,
including a novel mutation (D222N) in the putative channel pore, abolish
channel activity and reduce the activity of wild-type KvLQT1 by a
dominant-negative mechanism. By contrast, a JLN mutation truncating the
carboxyterminus of the KvLQT1 channel protein abolishes channel function
without having a dominant-negative effect. This fully explains the
different patterns of inheritance. Further, we identified a novel splice
variant of the KVLQT1 gene, but could not achieve functional expression of
this nor of a previously described heart-specific isoform.
相似文献
19.
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.
相似文献
20.
J. Bliek S. Snijder S.M. Maas A. Polstra K. van der Lip M. Alders A.C. Knegt M.M.A.M. Mannens 《European journal of medical genetics》2009,52(6):404-408
We report on two families in which the parental origin of duplications of the BWS imprinted regions on chromosome 11p15 influences the phenotype.In family A the transmission of a t(4; 11)(q35; p15.5) translocation results in duplication of BWSIC1 and BWSIC2. If this duplication is transmitted from the father, the extra chromosomal material has the paternal imprint. This results in overexpression of IGF2 and consequently an overgrowth phenotype. If the duplication is transmitted from the mother, the extra chromosomal material has the maternal imprint, resulting in overexpression of CDKN1C and a growth retardation phenotype.In family B an interstitial duplication of BWSIC1 results in an overgrowth phenotype when inherited from the father, similar to family A. However, no change in phenotype is observed if the duplication is transmitted through the mother suggesting that increased dosage of maternally expressed genes in the duplicated region has limited effect on the phenotype. 相似文献