Gene Summary

Gene:KCNQ1; potassium channel, voltage gated KQT-like subfamily Q, member 1
Aliases: LQT, RWS, WRS, LQT1, SQT2, ATFB1, ATFB3, JLNS1, KCNA8, KCNA9, Kv1.9, Kv7.1, KVLQT1
Summary:This gene encodes a voltage-gated potassium channel required for repolarization phase of the cardiac action potential. This protein can form heteromultimers with two other potassium channel proteins, KCNE1 and KCNE3. Mutations in this gene are associated with hereditary long QT syndrome 1 (also known as Romano-Ward syndrome), Jervell and Lange-Nielsen syndrome, and familial atrial fibrillation. This gene exhibits tissue-specific imprinting, with preferential expression from the maternal allele in some tissues, and biallelic expression in others. This gene is located in a region of chromosome 11 amongst other imprinted genes that are associated with Beckwith-Wiedemann syndrome (BWS), and itself has been shown to be disrupted by chromosomal rearrangements in patients with BWS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:potassium voltage-gated channel subfamily KQT member 1
Source:NCBIAccessed: 27 February, 2015


What does this gene/protein do?
Show (23)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Wilms Tumour
  • IGF2
  • Phenotype
  • KCNQ1 Potassium Channel
  • Case-Control Studies
  • Potassium Channels, Voltage-Gated
  • Tumor Markers
  • RNA, Untranslated
  • Loss of Heterozygosity
  • Long Noncoding RNA
  • Cell Line
  • Proteoglycans
  • Potassium Channels
  • Telomere
  • Base Sequence
  • Organic Cation Transport Proteins
  • Genomic Imprinting
  • Oligonucleotide Array Sequence Analysis
  • Polymorphism
  • Immunohistochemistry
  • Genetic Variation
  • Beckwith-Wiedemann syndrome
  • Protein Folding
  • Genome-Wide Association Study
  • DNA Methylation
  • Tumor Suppressor Proteins
  • Signal Transduction
  • Alleles
  • Genetic Predisposition
  • Chromosome 11
  • Hydatidiform Mole
  • Molecular Sequence Data
  • Cancer Gene Expression Regulation
  • Gene Expression Regulation
  • Membrane Proteins
  • KCNQ Potassium Channels
  • Pedigree
  • Protein-Serine-Threonine Kinases
  • Western Blotting
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: KCNQ1 (cancer-related)

Girault A, Privé A, Trinh NT, et al.
Identification of KvLQT1 K+ channels as new regulators of non-small cell lung cancer cell proliferation and migration.
Int J Oncol. 2014; 44(3):838-48 [PubMed] Related Publications
K+ channels, which are overexpressed in several cancers, have been identified as regulators of cell proliferation and migration, key processes in cancer development/propagation. Their role in lung cancer has not been studied extensively; but we showed previously that KvLQT1 channels are involved in cell migration, proliferation and repair of normal lung epithelial cells. We now investigated the role of these channels in lung cancer cell lines and their expression levels in human lung adenocarcinoma (AD) tissues. First, we observed that the wound-healing rates of A549 lung adenocarcinoma cell monolayers were reduced by clofilium and chromanol or after silencing with KvLQT1-specific siRNA. Dose-dependent decrease of A549 cell growth and cell accumulation in G0/G1 phase were seen after KvLQT1 inhibition. Clofilium also affected 2D and 3D migration of A549 cells. Similarly, H460 cell growth, migration and wound healing were diminished by this drug. Because K+ channel overexpression has been encountered in some cancers, we assessed KvLQT1 expression levels in tumor tissues from patients with lung AD. KvLQT1 protein expression in tumor samples was increased by 1.5- to 7-fold, compared to paired non-neoplastic tissues, in 17 of 26 patients. In summary, our data reveal that KvLQT1 channel blockade efficiently reduces A549 and H460 cell proliferation and migration. Moreover, KvLQT1 overexpression in AD samples suggests that it could be a potential therapeutic target in lung cancer.

Shimizu T, Fujii T, Takahashi Y, et al.
Up-regulation of Kv7.1 channels in thromboxane A2-induced colonic cancer cell proliferation.
Pflugers Arch. 2014; 466(3):541-8 [PubMed] Related Publications
Thromboxane A2 (TXA2) is known to stimulate colonic cancer cell proliferation, although the mechanism has not been clarified. In this study, we compared the expression levels of Kv7.1 K(+) channels between human colorectal cancer tissue and the accompanying non-tumor mucosa. Kv7.1 proteins were found to be consistently up-regulated in the cancer tissues from different patients. Kv7.1 was also expressed in human colonic cancer cell lines. Treatment of colonic cancer cells with 9,11-epithio-11,12-methano-thromboxane A2 (STA2), a stable analogue of TXA2, significantly increased whole-cell K(+) currents sensitive to chromanol 293B, an inhibitor of Kv7.1 channels, in parallel with an increased expression of Kv7.1 proteins. In contrast, TXB2, an inactive metabolite of TXA2, had no effects on expression level and function of Kv7.1. A TXA2 receptor antagonist (SQ29548) and an inhibitor of cAMP-dependent protein kinase (Rp-8-Br-MB-cAMPS) inhibited STA2-induced increases in both Kv7.1 expression and chromanol 293B-sensitive K(+) currents. Interestingly, STA2-stimulated proliferation of colonic cancer cells was inhibited by chromanol 293B. These results suggest that Kv7.1 channels are involved in the TXA2-induced cancer cell proliferation and that they are up-regulated by the TXA2 receptor-mediated cAMP pathway.

Wan J, Huang M, Zhao H, et al.
A novel tetranucleotide repeat polymorphism within KCNQ1OT1 confers risk for hepatocellular carcinoma.
DNA Cell Biol. 2013; 32(11):628-34 [PubMed] Related Publications
KCNQ1 overlapping transcript 1 (KCNQ1OT1), a long noncoding RNA responsible for silencing a cluster of genes in cis, has been shown to be involved in multiple cancers. However, much remains unclear of how KCNQ1OT1 contributes to carcinogenesis. By thoroughly analyzing 510 hepatocellular carcinoma (HCC) cases and 1014 healthy controls in a Chinese population, we identified a novel short tandem repeat (STR) polymorphism (rs35622507) within the KCNQ1OT1 coding region and evaluated its association with HCC susceptibility. Logistic regression analysis showed that compared with individuals carrying the homozygote 10-10 genotype, those heterozygote subjects who carry only one allele 10 had a significantly decreased risk of HCC (adjusted odds ratio [OR]=0.67, 95% confidence interval [CI]=0.53-0.86, p=0.0009), with the risk decreased even further in those without allele 10 (adjusted OR=0.38, 95% CI=0.21-0.69, p=0.0005). Furthermore, genotype-phenotype correlation studies using four hepatoma cell lines support a significant association between STR genotypes and the expression of KCNQ1OT1. Cell lines without allele 10 conferred a 20.9-33.3-fold higher expression of KCNQ1OT1. Meanwhile, KCNQ1OT1 expression was reversely correlated with the expression of the cyclin-dependent kinase inhibitor 1C (CDKN1C), a tumor suppressor gene located within the CDKN1C/KCNQ1OT1 imprinted region, in three hepatoma cell lines. Finally, in silico prediction suggested that different alleles could alter the local structure of KCNQ1OT1. Taken together, our findings suggest that the STR polymorphism within KCNQ1OT1 contributes to hepatocarcinogenesis, possibly by affecting KCNQ1OT1 and CDKN1C expression through a structure-dependent mechanism. The replication of our studies and further functional studies are needed to validate our hypothesis and understand the roles of KCNQ1OT1 polymorphisms in predisposition for HCC.

Than BL, Goos JA, Sarver AL, et al.
The role of KCNQ1 in mouse and human gastrointestinal cancers.
Oncogene. 2014; 33(29):3861-8 [PubMed] Free Access to Full Article Related Publications
Kcnq1, which encodes for the pore-forming α-subunit of a voltage-gated potassium channel, was identified as a gastrointestinal (GI) tract cancer susceptibility gene in multiple Sleeping Beauty DNA transposon-based forward genetic screens in mice. To confirm that Kcnq1 has a functional role in GI tract cancer, we created Apc(Min) mice that carried a targeted deletion mutation in Kcnq1. Results demonstrated that Kcnq1 is a tumor suppressor gene as Kcnq1 mutant mice developed significantly more intestinal tumors, especially in the proximal small intestine and colon, and some of these tumors progressed to become aggressive adenocarcinomas. Gross tissue abnormalities were also observed in the rectum, pancreas and stomach. Colon organoid formation was significantly increased in organoids created from Kcnq1 mutant mice compared with wild-type littermate controls, suggesting a role for Kcnq1 in the regulation of the intestinal crypt stem cell compartment. To identify gene expression changes due to loss of Kcnq1, we carried out microarray studies in the colon and proximal small intestine. We identified altered genes involved in innate immune responses, goblet and Paneth cell function, ion channels, intestinal stem cells, epidermal growth factor receptor and other growth regulatory signaling pathways. We also found genes implicated in inflammation and in cellular detoxification. Pathway analysis using Ingenuity Pathway Analysis and Gene Set Enrichment Analysis confirmed the importance of these gene clusters and further identified significant overlap with genes regulated by MUC2 and CFTR, two important regulators of intestinal homeostasis. To investigate the role of KCNQ1 in human colorectal cancer (CRC), we measured protein levels of KCNQ1 by immunohistochemistry in tissue microarrays containing samples from CRC patients with liver metastases who had undergone hepatic resection. Results showed that low expression of KCNQ1 expression was significantly associated with poor overall survival.

Hayashi M, Novak I
Molecular basis of potassium channels in pancreatic duct epithelial cells.
Channels (Austin). 2013 Nov-Dec; 7(6):432-41 [PubMed] Free Access to Full Article Related Publications
Potassium channels regulate excitability, epithelial ion transport, proliferation, and apoptosis. In pancreatic ducts, K(+) channels hyperpolarize the membrane potential and provide the driving force for anion secretion. This review focuses on the molecular candidates of functional K(+) channels in pancreatic duct cells, including KCNN4 (KCa 3.1), KCNMA1 (KCa 1.1), KCNQ1 (Kv 7.1), KCNH2 (Kv 11.1), KCNH5 (Kv 10.2), KCNT1 (KCa 4.1), KCNT2 (KCa 4.2), and KCNK5 (K 2P 5.1). We will give an overview of K(+) channels with respect to their electrophysiological and pharmacological characteristics and regulation, which we know from other cell types, preferably in epithelia, and, where known, their identification and functions in pancreatic ducts and in adenocarcinoma cells. We conclude by pointing out some outstanding questions and future directions in pancreatic K(+) channel research with respect to the physiology of secretion and pancreatic pathologies, including pancreatitis, cystic fibrosis, and cancer, in which the dysregulation or altered expression of K(+) channels may be of importance.

Egashira T, Yuasa S, Suzuki T, et al.
Disease characterization using LQTS-specific induced pluripotent stem cells.
Cardiovasc Res. 2012; 95(4):419-29 [PubMed] Related Publications
AIMS: Long QT syndrome (LQTS) is an inheritable and life-threatening disease; however, it is often difficult to determine disease characteristics in sporadic cases with novel mutations, and more precise analysis is necessary for the successful development of evidence-based clinical therapies. This study thus sought to better characterize ion channel cardiac disorders using induced pluripotent stem cells (iPSCs).
METHODS AND RESULTS: We reprogrammed somatic cells from a patient with sporadic LQTS and from controls, and differentiated them into cardiomyocytes through embryoid body (EB) formation. Electrophysiological analysis of the LQTS-iPSC-derived EBs using a multi-electrode array (MEA) system revealed a markedly prolonged field potential duration (FPD). The IKr blocker E4031 significantly prolonged FPD in control- and LQTS-iPSC-derived EBs and induced frequent severe arrhythmia only in LQTS-iPSC-derived EBs. The IKs blocker chromanol 293B did not prolong FPD in the LQTS-iPSC-derived EBs, but significantly prolonged FPD in the control EBs, suggesting the involvement of IKs disturbance in the patient. Patch-clamp analysis and immunostaining confirmed a dominant-negative role for 1893delC in IKs channels due to a trafficking deficiency in iPSC-derived cardiomyocytes and human embryonic kidney (HEK) cells.
CONCLUSIONS: This study demonstrated that iPSCs could be useful to characterize LQTS disease as well as drug responses in the LQTS patient with a novel mutation. Such analyses may in turn lead to future progress in personalized medicine.

Arai E, Chiku S, Mori T, et al.
Single-CpG-resolution methylome analysis identifies clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas.
Carcinogenesis. 2012; 33(8):1487-93 [PubMed] Free Access to Full Article Related Publications
To clarify the significance of DNA methylation alterations during renal carcinogenesis, methylome analysis using single-CpG-resolution Infinium array was performed on 29 normal renal cortex tissue (C) samples, 107 non-cancerous renal cortex tissue (N) samples obtained from patients with clear cell renal cell carcinomas (RCCs) and 109 tumorous tissue (T) samples. DNA methylation levels at 4830 CpG sites were already altered in N samples compared with C samples. Unsupervised hierarchical clustering analysis based on DNA methylation levels at the 801 CpG sites, where DNA methylation alterations had occurred in N samples and were inherited by and strengthened in T samples, clustered clear cell RCCs into Cluster A (n = 90) and Cluster B (n = 14). Clinicopathologically aggressive tumors were accumulated in Cluster B, and the cancer-free and overall survival rates of patients in this cluster were significantly lower than those of patients in Cluster A. Clear cell RCCs in Cluster B were characterized by accumulation of DNA hypermethylation on CpG islands and considered to be CpG island methylator phenotype (CIMP)-positive cancers. DNA hypermethylation of the CpG sites on the FAM150A, GRM6, ZNF540, ZFP42, ZNF154, RIMS4, PCDHAC1, KHDRBS2, ASCL2, KCNQ1, PRAC, WNT3A, TRH, FAM78A, ZNF671, SLC13A5 and NKX6-2 genes became hallmarks of CIMP in RCCs. On the other hand, Cluster A was characterized by genome-wide DNA hypomethylation. These data indicated that DNA methylation alterations at precancerous stages may determine tumor aggressiveness and patient outcome. Accumulation of DNA hypermethylation on CpG islands and genome-wide DNA hypomethylation may each underlie distinct pathways of renal carcinogenesis.

Lang F, Stournaras C
Serum and glucocorticoid inducible kinase, metabolic syndrome, inflammation, and tumor growth.
Hormones (Athens). 2013 Apr-Jun; 12(2):160-71 [PubMed] Related Publications
Serum-and-glucocorticoid-inducible-kinase-1 (SGK1) is under regulation of several hormones, mediators and cell stressors. More specifically, SGK1 expression is particularly sensitive to glucocorticoids, mineralocorticoids, and TGFβ. Moreover, SGK1 expression is exquisitely sensitive to hypertonicity, hyperglycemia, and ischemia. SGK1 is activated by insulin and growth factors via phosphatidylinositol-3-kinase, 3-phosphoinositide dependent-kinase PDK1, and mTOR. SGK1 up-regulates the Na⁺/K⁺-ATPase, a variety of carriers (e.g. NCC, NKCC, NHE1, NHE3, SGLT1, several amino acid transporters) and many ion channels (e.g. ENaC, SCN5A, TRPV4-6, Orai1/STIM1, ROMK, KCNE1/KCNQ1, GluR6, CFTR). SGK1 further up-regulates a number of enzymes (e.g. glycogen-synthase-kinase-3, ubiquitin-ligase Nedd4-2), and transcription factors (e.g. forkhead-transcription-factor FOXO3a, β-catenin, nuclear-factor-kappa-B NFκB). SGK1 sensitive functions contribute to regulation of epithelial transport, excitability, degranulation, matrix protein deposition, coagulation, platelet aggregation, migration, cell proliferation, and apoptosis. Apparently, SGK1 is not required for housekeeping functions, as the phenotype of SGK1 knockout mice is mild. However, excessive SGK1 expression and activity participates in the pathophysiology of several disorders, including hypertension, obesity, diabetes, thrombosis, stroke, inflammation, autoimmune disease, fibrosis, and tumor growth. A SGK1 gene variant (prevalence ~3-5% prevalence in Caucasians, ~10% in Africans) predisposes to hypertension, stroke, obesity, and type 2 diabetes. Moreover, excessive salt intake and/or excessive release of glucocorticoids, mineralocorticoids, and TGFβ up-regulates SGK1 expression thus predisposing to SGK1-related diseases.

Kim JC, Lee HC, Cho DH, et al.
Genome-wide identification of possible methylation markers chemosensitive to targeted regimens in colorectal cancers.
J Cancer Res Clin Oncol. 2011; 137(10):1571-80 [PubMed] Related Publications
PURPOSE: Few efficient methylation markers of chemosensitivity have been discovered. The genome-wide analysis of methylation markers is needed to identify chemosensitive candidates to targeted therapy.
METHODS: This study describes a two-step process to select chemosensitive candidates of methylation genes. A genome-wide screening of methylation genes was performed using a Beadarray and an in vitro chemosensitivity assay of 119 colorectal cancers (CRCs). Ten candidate genes identified during the initial screening were verified by biological utility assessment using cell viability assays of transfected CRC cells.
RESULTS: Five methylation genes related to sensitivity to bevacizumab regimens (RASSF1, MMP25, KCNQ1, ESR1, and GALR2) or cetuximab regimens (SCL18A2, GPX7, NID2, IGFBP3, and ALX4) were chosen during the first step. A viability assay revealed that GALR2-overexpressing HCT116 cells were significantly more chemosensitive to bevacizumab regimens than control cells (P = 0.022 and 0.019 for bevacizumab with FOLFIRI and FOLFOX, respectively), concurrently verified on a caspase-3 activity assay. GPX7- or ALX4-overexpressed RKO cells were significantly less viable to cetuximab regimens compared to control cells (GPX7: P = 0.027 each for cetuximab with FOLFIRI and FOLFOX; ALX4: P = 0.049 and 0.003 for cetuximab with FOLFIRI and FOLFOX, respectively), but caspase-3 activity was not prominent in GPX7-overexpressed RKO cells.
CONCLUSIONS: Two novel genes, GALR2 and ALX4, have been identified as chemosensitive methylation candidates to bevacizumab and cetuximab regimens, respectively. As our study did not include a clinical association study, the two candidates should be validated in large clinical cohorts, hopefully predicting responsive patients to targeted regimens.

Roepke TK, Purtell K, King EC, et al.
Targeted deletion of Kcne2 causes gastritis cystica profunda and gastric neoplasia.
PLoS One. 2010; 5(7):e11451 [PubMed] Free Access to Full Article Related Publications
Gastric cancer is the second leading cause of cancer death worldwide. Predisposing factors include achlorhydria, Helicobacter pylori infection, oxyntic atrophy and TFF2-expressing metaplasia. In parietal cells, apical potassium channels comprising the KCNQ1 alpha subunit and the KCNE2 beta subunit provide a K(+) efflux current to facilitate gastric acid secretion by the apical H(+)K(+)ATPase. Accordingly, genetic deletion of murine Kcnq1 or Kcne2 impairs gastric acid secretion. Other evidence has suggested a role for KCNE2 in human gastric cancer cell proliferation, independent of its role in gastric acidification. Here, we demonstrate that 1-year-old Kcne2(-/-) mice in a pathogen-free environment all exhibit a severe gastric preneoplastic phenotype comprising gastritis cystica profunda, 6-fold increased stomach mass, increased Ki67 and nuclear Cyclin D1 expression, and TFF2- and cytokeratin 7-expressing metaplasia. Some Kcne2(-/-) mice also exhibited pyloric polypoid adenomas extending into the duodenum, and neoplastic invasion of thin walled vessels in the sub-mucosa. Finally, analysis of human gastric cancer tissue indicated reduced parietal cell KCNE2 expression. Together with previous findings, the results suggest KCNE2 disruption as a possible risk factor for gastric neoplasia.

Paulin FL, Klein GJ, Gula LJ, et al.
QT prolongation and monomorphic VT caused by pheochromocytoma.
J Cardiovasc Electrophysiol. 2009; 20(8):931-4 [PubMed] Related Publications
INTRODUCTION: Pheochromocytoma may present with ECG abnormalities as one of the few clues to the diagnosis.
METHODS AND RESULTS: A 30-year-old woman presented with chest pain and a QTc of 525 ms. Four weeks later following a syncopal episode, her QTc was 660 ms. Short runs of monomorphic ventricular tachycardia were recorded. Investigations revealed an adrenal pheochromocytoma. Her QTc normalized after excision of the tumor. Comprehensive QT gene screening of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 was negative.
CONCLUSION: Pheochromocytoma may induce monomorphic VT and QT prolongation. The interaction of different catecholamines may have a compounding effect on cardiac repolarization.

Morokuma J, Blackiston D, Adams DS, et al.
Modulation of potassium channel function confers a hyperproliferative invasive phenotype on embryonic stem cells.
Proc Natl Acad Sci U S A. 2008; 105(43):16608-13 [PubMed] Free Access to Full Article Related Publications
Ion transporters, and the resulting voltage gradients and electric fields, have been implicated in embryonic development and regeneration. These biophysical signals are key physiological aspects of the microenvironment that epigenetically regulate stem and tumor cell behavior. Here, we identify a previously unrecognized function for KCNQ1, a potassium channel known to be involved in human Romano-Ward and Jervell-Lange-Nielsen syndromes when mutated. Misexpression of its modulatory wild-type beta-subunit XKCNE1 in the Xenopus embryo resulted in a striking alteration of the behavior of one type of embryonic stem cell: the pigment cell lineage of the neural crest. Depolarization of embryonic cells by misexpression of KCNE1 non-cell-autonomously induced melanocytes to overproliferate, spread out, and become highly invasive of blood vessels, liver, gut, and neural tube, leading to a deeply hyperpigmented phenotype. This effect is mediated by the up-regulation of Sox10 and Slug genes, thus linking alterations in ion channel function to the control of migration, shape, and mitosis rates during embryonic morphogenesis. Taken together, these data identify a role for the KCNQ1 channel in regulating key cell behaviors and reveal the molecular identity of a biophysical switch, by means of which neoplastic-like properties can be conferred upon a specific embryonic stem cell subpopulation.

Kim KP, Thurston A, Mummery C, et al.
Gene-specific vulnerability to imprinting variability in human embryonic stem cell lines.
Genome Res. 2007; 17(12):1731-42 [PubMed] Free Access to Full Article Related Publications
Disregulation of imprinted genes can be associated with tumorigenesis and altered cell differentiation capacity and so could provide adverse outcomes for stem cell applications. Although the maintenance of mouse and primate embryonic stem cells in a pluripotent state has been reported to disrupt the monoallelic expression of several imprinted genes, available data have suggested relatively higher imprint stability in the human equivalents. Identification of 202 heterozygous loci allowed us to examine the allelic expression of 22 imprinted genes in 22 human embryonic stem cell lines. Half of the genes examined (IPW, H19, MEG3, MEST isoforms 1 and 2, PEG10, MESTIT1, NESP55, ATP10A, PHLDA2, IGF2) showed variable allelic expression between lines, indicating vulnerability to disrupted imprinting. However, seven genes showed consistent monoallelic expression (NDN, MAGEL2, SNRPN, PEG3, KCNQ1, KCNQ1OT1, CDKN1C). Furthermore, four genes known to be monoallelic or to exhibit polymorphic imprinting in later-developing human tissues (TP73, IGF2R, WT1, SLC22A18) were always biallelic in hESCs. MEST isoform 1, PEG10, and NESP55 showed an association between the variability observed in interline allelic expression status and the DNA methylation of previously identified regulatory regions. Our results demonstrate gene-specific differences in the stability of imprinted loci in human embryonic stem cells and identify disrupted DNA methylation as one potential mechanism. We conclude the prudence of including comprehensive imprinting analysis in the continued characterization of human embryonic stem cell lines.

Bjornsson HT, Brown LJ, Fallin MD, et al.
Epigenetic specificity of loss of imprinting of the IGF2 gene in Wilms tumors.
J Natl Cancer Inst. 2007; 99(16):1270-3 [PubMed] Related Publications
Loss of imprinting (LOI) of the IGF2 gene (which encodes insulin-like growth factor II) is the most common genetic or epigenetic alteration in Wilms tumor; LOI involves aberrant activation of the normally repressed maternally inherited allele. We found previously that LOI of IGF2 occurs in approximately half of all Wilms tumors (i.e., those arising from lineage-committed nephrogenic progenitor cells). We investigated whether LOI of IGF2 is associated with relaxation of imprinting at loci other than IGF2 or with widespread alterations in DNA methylation. We stratified 59 Wilms tumor samples by IGF2 LOI status by use of hot-stop reverse transcription-polymerase chain reaction and/or methylation analysis of the differentially methylated region of the H19 gene and identified 31 samples with and 28 without LOI. We used quantitative allele-specific expression analysis to determine whether six other imprinted genes (i.e., H19, KCNQ1, LIT1, TSSC5, GRB10, and MEG3) had subtle LOI. No statistically significant difference in allele-specific expression between Wilms tumor with or without LOI was found for LIT1, TSSC5, GRB10, and MEG3. For the KCNQ1 gene there was a slight difference between the groups with (37.0%, 95% confidence interval [CI] = 31.8% to 42.2%) and without (27.7%, 95% CI = 21.8% to 33.5%) LOI (P = .02 for F test of group differences in a mixed-effects model). For H19, we also found a slight difference between the groups with (7.5%, 95% CI = 2.4% to 12.7%) and without (2.2%, 95% CI = -3.2% to 7.6%) LOI of IGF2 (P = .15 for F test). In 27 tumor samples, we also used a microarray technique to analyze methylation of 378 genes, 38 of which were suspected or confirmed imprinted genes. We found that statistically significant alterations in only the differentially methylated region of the H19 gene were associated with LOI of IGF2. Thus, epigenetic alterations in Wilms tumors are not widespread, supporting the gene and lineage specificity of LOI of IGF2.

Stathopoulos A, Melas C, Attali B, et al.
Overexpression of mouse IsK protein fused to green fluorescent protein induces apoptosis of human astroglioma cells.
Neurol Res. 2007; 29(6):628-31 [PubMed] Related Publications
Intracellular K(+) plays an important role in controlling ion homeostasis for maintaining cell volume and inhibiting activity of pro-apoptotic enzymes. Cytoplasmic K(+) concentration is regulated by K(+) uptake via Na(+) -K(+) -ATPase and K(+) efflux through K(+) channels in the plasma membrane. The IsK (KCNE1) protein is known to co-assemble with KCNQ1 (KvLQT1) protein to form a K(+) channel underlying the slowly activating delayed rectifier K(+) outward current which delays voltage activation. In order to further study the activity and cellular localization of IsK protein, we constructed a C-terminal fusion of IsK with EGFP (enhanced green fluorescent protein). Expression of the fusion protein appeared as clusters located in the plasma membrane and induced degeneration of both transiently or stably transfected cells.

Kato H, Wake N
Differential diagnosis between complete and partial mole using a TSSC3 antibody: correlation with DNA polymorphic marker analysis.
J Reprod Med. 2006; 51(11):861-7 [PubMed] Related Publications
OBJECTIVE: To investigate the use of maternally expressed, imprinted genes for the differential diagnosis of complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM).
STUDY DESIGN: Expression patterns of imprinted genes in CHM were validat ed by microarray analysis. Twenty CHMs and 10 PHMs were then subjected to Western blot analysis and immunostaining with appropriate antibodies.
RESULTS: TSSC3 (also known as PHLDA2, IPL), SLC22A1L, KCNQ1 and decorin were shown to be down-regulated, with the suppression of TSSC3 most marked. In all 20 CHM cases for which the diagnosis had been confirmed by DNA polymorphic markers, the expression of TSSC3 was completely lost on Western blots. In contrast, in 10 PHMs that had also been diagnosed by DNA analysis, TSSC3 was expressed normally. Immunohistochemistry showed an identical result.
CONCLUSION: Complete silencing of TSSC3 expression in CHM offers a convenient and novel diagnostic strategy for diagnosing molar lesions.

Feinberg AP
A genetic approach to cancer epigenetics.
Cold Spring Harb Symp Quant Biol. 2005; 70:335-41 [PubMed] Related Publications
In over 20 years since the discovery of altered methylation in cancer, many epigenetic alterations have been found in human cancer, including global and specific gene hypomethylation, hypermethylation, altered chromatin marks, and loss of genomic imprinting. Cancer epigenetics has been limited by questions of cause and effect, since epigenetic changes can arise secondary to the cancer process and its associated widespread changes in gene expression. Furthermore, mutations in the DNA methylation machinery have not been observed in tumors, whereas they have been for chromatin modification. To address the issue of human cancer etiology, we have taken a genetic approach to cancer epigenetics. One line of investigation has been on the disorder Beckwith-Wiedemann syndrome (BWS). We have found that loss of imprinting (LOI) of the autocrine growth factor gene IGF2 and of the untranslated antisense RNA LIT1, within the K(V)LQT1 gene, account for most cases of BWS, and that cancer risk is specifically associated with LOI of IGF2. Wilms' tumors, both in BWS and in the general population, involve LOI leading to an expansion of nephrogenic precursor cells. We have also developed an animal model for the role of LOI of IGF2 in cancer, showing that it cooperates with Apc mutations to increase cancer frequency, consistent with human data suggesting a severalfold increased cancer risk for this common epigenetic variant in the adult population. These data suggest that a major component of cancer risk involves epigenetic changes in normal cells that increase the probability of cancer after genetic mutation. They suggest a model of cancer prevention that involves the epigenetic analysis of normal cells for risk stratification and cancer prevention strategies.

Gallagher E, Mc Goldrick A, Chung WY, et al.
Gain of imprinting of SLC22A18 sense and antisense transcripts in human breast cancer.
Genomics. 2006; 88(1):12-7 [PubMed] Related Publications
The 11p15.5 region harbors three imprinted sense/antisense transcript pairs, SLC22A18/SLC22A18AS, IGF2/IGF2AS (PEG8), and KCNQ1/KCNQ1OT1 (LIT1). SLC22A18 (solute carrier family 22 (organic cation transporter) member 18) and its antisense transcript SLC22A18AS are paternally suppressed in fetal samples. In adult tissue, SLC22A18 displays polymorphic imprinting, but the imprinting status of SLC22A18AS remains elusive. SLC22AI8 DNA-PCR-RFLP analysis using NlaIII restriction digestion identified SLC22A18 heterozygotes within this breast tissue cohort (n = 89). Commercial sequencing identified informative SLC22A18AS samples. Random hexamer-primed cDNA synthesis, SLC22A18/SLC22A18AS-specific PCR, and imprinting evaluation by commercial sequencing demonstrated that SLC22A18AS displays a nonimprinted profile in reduction mastectomies (n = 6). However, SLC22A18 showed a gain of imprinting (GOI) in 1/4 of these normal cases. In the malignant cohort, GOI was also demonstrated in 18% for SLC22A18 and 14% for SLC22A18AS, occurring concomitantly in one case. This study reports the imprinting status of SLC22A18AS in adult tissue, and shows that GOI affects both the sense, and antisense transcripts at this locus in human breast tissue.

Sarzani R, Pietrucci F, Francioni M, et al.
Expression of potassium channel isoforms mRNA in normal human adrenals and aldosterone-secreting adenomas.
J Endocrinol Invest. 2006; 29(2):147-53 [PubMed] Related Publications
Increased aldosterone secretion has been found in a mouse lacking the KCNE1 gene which codes for a regulatory protein of the KCNQ1 gene product, forming the channel for the outward rectifying delayed K+ current. Abnormalities in proteins regulating the K+ fluxes across membranes may be responsible for aldosterone-secreting adenomas (aldosteronomas) also because K+ channels are involved in cell growth. Normal and adenomatous adrenal samples and NCI-H295 cell line were used to: a) evaluate KCNE1 and KCNQ1 gene expression, b) sequence the full length cDNAs of KCNE1 and both KCNQ1 isoforms. These differently spliced KCNE1 and KCNQ1 mRNAs were expressed in adrenal tissue. In contrast, KCNQ1 isoform 2 mRNA was not expressed in kidney control tissues and NCl-H295 cell line. NCI-H295 cell line also had a significantly lower expression of KCNQ1 isoform 1 mRNA than normal adrenals and aldosteronomas. We did not find any somatic mutations in the coding sequences of both genes. This different expression pattern of KCNQ1 isoforms in NCI-H295 cell line with the lack of the mRNA for the dominant-negative KCNQ1 isoform 2 supports the involvement of voltage-gated K+ channel in cell proliferation.

Kato H, Matsuda T, Hirakawa T, et al.
Differential diagnosis between complete and partial mole by TSSC3 antibody completely correlates to DNA diagnosis.
Diagn Mol Pathol. 2005; 14(3):164-9 [PubMed] Related Publications
Complete hydatidiform moles (CHMs) are a type of androgenetic fertilization without an ovum. Cases of CHM exhibit a generalized swelling of the villi and are known to be highly associated with persistent disease or carcinoma. In contrast, partial hydatidiform moles (PHMs) also show characteristic hydropic changes among the villi, but the incidence of secondary disease is relatively low. Because PHMs are fertilized by one ovum and two sperm and CHMs are fertilized by one or two sperm alone, we considered whether or not maternally imprinted genes might be useful for achieving a differential diagnosis. The validity of the imprinted genes in CHMs was assessed by implementation of a microarray technique. Among the genes examined, TSSC3, SLC22A1L, KCNQ1, and Decorin were shown to be down-regulated, and TSSC3 was the most markedly suppressed of these genes. In this study, 20 cases of CHM, the diagnosis of which was confirmed by DNA polymorphism, were investigated. In all of these cases, the expression of TSSC3 was completely absent, as determined by Western blot analysis. Conversely, 12 cases of PHM, also diagnosed by DNA polymorphism, were examined here; in all of these 12 cases, TSSC3 was found to be expressed normally. Immunohistochemical (IHC) analysis also produced the same results. The complete silencing of TSSC3 in cases of CHM will provide a novel, convenient strategy for the diagnosis of molar lesions in the placenta.

Dragan YP, Sargent LM, Babcock K, et al.
Alterations in specific gene expression and focal neoplastic growth during spontaneous hepatocarcinogenesis in albumin-SV40 T antigen transgenic rats.
Mol Carcinog. 2004; 40(3):150-9 [PubMed] Related Publications
Transgenic rats containing the mouse albumin promoter and enhancer directing the expression of simian virus (SV40) T antigen (T Ag) exhibited a 100% incidence of hepatic neoplasms by 24-36 wk of age. These transgenic rats exhibited expression of large T Ag and c-myc protein within focal basophilic lesions and nodules, but not in surrounding hepatocytes. At 24 wk of age, female TG+ rats exhibited a significantly greater number of lesions and a much greater percentage of the liver occupied by TG+ focal hepatic lesions than did their male TG+ littermates. Previous studies on these animals [Sargent et al., Cancer Res 1997;57:3451-3456] demonstrate that at 12 wk of age approximately one-third of metaphases in hepatocytes exhibit a duplication of the 1q3.7-1q4.1 region of rat chromosome 1, with the smallest common region of duplication being that of 1q4.1. Duplication of the 1q3.7-1q4.3 region is also noted in many primary hepatic neoplasms resulting from the multistage model of Initiation-Promotion-Progression (IPP) [Sargent et al., Cancer Res 1996;56:2985-2991]. This region is syntenic with human 11p15.5 and mouse 7ter, which have been implicated in the development of specific neoplasms. Within the syntenic region was a cluster of imprinted genes whose expression we investigated in livers and neoplasms of TG+ rats. H19 was expressed in almost all of the neoplasms, but not in normal adult liver cells. Igf2 expression was detected in the majority of hepatic neoplasms of female TG+ rats, but in a relatively smaller number of neoplasms of TG+ males. The expression of p57Kip2 (Kip2), a cyclin-dependent kinase inhibitor that was also in the imprinted region, exhibited some variable increased expression predominantly in hepatic neoplasms from livers of female TG+ rats. Other imprinted genes within the imprinted gene cluster-insulin II (Ins2), Mash2 (which codes for a basic helix-loop-helix transcription factor), and Kvlqt1 (coding for a component of a potassium transport channel)-showed no consistently different expression from that seen in normal hepatocytes. Another gene, also located on the long arm of chromosome 1, that showed changes was the ribonucleotide reductase M1 subunit (Rrm1), in which an increase in its expression was found. This was seen in hepatic neoplasms of TG+ rats of both sexes compared with surrounding normal-appearing liver. Because hepatic neoplasms developing in livers of rats treated with chemical carcinogens commonly exhibit an increased expression of c-myc mRNA, expression of this gene was investigated in focal lesions and livers of TG+ rats, although c-myc was not located on chromosome 1. c-myc mRNA was increased in focal lesions, nodules, and neoplasms in both male and female TG+ rats compared with adult and surrounding liver. Immunostaining for c-myc protein demonstrated detectable levels in isolated single cells as well as focal lesions and neoplasms. Thus, the enhanced c-myc expression, common to all hepatic neoplasms in this system, coupled with enhanced expression of Igf2 in female TG+ rats, may be responsible for the increase in growth rate in hepatic neoplasms of female TG+ rats compared with that in livers of male TG+ rats and may contribute to neoplastic progression in the liver of this transgenic model.

Hertel NT, Carlsen N, Kerndrup G, et al.
Late relapse of adrenocortical carcinoma in Beckwith-Wiedemann syndrome. Clinical, endocrinological and genetic aspects.
Acta Paediatr. 2003; 92(4):439-43 [PubMed] Related Publications
UNLABELLED: We report on a girl with an unusual Beckwith-Wiedemann syndrome (BWS) and hemihypertrophy, who developed an adrenocortical carcinoma with atypical clinical behaviour. At 4 y of age the girls was admitted to hospital with cushingoid features, virilization, increased excretion of steroids and low serum ACTH. A right-sided adrenocortical carcinoma was removed. At age 12.5 y the cushingoid features reappeared together with a tumour in the left thigh. A CT scan of the thorax and abdomen revealed pulmonary metastasis only. Corticosteroid excretion was increased and serum ACTH level suppressed. The femoral and the pulmonary metastases were removed and histology showed adrenocortical carcinoma. Excretion of corticosteroids subsequently normalized. Meningeal and pulmonary metastases with similar histologies appeared one year later with normal hormone values. Twenty-two months after the recurrence the girl died of an intracranial metastasis. Southern blot analysis of the LITI transcript in the KvLQT1 gene in the BWS region on chromosome 11p15 revealed hypomethylation of the maternal allele.
CONCLUSION: Adrenocortical carcinoma in childhood may recur years after onset and at rare sites and hormonal levels may be an insufficient indicator of small metastases.

Weksberg R, Nishikawa J, Caluseriu O, et al.
Tumor development in the Beckwith-Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of KCNQ1OT1.
Hum Mol Genet. 2001; 10(26):2989-3000 [PubMed] Related Publications
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.

Gaston V, Le Bouc Y, Soupre V, et al.
Analysis of the methylation status of the KCNQ1OT and H19 genes in leukocyte DNA for the diagnosis and prognosis of Beckwith-Wiedemann syndrome.
Eur J Hum Genet. 2001; 9(6):409-18 [PubMed] Related Publications
Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder involving developmental abnormalities, tissue and organ hyperplasia and an increased risk of embryonal tumours (most commonly Wilms tumour). This multigenic disorder is caused by dysregulation of the expression of imprinted genes in the 11p15 chromosomal region. Molecular diagnosis of BWS is currently difficult, mostly due to the large spectrum of genetic and epigenetic abnormalities. The other difficulty in managing BWS is the identification of patients at risk of tumour. An imprinted antisense transcript within KCNQ1, called KCNQ1OT (also known as LIT1), was recently shown to be normally expressed from the paternal allele. A loss of imprinting of the KCNQ1OT gene, associated with the loss of maternal allele-specific methylation of the differentially methylated region KvDMR1 has been described in BWS patients. The principal aim of this study was to evaluate the usefulness of KvDMR1 methylation analysis of leukocyte DNA for the diagnosis of BWS. The allelic status of the 11p15 region and the methylation status of the KCNQ1OT and H19 genes were investigated in leukocyte DNA from 97 patients referred for BWS and classified into two groups according to clinical data: complete BWS (CBWS) (n=61) and incomplete BWS (IBWS) (n=36). Fifty-eight (60%) patients (39/61 CBWS and 19/36 IBWS) displayed abnormal demethylation of KvDMR1. In 11 of the 56 informative cases, demethylation of KvDMR1 was related to 11p15 uniparental disomy (UPD) (nine CBWS and two IBWS). Thirteen of the 39 patients with normal methylation of KvDMR1 displayed hypermethylation of the H19 gene. These 13 patients included two siblings with 11p15 trisomy. These results show that analysis of the methylation status of KvDMR1 and the H19 gene in leukocyte DNA is useful in the diagnosis of 11p15-related overgrowth syndromes, resulting in the diagnosis of BWS in more than 70% of investigated patients. We also evaluated clinical and molecular features as prognostic factors for tumour and showed that mosaicism for 11p15 UPD and hypermethylation of the H19 gene in blood cells were associated with an increased risk of tumour.

Tanaka K, Shiota G, Meguro M, et al.
Loss of imprinting of long QT intronic transcript 1 in colorectal cancer.
Oncology. 2001; 60(3):268-73 [PubMed] Related Publications
Loss of imprinting (LOI) of the insulin-like growth factor 2 (IGF2) and H19 genes on human chromosome 11 has been found not only in childhood tumors but also in common adult cancers including colorectal cancer. Recently, a transcript called LIT1 (long QT intronic transcript 1) has been identified within the KvLQT1 locus on chromosome 11. LIT1 is expressed preferentially from the paternal allele and is transcribed in most human tissues. LOI of LIT1 was found in a considerable number of Beckwith-Wiedemann syndrome (BWS) patients, suggesting that it is associated with the etiology of BWS. Since LOI of IGF2 was observed in association with overexpression of IGF2 in colorectal cancer in our previous study, we examined the status of genomic imprinting of LIT1 and H19 in comparison with IGF2 in colorectal cancer. We examined 44 surgically dissected colorectal cancer tissues. Ten of them represented informative cases for LIT1. None of these patients exhibited loss of heterozygosity (LOH) of LIT1, and LOI of LIT1 was observed in 4 of the 10 (40%) informative patients, but not in non-cancerous tissues. Neither LOH nor LOI of H19 was observed. LOI of IGF2 was observed in 4 of 18 (22%) informative patients. These results suggest that LOI of LIT1 is frequently observed in colorectal cancer and may be a useful marker for diagnosis of colorectal cancer.

Bliek J, Maas SM, Ruijter JM, et al.
Increased tumour risk for BWS patients correlates with aberrant H19 and not KCNQ1OT1 methylation: occurrence of KCNQ1OT1 hypomethylation in familial cases of BWS.
Hum Mol Genet. 2001; 10(5):467-76 [PubMed] Related Publications
Beckwith-Wiedemann syndrome (BWS) is an overgrowth malformation syndrome that maps to human chromosome 11p15.5, a region that harbours a number of imprinted genes. We studied the methylation status of H19 and KCNQ1OT1 (LIT1/KvDMR1) in a large series of BWS patients. Different patient groups were identified: group I patients (20%) with uniparental disomy and hence aberrant methylation of H19 and KCNQ1OT1; group II patients (7%) with a BWS imprinting centre 1 (BWSIC1) defect causing aberrant methylation of H19 only; group III patients (55%) with a BWS imprinting centre 2 (BWSIC2) defect causing aberrant methylation of KCNQ1OT1 only; and group IV patients (18%) with normal methylation patterns for both H19 and KCNQ1OT1. BWS patients have an increased risk of developing childhood tumours. In our patient group, out of 31 patients (group III) with KCNQ1OT1 demethylation only, none developed a tumour. However, tumours were found in 33% of patients with H19 hypermethylation (group I and II) and in 20% of patients with no detectable genetic defect (group IV). All four familial cases of BWS showed reduced methylation of KCNQ1OT1, suggesting that in these cases the imprinting switch mechanism is disturbed.

Xin Z, Soejima H, Higashimoto K, et al.
A novel imprinted gene, KCNQ1DN, within the WT2 critical region of human chromosome 11p15.5 and its reduced expression in Wilms' tumors.
J Biochem. 2000; 128(5):847-53 [PubMed] Related Publications
WT2 is defined by a maternal-specific loss of heterozygosity on human chromosome 11p15.5 in Wilms' and other embryonal tumors. Therefore, the imprinted genes in this region are candidates for involvement in Wilms' tumorigenesis. We now report a novel imprinted gene, KCNQ1DN (KCNQ1 downstream neighbor). This gene is located between p57(KIP2) and KvLQT1 (KCNQ1) of 11p15.5 within the WT2 critical region. KCNQ1DN is imprinted and expressed from the maternal allele. We examined the expression of KCNQ1DN in Wilms' tumors. Seven of eighteen (39%) samples showed no expression. In contrast, other maternal imprinted genes in this region, including p57(KIP2), IMPT1, and IPL exhibited almost normal expression in these samples, although some samples expressed IGF2 biallelically. These results suggest that KCNQ1DN existing far from the H19/IGF2 region may play some role in Wilms' tumorigenesis along with IGF2.

Prawitt D, Enklaar T, Klemm G, et al.
Identification and characterization of MTR1, a novel gene with homology to melastatin (MLSN1) and the trp gene family located in the BWS-WT2 critical region on chromosome 11p15.5 and showing allele-specific expression.
Hum Mol Genet. 2000; 9(2):203-16 [PubMed] Related Publications
Alterations within human chromosomal region 11p15.5 are associated with the Beckwith-Wiedemann syndrome (BWS) and predisposition to a variety of neoplasias, including Wilms' tumors (WTs), rhabdoid tumors and rhabdomyosarcomas. To identify candidate genes for 11p15. 5-related diseases we compared human genomic sequence with expressed sequence tag and protein databases from different organisms to discover evolutionarily conserved sequences. Herein we describe the identification and characterization of a novel human transcript related to a putative Caenorhabditis elegans protein and the trp (transient receptor potential) gene. The highest homologies are observed with the human TRPC7 and with melastatin 1 ( MLSN1 ), whose transcript is downregulated in metastatic melanomas. Other genes related to and interacting with the trp family include the Grc gene, which codes for a growth factor-regulated channel protein, and PKD1/PKD2, involved in polycystic kidney disease. The novel gene presented here (named MTR1 for MLSN1 - and TRP -related gene 1) resides between TSSC4 and KvLQT1. MTR1 is expressed as a 4.5 kb transcript in a variety of fetal and adult tissues. The putative open reading frame is encoded in 24 exons, one of which is alternatively spliced leading to two possible proteins of 872 or 1165 amino acids with several predicted membrane-spanning domains in both versions. MTR1 transcripts are present in a large proportion of WTs and rhabdomyosarcomas. RT-PCR analysis of somatic cell hybrids harboring a single human chromosome 11 demonstrated exclusive expression of MTR1 in cell lines carrying a paternal chromosome 11, indicating allele-specific inactivation of the maternal copy by genomic imprinting.

Dao D, Walsh CP, Yuan L, et al.
Multipoint analysis of human chromosome 11p15/mouse distal chromosome 7: inclusion of H19/IGF2 in the minimal WT2 region, gene specificity of H19 silencing in Wilms' tumorigenesis and methylation hyper-dependence of H19 imprinting.
Hum Mol Genet. 1999; 8(7):1337-52 [PubMed] Related Publications
WT2 is defined by maternal-specific loss of heterozygosity (LOH) on chromosome 11p15.5 in Wilms' tumors (WTs). The imprinted H19 gene, in this region, is silenced and hypermethylated in most WTs, and this is linked to pathological biallelic expression of IGF2. However, H19 and IGF2 lie within a larger imprinted domain, and the gene specificity of H19 epimutation has been a persistent question. To address this, we assessed LOH, gene expression and DNA methylation at multiple sites in and around the imprinted domain. LOH mapping showed that the entire domain, including IGF2/H19, is within the minimal WT2 region. Genes within the domain, including IPL/TSSC3/BWR1C, IMPT1/ORCTL2/BWR1A/TSSC5, KvLQT1/KCNA9 and TAPA1/CD81, as well as the zinc finger gene ZNF195/ZNFP104 near the centromeric border, were expressed persistently in many WTs. DNA hypermethylation was not detected with 5" upstream probes for IPL, IMPT1, KvLQT1 and ZNF195 in WTs or WT-associated kidneys. Fully developed WTs showed variable hypomethylation at an imprinted CpG island in a KvLQT1 intron, but this was only complete in the cases with LOH and was not observed in pre-neoplastic WT-associated kidneys with H19 epimutation. Analysis of the corresponding region of mouse chromosome 7 using methyltransferase-hypomorphic mice showed that the H19 imprint was fully erased, but that the allelic bias at Ipl, Impt1, p57 Kip2 and, to a lesser extent, Kvlqt1, persisted. Pre-existing massive allelic asymmetry for DNA methylation and hyper-dependence of transcription on methylation status may underlie the mechanism of gene-specific silencing of H19 in Wilms' tumorigenesis.

Mitsuya K, Meguro M, Lee MP, et al.
LIT1, an imprinted antisense RNA in the human KvLQT1 locus identified by screening for differentially expressed transcripts using monochromosomal hybrids.
Hum Mol Genet. 1999; 8(7):1209-17 [PubMed] Related Publications
Mammalian imprinted genes are frequently arranged in clusters on particular chromosomes. The imprinting cluster on human chromosome 11p15 is associated with Beckwith-Wiedemann syndrome (BWS) and a variety of human cancers. To clarify the genomic organization of the imprinted cluster, an extensive screen for differentially expressed transcripts in the 11p15 region was performed using monochromosomal hybrids with a paternal or maternal human chromosome 11. Here we describe an imprinted antisense transcript identified within the KvLQT1 locus, which is associated with multiple balanced chromosomal rearrangements in BWS and an additional breakpoint in embryonal rhabdoid tumors. The transcript, called LIT1 (long QT intronic transcript 1), was expressed preferentially from the paternal allele and produced in most human tissues. Methylation analysis revealed that an intronic CpG island was specifically methylated on the silent maternal allele and that four of 13 BWS patients showed complete loss of maternal methylation at the CpG island, suggesting that antisense regulation is involved in the development of human disease. In addition, we found that eight of eight Wilms' tumors exhibited normal imprinting of LIT1 and five of five tumors displayed normal differential methylation at the intronic CpG island. This contrasts with five of six tumors showing loss of imprinting of IGF2. We conclude that the imprinted gene domain at the KvLQT1 locus is discordantly regulated in cancer from the imprinted domain at the IGF2 locus. Thus, this positional approach using human monochromosomal hybrids could contribute to the efficient identification of imprinted loci in humans.

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