This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Falls, J. G. Articles by Jirtle, R. L. Search for Related Content PubMed PubMed Citation Articles by Falls, J. G. Articles by Jirtle, R. L.

(American Journal of Pathology. 1999;154:635-647.)
© 1999 American Society for Investigative Pathology

Review

Genomic Imprinting: Implications for Human Disease

J. Greg Falls* , David J. Pulford* , Andrew A. Wylie* and Randy L. Jirtle*

From the Department of Radiation Oncology,* Duke University Medical Center, Durham, North Carolina, and Department of Safety of Medicines, Zeneca Pharmaceuticals, Ltd., Cheshire, United Kingdom

	Abstract

Top Abstract Introduction Background Imprinting of Specific Genes Characteristics of Imprinted... Imprinting in Genetic Diseases Imprinting in Brain and... Imprinting in Human Cancer References

 
Genomic imprinting refers to an epigenetic marking of genes that results in monoallelic expression. This parent-of-origin dependent phenomenon is a notable exception to the laws of Mendelian genetics. Imprinted genes are intricately involved in fetal and behavioral development. Consequently, abnormal expression of these genes results in numerous human genetic disorders including carcinogenesis. This paper reviews genomic imprinting and its role in human disease. Additional information about imprinted genes can be found on the Genomic Imprinting Website at http://www.geneimprint.com.

	Introduction

Top Abstract Introduction Background Imprinting of Specific Genes Characteristics of Imprinted... Imprinting in Genetic Diseases Imprinting in Brain and... Imprinting in Human Cancer References

View larger version (28K): [in this window] [in a new window]   Figure 1. Imprint establishment and propagation during gametogenesis and development. The paternal allele (dashed line) is imprinted and the maternal allele is expressed (solid line). The "imprint mark" (black box) represents a parental-specific methylation established during gametogenesis. A: The maternal and paternal genomes have different imprint patterns following fertilization. B: Both "imprint marks" and imprint reading are maintained during somatic cell division. C: The parental specific imprints are erased in the primordial germ cells. D: The appropriate "imprint marks" are reestablished for the next generation.

View larger version (20K): [in this window] [in a new window]   Figure 2. Total number of papers published on genomic imprinting versus time.

	Background

Top Abstract Introduction Background Imprinting of Specific Genes Characteristics of Imprinted... Imprinting in Genetic Diseases Imprinting in Brain and... Imprinting in Human Cancer References

Experimental evidence for the requirement of both the maternal and paternal chromosomal complements was demonstrated through the manipulation of mouse embryos.^9,10 Mouse embryos were altered in vitro to produce diploid Ag or diploid parthenogenetic (Pg) embryos, possessing only paternal or maternal chromosomes, respectively. Similarities to the human pregnancy aberrations were apparent since Ag mouse embryos had reduced fetal growth and proliferative extraembryonic growth while Pg embryos maintained relatively normal fetal growth but exhibited poor extraembryonic growth. Neither Ag nor Pg embryos were viable to term.^9,10 This demonstrates that genes expressed exclusively from one parental genome exist, and abnormal embryonic development results from the loss of function of these monoallelically expressed genes. A mark or imprint conferring parental memory must therefore differentiate between the parental genomes, be present on the parental chromosomes through cell division, and be inheritable. This was confirmed when nuclei from early haploid preimplantation embryos were transplanted into fertilized eggs following the removal of one pronucleus. The embryo was viable only if the sex of the donor nucleus was opposite that of the remaining pronucleus.¹¹

The chromosomal regions responsible for the genomic imprinting effects observed in mouse embryos were mapped to specific mouse chromosomes by artificially generating uniparental disomies (UPD) in mice. Certain regions of distinct chromosomes were responsible for markedly different phenotypes ranging from embryonic lethality to various growth and developmental defects apparent only after birth. These effects were dependent on whether the two copies were inherited entirely from one parent, resulting in either duplication or deficiency of genes in these chromosomal regions.^12-14 It was initially postulated that only mouse chromosomes 2, 6, 7, 11, 12, and 17 harbored imprinted chromosomal regions.¹⁵ However, there are now reports of other chromosomes either containing more localized areas of genomic imprinting or harboring genes that show more subtle imprinted effects.

UPD also results in phenotypic abnormalities in humans. These include maternal UPD for chromosomes 2, 7, 14, 15, and 16, and paternal UPD for chromosomes 6, 11, 14, 15, and 20.¹⁶ Classic examples of diseases associated with regional maternal and paternal UPD on chromosome 15 include the Prader-Willi syndrome and Angelman syndrome, respectively. Investigations of these genetic diseases are now helping to elucidate the mechanisms of genomic imprinting in humans.

	Imprinting of Specific Genes

Top Abstract Introduction Background Imprinting of Specific Genes Characteristics of Imprinted... Imprinting in Genetic Diseases Imprinting in Brain and... Imprinting in Human Cancer References

 
The first endogenous imprinted gene identified was mouse insulin-like growth factor 2 (Igf2), which encodes for a critical fetal-specific growth factor. A targeted mutation in Igf2 gave rise to a heterozygous dwarfing phenotype when the mutation was passed from the father while the offspring were normal when the mutation was inherited from the mother.¹⁷ Furthermore, the dwarfing phenotype was observed in paternal heterozygotes and homozygotes suggesting that Igf2 gene expression is exclusively from the paternal allele. At about the same time, the mannose 6-phosphate/insulin-like growth factor type 2 receptor (M6p/Igf2r) gene was shown to be imprinted and maternally expressed in mice.¹⁸ Interestingly, the products of these oppositely imprinted genes interact at the biochemical level since the degradation of Igf2 occurs via the M6p/Igf2r.¹⁹ When a mutation was targeted to the M6p/Igf2r in mice, maternal heterozygotes or homozygotes showed a 30% increase in fetal growth, but they were not viable at birth.²⁰ Thus, the reciprocally imprinted Igf2 and M6p/Igf2r genes both play an important role in regulating embryonic development and fetal growth.^17,20

Numerous techniques have now been used to identify additional imprinted genes. Positional cloning coupled with candidate gene testing has identified novel human imprinted genes located in imprinted clusters at chromosome positions 11p15.5 and 15q11-q13. Techniques have also used parental differences in DNA methylation and expression to identify imprinted genes. Subtractive hybridization or differential display using cDNA from Pg, Ag, and fertilized embryos have yielded novel imprinted genes such as Peg1/Mest, a mesoderm restricted hydrolase at mouse chromosome 6; Peg3, a novel zinc-finger protein on proximal mouse chromosome 7; and Peg5/Nnat located on mouse chromosome 2.^21-23 The Grf1 and U2afl-rs1 imprinted genes were identified by a genome-wide screen termed restriction landmark genome screening (RLGS).^24,25 Finally, three GABAA receptor subunit genes (GABRB3, GABRA5, and GABRG3) were shown to be exclusively expressed from the paternal allele by microcell-mediated chromosome transfer.²⁶ More recently, results from a somatic-cell hybrid system indicated that these receptor subunit genes were not imprinted.²⁷

	Characteristics of Imprinted Genes

Top Abstract Introduction Background Imprinting of Specific Genes Characteristics of Imprinted... Imprinting in Genetic Diseases Imprinting in Brain and... Imprinting in Human Cancer References

 
Several theories have been proposed for the endogenous function of genomic imprinting. Moore and Haig²⁸ have suggested that genomic imprinting in mammals has evolved from a conflict of interest between the paternal and maternal genome in regulating fetal growth. Whereas benefits of a large placenta and fetus might ensure future propagation of a paternal line, the result may tax the resources of the mother, thereby compromising future pregnancies. Conversely, if fetal and placental growth is held in check, more offspring from the mother's (and possibly different father's) lineage may be produced. Accordingly, the mother would be predicted to imprint or silence genes that promote placental and fetal growth, whereas the father would imprint genes that inhibit growth.

In support of this theory, the gene encoding the fetal growth factor, Igf2, is maternally imprinted, whereas H19, which encodes for an untranslated RNA involved in silencing Igf2 expression, is paternally imprinted.^17,29,30 The result of this reciprocal imprinting is parent-of-origin, monoallelic paternal expression of the gene encoding for Igf2. Interestingly, the genes that encode for the M6p/Igf2r which degrades Igf2, and Meg1/Grb10 which inhibits Igf2 signaling are both paternally imprinted, adding further support for this theory.^18,19,31

An alternative proposal for imprinting suggests that the cytosine methylation involved in imprint regulation evolved as a defense mechanism for the inactivation of parasitic sequences such as transposable elements and proviral DNA.³² This is supported by the finding that 5-aza-deoxycytidine, an inhibitor of cytosine DNA methyltransferase, activates silent retroviruses.³³ Irrespective of the reason for the evolution of genomic imprinting in mammals, the functional consequences of genomic imprinting include the inhibition of parthenogenesis and the loss of protection from deleterious recessive mutations.

As more imprinted genes are identified, the characteristics of imprinting are becoming apparent. For example, two chromosomal regions harbor more than one imprinted gene. These imprinting clusters reside at human chromosome 11p15.5 (syntenic to the distal region of mouse chromosome 7) and human chromosome 15q11-q13 (syntenic to the central region of mouse chromosome 7). Within these imprinted gene clusters, genes have been identified that encode for untranslated RNA^34,35 and antisense RNA^36,37 that may be involved in imprint control. Some imprinted genes, such as H19 and IGF2, that are located in imprinted clusters show coordinate regulation. Imprinted genes also often reside in chromosomal regions that undergo asynchronous replication,^38,39 and the meiotic recombination frequencies in these regions may differ between the male and female germ cells.⁴⁰ Another characteristic of imprinted genes is an associated allele-specific DNA methylation of cytosine residues in CpG dinucleotides that appears to distinguish the parental alleles.^41-43 Repetitive elements associated with the areas of differential methylation have also been identified in several imprinted genes (ie, H19, M6p/Igf2r, U2afbp-rs, and p57^KIP2).^44-48

	Imprinting in Genetic Diseases

Top Abstract Introduction Background Imprinting of Specific Genes Characteristics of Imprinted... Imprinting in Genetic Diseases Imprinting in Brain and... Imprinting in Human Cancer References

 
Beckwith-Wiedemann Syndrome

There are a number of human genetic diseases associated with imprinting defects (reviewed in ^{49 and 50} ). Beckwith-Wiedemann syndrome (BWS) maps to 11p15 and is characterized by general overgrowth with symptoms including hemihypertrophy, macroglossia, and visceromegaly. Genomic imprinting in BWS was first suspected when preferential maternal transmission of mutations was observed in some BWS families.⁵¹ Additionally, approximately 10–20% of BWS individuals are predisposed to embryonal tumors, the most frequent of which are Wilms' tumors and adenocortical carcinoma.⁵² The rate of Wilms' tumor formation in the BWS population is 1000-fold higher than in the normal population, and these tumors often show preferential loss of maternal 11p15.⁵³ The majority of BWS cases arise sporadically; however, in both sporadic and familial forms, a small percentage exhibits UPD at chromosome 11p15. In these cases, the remainder of the chromosome is biparental in inheritance, indicative of somatic mosaicism through a postfertilization mitotic recombination event.^54,55

The most common molecular event occurring in BWS patients that do not have cytogenetic abnormalities is the biallelic expression of IGF2 due to loss of imprinting (LOI).^56,57 LOI at the IGF2 locus may be accompanied by the methylation and/or silencing of the active maternal allele of H19.^58,59 This H19-dependent event is consistent with an enhancer-competition model for the co-regulation of these genes.⁶⁰

Translocations in BWS patients may also lead to LOI at the IGF2 locus, but without loss of H19 imprinting.⁶¹ These translocations affect imprinting by disrupting a gene involved in imprint control, or by altering the function of an imprinting center (IC). Therefore, disruption of IGF2 imprinting in BWS may also occur via an H19-independent event.^56,57 The imprinted KvLQT1 gene located centromeric to IGF2 spans a common breakpoint region in BWS, and has been proposed to maintain regional imprint control at 11p15.5.⁶⁰ KvLQT1 shows preferential expression from the maternal allele in most tissues examined except the heart where it is biallelically expressed.⁶² This explains why KvLQT1, responsible for the autosomal dominant cardiac arrhythmia long QT syndrome, shows no parent-of-origin effect in this disorder. The maternally expressed p57^KIP2, which encodes for a cyclin-dependent kinase inhibitor, also maps to 11p15.5. Abnormal imprinting and epigenetic silencing of p57^KIP2 is found in some individuals with BWS,⁶³ and mutations are present in about 5% of BWS patients.^64-66

To date, ten imprinted genes have been mapped to 11p15.5 (Table 1) . Flanking these imprinted genes are the non-imprinted NAP2 (centromeric border) and L23MRP (telomeric border) genes.⁶⁷ The syntenic region in the mouse, distal chromosome 7, confirms the existence of an imprinting cluster at this chromosomal location.⁶⁸ A possible explanation for the involvement of multiple genes in BWS (even if IGF2 overexpression is directly responsible for BWS) is that one or more of the adjacent genes (eg, H19, p57^KIP2, KvLQT1) are involved in the regulation of IGF2 expression. Experimental evidence supports this postulate since transgenic mice that overexpress Igf2 develop symptoms similar to BWS.⁶⁹

Prader-Willi and Angelman Syndromes

Two clinically distinct genetic diseases associated with genomic imprinting on chromosome 15q11-q13 are the Prader-Willi syndrome (PWS) and the Angelman syndrome (AS). Each syndrome is associated with deficiencies in sexual development and growth, and behavioral and mental problems including retardation.^70,71 Major diagnostic criteria for PWS patients include hypotonia, hyperphagia and obesity, hypogonadism and developmental delay.⁷² AS patients often display ataxia, tremulousness, sleep disorders, seizures, and hyperactivity. Severe mental retardation accompanied with a lack of speech may also be present, but AS individuals often display a happy disposition with outbreaks of laughter.⁷³

PWS and AS are autosomal dominant disorders showing parent-of-origin effects since the inherited diseases are transmitted from only one of the parents. Approximately 70% of PWS and AS individuals have a de novo 3- to 4-megabase deletion in their paternal or maternal chromosome 15q11-q13, respectively. Maternal UPD occurs in most of the remaining PWS patients (25%); however, paternal UPD only occurs in about 4% of AS patients.^16,74 The preferential loss of parental alleles associated with different phenotypes, coupled with the instances of UPD indicate the involvement of imprinted genes (ie, paternally expressed gene(s) for PWS and maternally expressed gene(s) for AS).⁷⁰ Recently, approximately 20% of the AS patients without a chromosomal deletion were found to have truncating mutations in UBE3A, a gene encoding a ubiquitin protein ligase involved in protein turnover.^75,76 UBE3A, mapped to 15q11-q13, has now been reported to be maternally expressed in the human brain.^77,78 Thus, abnormalities in the maternal-specific expression of UBE3A during brain development has been proposed for AS.⁷⁹ This region also harbors four imprinted, paternally expressed candidate PWS genes: small nuclear riboprotein-associated polypeptide N (SNRPN), Imprinted in Prader-Willi (IPW), zinc finger 127 (ZNF127), and necdin (NDN).^35,80-82 The imprinted, paternally expressed transcripts of PAR1, PAR5, and PAR-SN may also be involved in PWS.

Imprinting defects resulting from microdeletions targeted to the SNRPN gene have been identified in a small percentage of PWS patients that maintain both parental complements of 15q11-q13.^80,83,84 These deletions alter SNRPN promoter methylation and prevent expression of its paternal allele. This results in the silencing of other paternally expressed genes in the cluster.^83,85 These microdeletions apparently disrupt an imprinting center⁸⁵ involved in resetting the correct imprinting pattern during gametogenesis.^84,85 The alternate use of SNRPN transcripts (BD exons) may be involved in the normal imprinting process.⁸⁶ Offspring inheriting microdeletions from their mother exhibit no apparent phenotype; however, a subsequent paternal transmission results in PWS. In comparison, a small percentage of AS patients have similar microdeletions in the SNRPN gene (albeit in a region farther upstream) that disrupt the resetting of the imprinting pattern. In this case, progeny inheriting paternal microdeletions do not develop AS, but maternal transmission to offspring results in AS. These PWS and AS microdeletion results support the IC hypothesis, but a bipartite structure must be present since the minimally deleted regions responsible for PWS and AS are distinct.⁸⁷ An alternate mechanism for imprinting maintenance in this region relies on an enhancer-competition model between cis-linked genes;^4,88 however, methylation analysis of the PWS/AS region reported by Schumacher et al⁸⁹ does not support this.

	Imprinting in Brain and Behavior Development

Top Abstract Introduction Background Imprinting of Specific Genes Characteristics of Imprinted... Imprinting in Genetic Diseases Imprinting in Brain and... Imprinting in Human Cancer References

 
The paternally expressed human MEST gene maps to 7q32, a region where maternal UPD is associated with intrauterine and postnatal growth retardation.^21,90 Recently, a targeted deletion was introduced into the coding sequence of the mouse Mest gene to determine its function.⁹¹ When the deletion was paternally derived, Mest +/- mice were viable and fertile; however, they exhibited growth retardation and increased lethality. Mest-/+ animals (deletion maternally derived) showed none of these effects indicating that the phenotypic consequences of this mutation are detected only through paternal inheritance. Interestingly, Lefebvre et al⁹¹ found decreased reproductive fitness in the females that inherited the targeted disruption from their father. This effect was not based on the genotype of the progeny, but rather was due to an abnormal nurturing behavior of the mutant parturient females. Aberrant behavior of the mothers included failure to ingest the extraembryonic tissues (a normal behavior in most mammals), reduced rate of nest building, and pup neglecting. When the pups were fostered to wild-type females, no phenotypic differences between wild-type pups and Mest-/+ pups were apparent.

The results of this study demonstrate that the paternally expressed Mest is a positive regulator of embryonic growth, and is involved in the regulation of mammalian behavior associated with the rearing of offspring. These findings are consistent with the hypothesis that the imprinting of genes arises from the conflict of interest of the parental genomes in mammals,²⁸ and supports the importance of imprinted genes in brain development. Previous results using Pg and Ag mouse embryos suggested that both maternally and paternally derived genes contribute to the growth and function of specific brain regions in a complementary fashion.⁹² Keverne et al⁹³ found that Ag cells primarily contributed to hypothalamic composition, whereas Pg cells localized to the cortex, striatum, and hippocampus, but not to the hypothalamus. Brain growth was enhanced by Pg cells and retarded by Ag cells, further supporting the postulate that genomic imprinting is critically involved in mammalian brain development.

Evidence for imprinting effects in human diseases associated with mental abnormalities includes the aforementioned Prader-Willi and Angelman syndromes. There is now also evidence of cognitive imprinting effects in humans displaying normal intelligence. Skuse et al⁹⁴ recently reported that an imprinted X-linked locus is potentially responsible for differences in cognitive function of females with Turner's syndrome. Although normal females (46,XX) inherit an X chromosome from both their mother and father, only one X chromosome is inactivated. Turner's syndrome is a sporadic disorder resulting when all or part of one X chromosome is deleted in females. These females display normal intelligence, but overall have a higher incidence of social difficulties.^95,96 Turner syndrome women who inherit the X chromosome from their mother (45,Xm) generally exhibit more behavioral difficulties than those inheriting the X chromosome from their father (45,Xp). This finding provides the first evidence of genomic imprinting on the human X chromosome.⁹⁴ Based on cytogenetic analysis of these patients, partial deletions of the short arm of the paternally derived X chromosome were found. This suggests that the putative imprinted locus escapes X-inactivation and potentially lies in Xp11.23-Xqter. Interestingly, Miller and Willard⁹⁷ have recently identified a 5.5 megabase region on the human Xp11.21-p11.22 that contains eight expressed sequences which escape X inactivation. However, an imprinted gene(s) in this region is yet to be identified.

Parent-of-origin effects involved in other behavioral and brain disorders have also been reported. Included among these are bipolar affective disorder,^98-100 schizophrenia,^101,102 and autism.¹⁰³ However, the involvement of genomic imprinting in these examples remains to be elucidated. For an extensive summary of parent-of-origin effects in human disease, consult Morison and Reeve.¹⁰⁴

	Imprinting in Human Cancer

Top Abstract Introduction Background Imprinting of Specific Genes Characteristics of Imprinted... Imprinting in Genetic Diseases Imprinting in Brain and... Imprinting in Human Cancer References

 
There are numerous reports of tumors showing a bias in allelic loss. On a genome-wide scale, the complete hydatidiform mole and benign ovarian dermoid cyst arise from cells that are completely Ag or Pg in origin, respectively.^105,106 In addition, numerous tumors are associated with the preferential loss of a particular parental chromosome, indicating the involvement of imprinted genes. Examples include neuroblastoma (maternal chromosome 1p36 and paternal chromosome 2),¹⁰⁷ acute myeloblastic leukemia (paternal chromosome 7),¹⁰⁸ Wilms' tumor (maternal chromosome 11p15.5),¹⁰⁹ rhabdomyosarcoma (maternal chromosome 11p15.5),¹¹⁰ and sporadic osteosarcoma (maternal chromosome 13).¹¹¹ A role for genomic imprinting has also been implicated in the development of familial glomus tumors based on inheritance patterns since tumor susceptibility is inherited paternally.¹¹²

Imprinted genes can be involved in carcinogenesis in several ways (Figure 3) . Loss of heterozygosity or UPD at an imprinted region may result in the deletion of the only functional copy of a tumor suppressor gene. Alternatively, LOI or UPD of an imprinted gene that promoted cell growth may allow gene expression to be inappropriately increased. Finally, mutational inactivation of an IC might result in the aberrant expression of multiple imprinted oncogenes and/or tumor suppressor genes present in an imprinted chromosomal region.

View larger version (50K): [in this window] [in a new window]   Figure 3. A: Only one allele of a tumor suppressor gene (T) is expressed because of genomic imprinting (TX). Loss of heterozygosity (LOH) of the expressed allele or an inactivating mutation in the expressed allele (TM) results in loss of tumor suppressor function. B: Only one allele of the proto-oncogene (P) is expressed because of genomic imprinting (PX). Loss of imprinting (LOI) or uniparental disomy (UPD) results in biallelic expression of the proto-oncogene.

Recent reports demonstrate that the M6P/IGF2R at 6q26 is inactivated in a variety of tumors at the earliest stage of transformation.^126-128 The M6P/IGF2R plays an integral part in the intracellular sorting of lysosomal enzymes, the activation of the growth inhibitor transforming growth factor-ß1 (TGF-ß1), and the degradation of IGF2, but it is not directly involved in cell signaling.^19,130 The M6P/IGF2R is mutated in 60% of dysplastic liver lesions and hepatocellular carcinomas of patients with or without hepatitis virus infection.^125,126,128 The M6P/IGF2R is also mutated in 30% of breast tumors,¹²⁷ and the gene contains a polyG region that is a common mutational target in colon, gastric and endometrial tumors with mismatch repair deficiencies and microsatellite instability.^128,131,132 Moreover, it has recently been reported that the M6P/IGF2R is mutated in human glioma samples that do not contain mutations in the transforming growth factor-ß type II receptor (TGFBRII) or Bax genes.¹³³ In both breast^127,134 and liver carcinogenesis,¹²⁸ the allelic inactivation of M6P/IGF2R occurs as an early event, during the initiation rather than the progression stage of transformation.

Although imprinting among individuals and mammalian species is generally conserved, the imprint status of M6P/IGF2R in humans and rodents is strikingly different. The M6p/Igf2r is imprinted in mice¹⁸ and rats,¹³⁵ but imprinting at this locus appears to be a polymorphic trait in humans, with most individuals having biallelic expression.^136-138 The existence of individuals with an imprinted M6P/IGF2R tumor suppressor suggests that they may have increased susceptibility to tumor development because of aberrant imprint control. This postulate is supported by Xu et al¹³⁹ who recently reported partial imprinting of M6P/IGF2R in 50% of Wilms' tumor patients.

The precise molecular mechanism for genomic imprinting of M6P/IGF2R is not completely defined. Methylation of a CpG rich region in intron 2 (Region 2) of the expressed maternal allele has been shown to carry the imprint signal for this gene in mice.^46,140 Birger et al¹⁴¹ have identified a 113-bp sequence, in region 2 of the mouse M6p/Igf2r gene, that serves as a methylation imprinting box responsible for the establishment of differential methylation. Furthermore, this region appears to function as the promoter of an antisense transcript that originates only from the repressed paternal allele. This indicates that a form of expression competition regulates imprinting of the M6p/Igf2r gene in mice.¹⁴⁰ Region 2 of the human M6P/IGF2R also contains parent-of-origin methylation, but gene expression is biallelic.^142,143 Consequently, humans and mice appear to possess an altered ability to read the M6P/IGF2R imprint marks.

Functional polymorphic imprinting has also been observed for human genes encoding IGF2,¹⁴⁴WT1,¹²⁰ and the human 5-HT2A receptor gene HTR2A.¹⁴⁵ Recently, the mouse Kvlqt1 gene has been shown to undergo developmental relaxation of imprinting in a strain-dependent fashion.¹⁴⁶ Whether polymorphic genomic imprinting occurs in other genes, and functions in determining individual and/or species differences in susceptibility to diseases remains to be determined.

	Footnotes

 
Address reprint requests to Randy L. Jirtle, Box 3433, Duke University Medical Center, Durham, NC 27710. E-mail: jirtle{at}radonc.duke.edu

Supported by National Institutes of Health grants CA25951 and ES08823, Department of Defense Grant DAMD17-98-1-8305 (to J.G.F. and R.L.J.), and Zeneca Pharmaceuticals (to D.J.P. and A.A.W).

Accepted for publication January 6, 1999.

	References

Top Abstract Introduction Background Imprinting of Specific Genes Characteristics of Imprinted... Imprinting in Genetic Diseases Imprinting in Brain and... Imprinting in Human Cancer References

 

1. Barlow DP: Gametic imprinting in mammals. Science 1995, 270:1610-1613[Abstract/Free Full Text]
2. Reik W, Walter J: Imprinting mechanisms in mammals. Curr Opin Genet Dev 1998, 8:154-164[Medline]
3. Constancia M, Pickard B, Kelsey G, Reik W: Imprinting mechanisms. Genome Res 1998, 8:881-900[Abstract/Free Full Text]
4. Barlow DP: Competition—a common motif for the imprinting mechanism? EMBO J 1997, 16:6899-6905[Medline]
5. Lindor NM, Ney JA, Gaffey TA, Jenkins RB, Thibodeau SN, Dewald GW: A genetic review of complete and partial hydatidiform moles and nonmolar triploidy. Mayo Clin Proc 1992, 67:791-799[Medline]
6. Kajii T, Ohama K: Androgenetic origin of hydatidiform mole. Nature 1977, 268:633-634[Medline]
7. Ohama K, Kajii T, Okamoto E, Fukuda Y, Imaizumi K, Tsukahara M, Kobayashi K, Hagiwara K: Dispermic origin of XY hydatidiform moles. Nature 1981, 292:551-552[Medline]
8. Ohama K, Nomura K, Okamoto E, Fukuda Y, Ihara T, Fujiwara A: Origin of immature teratoma of the ovary. Am J Obstet Gynecol 1985, 152:896-900[Medline]
9. McGrath J, Solter D: Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell 1984, 37:179-183[Medline]
10. Surani MA, Barton SC, Norris ML: Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature 1984, 308:548-550[Medline]
11. Surani MA, Reik W, Norris ML, Barton SC: Influence of germline modifications of homologous chromosomes on mouse development. J Embryol Exp Morphol 1986, 97(Suppl):123-136
12. Cattanach BM, Kirk M: Differential activity of maternally and paternally derived chromosome regions in mice. Nature 1985, 315:496-498[Medline]
13. Searle AG, Beechey CV: Complementation studies with mouse translocations. Cytogenet Cell Genet 1978, 20:282-303[Medline]
14. Searle AG, Beechey CV: Genome imprinting phenomena on mouse chromosome 7. Genet Res 1990, 56:237-244[Medline]
15. Cattanach BM, Jones J: Genetic imprinting in the mouse: implications for gene regulation. J Inherit Metab Dis 1994, 17:403-420[Medline]
16. Ledbetter DH, Engel E: Uniparental disomy in humans: development of an imprinting map and its implications for prenatal diagnosis. Hum Mol Genet 1995, 4:1757-1764[Abstract]
17. DeChiara TM, Robertson EJ, Efstratiadis A: Parental imprinting of the mouse insulin-like growth factor II gene. Cell 1991, 64:849-859[Medline]
18. Barlow DP, Stöger R, Herrmann BG, Saito K, Schweifer N: The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus. Nature 1991, 349:84-87[Medline]
19. Kornfeld S: Structure and function of the mannose 6-phosphate/insulinlike growth factor II receptors. Annu Rev Biochem 1992, 61:307-330[Medline]
20. Wang ZQ, Fung MR, Barlow DP, Wagner EF: Regulation of embryonic growth and lysosomal targeting by the imprinted Igf2/Mpr gene. Nature 1994, 372:464-467[Medline]
21. Kaneko-Ishino T, Kuroiwa Y, Miyoshi N, Kohda T, Suzuki R, Yokoyama M, Viville S, Barton SC, Ishino F, Surani MA: Peg1/Mest imprinted gene on chromosome 6 identified by cDNA subtraction hybridization. Nat Genet 1995, 11:52-59[Medline]
22. Kuroiwa Y, Kaneko-Ishino T, Kagitani F, Kohda T, Li LL, Tada M, Suzuki R, Yokoyama M, Shiroishi T, Wakana S, Barton SC, Ishino F, Surani MA: Peg3 imprinted gene on proximal chromosome 7 encodes for a zinc finger protein. Nat Genet 1996, 12:186-190[Medline]
23. Kagitani F, Kuroiwa Y, Wakana S, Shiroishi T, Miyoshi N, Kobayashi S, Nishida M, Kohda T, Kaneko-Ishino T, Ishino F: Peg5/Neuronatin is an imprinted gene located on sub-distal chromosome 2 in the mouse. Nucleic Acids Res 1997, 25:3428-3432[Abstract/Free Full Text]
24. Plass C, Shibata H, Kalcheva I, Mullins L, Kotelevtseva N, Mullins J, Kato R, Sasaki H, Hirotsune S, Okazaki Y, Held WA, Hayashizaki Y, Chapman VM: Identification of Grf1 on mouse chromosome 9 as an imprinted gene by RLGS-M. Nat Genet 1996, 14:106-109[Medline]
25. Hatada I, Sugama T, Mukai T: A new imprinted gene cloned by a methylation-sensitive genome scanning method. Nucleic Acids Res 1993, 21:5577-5582[Abstract/Free Full Text]
26. Meguro M, Mitsuya K, Sui H, Shigenami K, Kugoh H, Nakao M, Oshimura M: Evidence for uniparental, paternal expression of the human GABAA receptor subunit genes, using microcell-mediated chromosome transfer. Hum Mol Genet 1997, 6:2127-2133[Abstract/Free Full Text]
27. Gabriel JM, Higgins MJ, Gebuhr TC, Shows TB, Saitoh S, Nicholls RD: A model system to study genomic imprinting of human genes. Proc Natl Acad Sci USA 1998, 95:14857-14862[Abstract/Free Full Text]
28. Moore T, Haig D: Genomic imprinting in mammalian development: a parental tug-of-war. Trends Genet 1991, 7:45-49[Medline]
29. DeChiara TM, Efstratiadis A, Robertson EJ: A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature 1990, 345:78-80[Medline]
30. Bartolomei MS, Zemel S, Tilghman SM: Parental imprinting of the mouse H19 gene. Nature 1991, 351:153-155[Medline]
31. Miyoshi N, Kuroiwa Y, Kohda T, Shitara H, Yonekawa H, Kawabe T, Hasegawa H, Barton SC, Surani MA, Kaneko-Ishino T, Ishino F: Identification of the Meg1/Grb10 imprinted gene on mouse proximal chromosome 11, a candidate for the Silver-Russell syndrome gene. Proc Natl Acad Sci USA 1998, 95:1102-1107[Abstract/Free Full Text]
32. Bestor TH, Tycko B: Creation of genomic methylation patterns. Nat Genet 1996, 12:363-367[Medline]
33. Jaenisch R, Schnieke A, Harbers K: Treatment of mice with 5-azacytidine efficiently activates silent retroviral genomes in different tissues. Proc Natl Acad Sci USA 1985, 82:1451-1455[Abstract/Free Full Text]
34. Zhang Y, Tycko B: Monoallelic expression of the human H19 gene. Nature Genet 1992, 1:40-44[Medline]
35. Wevrick R, Kerns JA, Francke U: Identification of a novel paternally expressed gene in the Prader-Willi syndrome region. Hum Mol Genet 1994, 3:1877-1882[Abstract/Free Full Text]
36. Moore T, Constancia M, Zubair M, Bailleul B, Feil R, Sasaki H, Reik W: Multiple imprinted sense and antisense transcripts, differential methylation and tandem repeats in a putative imprinting control region upstream of mouse Igf2. Proc Natl Acad Sci USA 1997, 94:12509-12514[Abstract/Free Full Text]
37. Wutz A, Smrzka OW, Barlow DP: Making sense of imprinting the mouse and human IGF2R loci. Novartis Found Symp 1998, 214:251-259[Medline]
38. Knoll JH, Cheng SD, Lalande M: Allele specificity of DNA replication timing in the Angelman/Prader-Willi syndrome imprinted chromosomal region. Nat Genet 1994, 6:41-46[Medline]
39. Kitsberg D, Selig S, Brandeis M, Simon I, Keshet I, Driscoll DJ, Nicholls RD, Cedar H: Allele-specific replication timing of imprinted gene regions. Nature 1993, 364:459-463[Medline]
40. Robinson WP, Lalande M: Sex-specific meiotic recombination in the Prader–Willi/Angelman syndrome imprinted region. Hum Mol Genet 1995, 4:801-806[Abstract/Free Full Text]
41. Laird PW, Jaenisch R: The role of DNA methylation in cancer genetics and epigenetics. Annu Rev Genet 1996, 30:441-464[Medline]
42. Tycko B: DNA methylation in genomic imprinting. Mutat Res 1997, 386:103-105[Medline]
43. Razin A, Cedar H: DNA methylation and genomic imprinting. Cell 1994, 77:473-476[Medline]
44. Bartolomei MS, Webber AL, Brunkow ME, Tilghman SM: Epigenetic mechanisms underlying the imprinting of the mouse H19 gene. Genes Dev 1993, 7:1663-1673[Abstract/Free Full Text]
45. Ferguson-Smith AC, Sasaki H, Cattanach BM, Surani MA: Parental-origin-specific epigenetic modification of the mouse H19 gene. Nature 1993, 362:751-755[Medline]
46. Stöger R, Kubicka P, Liu CG, Kafri T, Razin A, Cedar H, Barlow DP: Maternal-specific methylation of the imprinted mouse Igf2r locus identifies the expressed locus as carrying the imprinting signal. Cell 1993, 73:61-71[Medline]
47. Hatada I, Kitagawa K, Yamaoka T, Wang X, Arai Y, Hashido K, Ohishi S, Masuda J, Ogata J, Mukai T: Allele-specific methylation and expression of an imprinted U2af1-rs1 (SP2) gene. Nucleic Acids Res 1995, 23:36-41[Abstract/Free Full Text]
48. Hatada I, Mukai T: Genomic imprinting of p57^KIP2, cyclin-dependent kinase inhibitor, in mouse. Nat Genet 1995, 11:204-206[Medline]
49. Lalande M: Parental imprinting and human disease. Annu Rev Genet 1996, 30:173-195
50. Hall JG: Genomic imprinting: nature and clinical relevance. Annu Rev Med 1997, 48:35-44[Medline]
51. Viljoen D, Ramesar R: Evidence for paternal imprinting in familial Beckwith-Wiedemann syndrome. J Med Genet 1992, 29:221-225[Abstract]
52. Ward A: Beck-Wiedemann syndrome, and Wilms' tumour. Mol Hum Reprod 1997, 3:157-168[Abstract/Free Full Text]
53. Feinberg AP: Genomic Imprinting: The Genetic Basis of Human Cancer. Edited by Vogelstein B, Kinzler KW. New York, McGraw-Hill Health Professions Division, 1998, pp 95–107
54. Bischoff FZ, Feldman GL, McCaskill C, Subramanian S, Hughes MR, Shaffer LG: Single cell analysis demonstrating somatic mosaicism involving 11p in a patient with paternal isodisomy and Beckwith-Wiedemann syndrome. Hum Mol Genet 1995, 4:395-399[Abstract/Free Full Text]
55. Henry I, Puech A, Riesewijk A, Ahnine L, Mannens M, Beldjord C, Bitoun P, Tournade MF, Landrieu P, Junien C: Somatic mosaicism for partial paternal isodisomy in Wiedemann-Beckwith syndrome: a post-fertilization event. Eur J Hum Genet 1993, 1:19-29[Medline]
56. Weksberg R, Shen DR, Fei YL, Song QL, Squire J: Disruption of insulin-like growth factor 2 imprinting in Beckwith-Wiedemann syndrome. Nat Genet 1993, 5:143-150[Medline]
57. Joyce JA, Lam WK, Catchpoole DJ, Jenks P, Reik W, Maher ER, Schofield PN: Imprinting of IGF2 and H19: lack of reciprocity in sporadic Beckwith-Wiedemann syndrome. Hum Mol Genet 1997, 6:1543-1548[Abstract/Free Full Text]
58. Reik W, Brown KW, Schneid H, Le Bouc Y, Bickmore W, Maher ER: Imprinting mutations in the Beckwith-Wiedemann syndrome suggested by altered imprinting pattern in the IGF2–H19 domain. Hum Mol Genet 1995, 4:2379-2385[Abstract/Free Full Text]
59. Catchpoole D, Lam WW, Valler D, Temple IK, Joyce JA, Reik W, Schofield PN, Maher ER: Epigenetic modification and uniparental inheritance of H19 in Beckwith-Wiedemann syndrome. J Med Genet 1997, 34:353-359[Abstract]
60. Reik W, Maher ER: Imprinting in clusters: lessons from Beckwith-Wiedemann syndrome. Trends Genet 1997, 13:330-334[Medline]
61. Brown KW, Villar AJ, Bickmore W, Clayton-Smith J, Catchpoole D, Maher ER, Reik W: Imprinting mutation in the Beckwith-Wiedemann syndrome leads to biallelic IGF2 expression through an H19-independent pathway. Hum Mol Genet 1996, 5:2027-2032[Abstract/Free Full Text]
62. Lee MP, Hu RJ, Johnson LA, Feinberg AP: Human KVLQT1 gene shows tissue-specific imprinting, and encompasses Beckwith-Wiedemann syndrome chromosomal rearrangements. Nat Genet 1997, 15:181-185[Medline]
63. Thompson JS, Reese KJ, DeBaun MR, Perlman EJ, Feinberg AP: Reduced expression of the cyclin-dependent kinase inhibitor gene p57KIP2 in Wilms' tumor. Cancer Res 1996, 56:5723-5727[Abstract/Free Full Text]
64. Hatada I, Ohashi H, Fukushima Y, Kaneko Y, Inoue M, Komoto Y, Okada A, Ohishi S, Nabetani A, Morisaki H, Nakayama M, Niikawa N, Mukai T: An imprinted gene p57^KIP2 is mutated in Beckwith-Wiedemann syndrome. Nat Genet 1996, 14:171-173[Medline]
65. O'Keefe D, Dao D, Zhao L, Sanderson R, Warburton D, Weiss L, Anyane-Yeboa K, Tycko B: Coding mutations in p57KIP2 are present in some cases of Beckwith-Wiedemann syndrome but are rare or absent in Wilms' tumors. Am J Hum Genet 1997, 61:295-303[Medline]
66. Lee MP, DeBaun M, Randhawa G, Reichard BA, Elledge SJ, Feinberg AP: Low frequency of p57KIP2 mutation in Beckwith-Wiedemann syndrome. Am J Hum Genet 1997, 61:304-309[Medline]
67. Reid LH, Davies C, Cooper PR, Crider-Miller SJ, Sait SN, Nowak NJ, Evans G, Stanbridge EJ, deJong P, Shows TB, Weissman BE, Higgins MJ: A 1-Mb physical map, and PAC contig of the imprinted domain in 11p15.5 that contains TAPA1, and the BWSCR1/WT2 region. Genomics 1997, 43:366-375[Medline]
68. 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: Syntenic organization of the mouse distal chromosome 7 imprinting cluster and the Beckwith-Wiedemann syndrome region in chromosome 11p15.5. Hum Mol Genet 1998, 7:1149-1159[Abstract/Free Full Text]
69. Sun FL, Dean WL, Kelsey G, Allen ND, Reik W: Transactivation of Igf2 in a mouse model of Beckwith-Wiedemann syndrome. Nature 1997, 389:809-815[Medline]
70. Bartolomei MS, Tilghman SM: Genomic imprinting in mammals. Annu Rev Genet 1997, 31:493-525[Medline]
71. Nicholls RD, Saitoh S, Horsthemke B: Imprinting in Prader-Willi and Angelman syndromes. Trends Genet 1998, 14:194-200[Medline]
72. Holm VA, Cassidy SB, Butler MG, Hanchett JM, Greenswag LR, Whitman BY, Greenberg F: Prader-Willi syndrome: consensus diagnostic criteria. Pediatrics 1993, 91:398-402[Abstract/Free Full Text]
73. Williams CA, Angelman H, Clayton-Smith J, Driscoll DJ, Hendrickson JE, Knoll JH, Magenis RE, Schinzel A, Wagstaff J, Whidden EM, et al: Angelman syndrome: consensus for diagnostic criteria. Angelman Syndrome Foundation. Am J Med Genet 1995, 56:237-238[Medline]
74. Nicholls RD: Genomic imprinting and uniparental disomy in Angelman and Prader-Willi syndromes: a review. Am J Med Genet 1993, 46:16-25[Medline]
75. Matsuura T, Sutcliffe JS, Fang P, Galjaard RJ, Jiang YH, Benton CS, Rommens JM, Beaudet AL: De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat Genet 1997, 15:74-77[Medline]
76. Kishino T, Lalande M, Wagstaff J: UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet 1997, 15:70-73[Medline]
77. Rougeulle C, Glatt H, Lalande M: The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain. Nat Genet 1997, 17:14-15[Medline]
78. Vu TH, Hoffman AR: Imprinting of the Angelman syndrome gene, UBE3A, is restricted to brain. Nat Genet 1997, 17:12-13[Medline]
79. Albrecht U, Sutcliffe JS, Cattanach BM, Beechey CV, Armstrong D, Eichele G, Beaudet AL: Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. Nat Genet 1997, 17:75-78[Medline]
80. Glenn CC, Nicholls RD, Robinson WP, Saitoh S, Niikawa N, Schinzel A, Horsthemke B, Driscoll DJ: Modification of 15q11–q13 DNA methylation imprints in unique Angelman and Prader-Willi patients. Hum Mol Genet 1993, 2:1377-1382[Abstract/Free Full Text]
81. Reed ML, Leff SE: Maternal imprinting of human SNRPN, a gene deleted in Prader-Willi syndrome. Nat Genet 1994, 6:163-167[Medline]
82. Sutcliffe JS, Han M, Christian SL, Ledbetter DH: Neuronally-expressed necdin gene: an imprinted candidate gene in Prader-Willi syndrome. Lancet 1997, 350:1520-1521[Medline]
83. Reis A, Dittrich B, Greger V, Buiting K, Lalande M, Gillessen-Kaesbach G, Anvret M, Horsthemke B: Imprinting mutations suggested by abnormal DNA methylation patterns in familial Angelman and Prader-Willi syndromes. Am J Hum Genet 1994, 54:741-747[Medline]
84. Sutcliffe JS, Nakao M, Christian S, Orstavik KH, Tommerup N, Ledbetter DH, Beaudet AL: Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region. Nat Genet 1994, 8:52-58[Medline]
85. Buiting K, Saitoh S, Gross S, Dittrich B, Schwartz S, Nicholls RD, Horsthemke B: Inherited microdeletions in the Angelman and Prader-Willi syndromes define an imprinting centre on human chromosome 15. Nat Genet 1995, 9:395-400[Medline]
86. Dittrich B, Buiting K, Korn B, Rickard S, Buxton J, Saitoh S, Nicholls RD, Poustka A, Winterpacht A, Zabel B, Horsthemke B: Imprint switching on human chromosome 15 may involve alternative transcripts of the SNRPN gene. Nat Genet 1996, 14:163-170[Medline]
87. Horsthemke B: Structure and function of the human chromosome 15 imprinting center. J Cell Physiol 1997, 173:237-241[Medline]
88. Tilghman SM, Caspary T, Ingram RS: Competitive edge at the imprinted Prader-Willi/Angelman region? Nat Genet 1998, 18:206-208[Medline]
89. Schumacher A, Buiting K, Zeschnigk M, Doerfler W, Horsthemke B: Methylation analysis of the PWS/AS region does not support an enhancer- competition model. Nat Genet 1998, 19:324-325[Medline]
90. Spotila LD, Sereda L, Prockop DJ: Partial isodisomy for maternal chromosome 7 and short stature in an individual with a mutation at the COL1A2 locus. Am J Hum Genet 1992, 51:1396-1405[Medline]
91. Lefebvre L, Viville S, Barton SC, Ishino F, Keverne EB, Surani MA: Abnormal maternal behaviour and growth retardation associated with loss of the imprinted gene Mest. Nat Genet 1998, 20:163-169[Medline]
92. Fundele RH, Surani MA: Experimental embryological analysis of genetic imprinting in mouse development. Dev Genet 1994, 15:515-522[Medline]
93. Keverne EB, Fundele R, Narasimha M, Barton SC, Surani MA: Genomic imprinting and the differential roles of parental genomes in brain development. Brain Res Dev Brain Res 1996, 92:91-100[Medline]
94. Skuse DH, James RS, Bishop DVM, Coppin B, Dalton P, Aamodt-Leeper G, Bacarese-Hamilton M, Creswell C, McGurk R, Jacobs PA: Evidence from Turner's syndrome of an imprinted X-linked locus affecting cognitive function. Nature 1997, 387:705-708[Medline]
95. McCauley E, Ito J, Kay T: Psychosocial functioning in girls with Turner's syndrome and short stature: social skills, behavior problems, and self-concept. J Am Acad Child Psychiatry 1986, 25:105-112[Medline]
96. McCauley E, Kay T, Ito J, Treder R: The Turner syndrome: cognitive deficits, affective discrimination, and behavior problems. Child Dev 1987, 58:464-473[Medline]
97. Miller AP, Willard HF: Chromosomal basis of X chromosome inactivation: identification of a multigene domain in Xp11.21-p11.22 that escapes X inactivation. Proc Natl Acad Sci USA 1998, 95:8709-8714[Abstract/Free Full Text]
98. McMahon FJ, Stine OC, Meyers DA, Simpson SG, DePaulo JR: Patterns of maternal transmission in bipolar affective disorder. Am J Hum Genet 1995, 56:1277-1286[Medline]
99. Kato T, Winokur G, Coryell W, Keller MB, Endicott J, Rice J: Parent-of-origin effect in transmission of bipolar disorder. Am J Med Genet 1996, 67:546-550[Medline]
100. Grigoroiu-Serbanescu M, Wickramaratne PJ, Hodge SE, Milea S, Mihailescu R: Genetic anticipation and imprinting in bipolar I illness. Br J Psychiatry 1997, 170:162-166[Abstract/Free Full Text]
101. Asherson P, Walsh C, Williams J, Sargeant M, Taylor C, Clements A, Gill M, Owen M, McGuffin P: Imprinting and anticipation. Are they relevant to genetic studies of schizophrenia? Br J Psychiatry 1994, 164:619-624[Abstract/Free Full Text]
102. Ohara K, Xu HD, Mori N, Suzuki Y, Xu DS, Wang ZC: Anticipation and imprinting in schizophrenia. Biol Psychiatry 1997, 42:760-766[Medline]
103. Cook EH, Jr, Lindgren V, Leventhal BL, Courchesne R, Lincoln A, Shulman C, Lord C, Courchesne E: Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am J Hum Genet 1997, 60:928-934[Medline]
104. Morison IM, Reeve AE: A catalogue of imprinted genes and parent-of-origin effects in humans and animals. Hum Mol Genet 1998, 7:1599-1609[Abstract/Free Full Text]
105. Wake N, Fujino T, Hoshi S, Shinkai N, Sakai K, Kato H, Hashimoto M, Yasuda T, Yamada H, Ichinoe K: The propensity to malignancy of dispermic heterozygous moles. Placenta 1987, 8:319-326[Medline]
106. Linder D, McCaw BK, Hecht F: Parthenogenetic origin of benign ovarian teratomers. N Engl J Med 1975, 292:63-66[Abstract]
107. Caron H, van Sluis P, van Hoeve M, de Kraker J, Bras J, Slater R, Mannens M, Voute PS, Westerveld A, Versteeg R: Allelic loss of chromosome 1p36 in neuroblastoma is preferential maternal origin and correlates with N-myc amplification. Nat Genet 1993, 4:187-190[Medline]
108. Katz F, Webb D, Gibbons B, Reeves B, McMahon C, Cheselles J, Mitchell C: Possible evidence for genomic imprinting in childhood acute myeloblastic leukaemia associated with monosomy for chromosome 7. Br J Haematol 1992, 80:332-336[Medline]
109. Tycko B: Genomic imprinting in Wilms' tumor. 1996 Med Ped Oncol
110. Scrable H, Cavenne W, Ghavimi F, Lovell M, Morgan K, Sapienza C: A model for embryonal rhabdomyosarcoma tumorigenesis that involves genome imprinting. Proc Natl Acad Sci USA 1989, 86:7480-7484[Abstract/Free Full Text]
111. Toguchida J, Ishizaki K, Sasaki MS, Nakamura Y, Ikenaga M, Kato M, Sugimot M, Kotoura Y, Yamamuro T: Preferential mutation of paternally derived RB gene as the initial event in sporadic osteosarcoma. Nature 1989, 338:156-158[Medline]
112. Milunsky J, DeStefano AL, Huang XL, Baldwin CT, Michels VV, Jako G, Milunsky A: Familial paragangliomas: linkage to chromosome 11q23 and clinical implications. Am J Med Genet 1997, 72:66-70[Medline]
113. Rainier S, Johnson LA, Dobry CJ, Ping AJ, Grundy PE, Feinberg AP: Relaxation of imprinted genes in human cancer. Nature 1993, 362:747[Medline]
114. Ogawa O, Eccles MR, Szeto J, McNoe LA, Yun K, Maw MA, Smith PJ, Reeve AE: Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms' tumour. Nature 1993, 362:749-751[Medline]
115. Steenman MJC, Rainier S, Dobry CJ, Grundy P, Horon IL, Feinberg AP: Loss of imprinting of IGF2 is linked to reduced expression and abnormal methylation of H19 in Wilms' tumour. Nat Genet 1994, 7:433-439[Medline]
116. Hao Y, Crenshaw T, Moulton T, Newcomb E, Tycko B: Tumor-suppressor activity of H19. Nature 1993, 365:764-767[Medline]
117. Webber AL, Ingram RS, Levorse JM, Tilghman SM: Location of enhancers is essential for the imprinting of H19 and Igf2 genes. Nature 1998, 391:711-715[Medline]
118. Leighton PA, Ingram RS, Eggenschwiler J, Efstratiatis A, Tilghman SM: Disruption of imprinting caused by deletion of the H19 gene region in mice. Nature 1995, 375:34-39[Medline]
119. Okamoto K, Morison IM, Taniguchi T, Reeve AE: Epigenetic changes at the insulin-like growth factor II/H19 locus in developing kidney is an early event in Wilms' tumorigenesis. Proc Natl Acad Sci USA 1997, 94:5367-5371[Abstract/Free Full Text]
120. Jinno Y, Yun K, Nishiwaki K, Kubota T, Ogawa O, Reeve AE, Nikawa N: Mosaic and polymorphic imprinting of the WT1 gene in humans. Nat Genet 1994, 6:305-309[Medline]
121. Rauscher FJd: The Wt1 Wilms' tumor gene product: a developmentally regulated transcription factor in the kidney that functions as a tumor suppressor. FASEB J 1993, 7:896-903[Abstract]
122. Chung WY, Yuan L, Feng L, Hensle T, Tycko B: Chromosome 11p15.5 regional imprinting: comparative analysis of KIP2 and H19 in human tissues and Wilms' tumors. Hum Mol Genet 1996, 5:1101-1108[Abstract/Free Full Text]
123. 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: Genomic imprinting of human p57^KIP2 and its reduced expression in Wilms' tumors. Hum Mol Genet 1996, 5:783-788[Abstract/Free Full Text]
124. Kondo M, Matsuoka S, Uchida K, Osada H, Nagatake M, Takagi K, Harper JW, Takahashi T, Elledge SJ, Takahashi T: Selective maternal-allele loss in human lung cancers of the maternally expressed p57KIP2 gene at 11p15.5. Oncogene 1996, 12:1365-1368[Medline]
125. De Souza AT, Hankins GR, Washington MK, Fine RL, Orton TC, Jirtle RL: Frequent loss of heterozygosity on 6q at the mannose 6- phosphate/insulin-like growth factor II receptor locus in human hepatocellular tumors. Oncogene 1995, 10:1725-1729[Medline]
126. De Souza AT, Hankins GR, Washington MK, Orton TC, Jirtle RL: M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity. Nat Genet 1995, 11:447-449[Medline]
127. Hankins GR, De Souza AT, Bentley RC, Patel MR, Marks JR, Iglehart JD, Jirtle RL: M6P/IGF2 receptor: a candidate breast tumor suppressor gene. Oncogene 1996, 12:2003-2009[Medline]
128. Yamada T, De Souza AT, Finkelstein S, Jirtle RL: Loss of the gene encoding mannose 6-phosphate/insulin-like growth factor II receptor is an early event in liver carcinogenesis. Proc Natl Acad Sci USA 1997, 94:10351-10355[Abstract/Free Full Text]
129. Yu Y, Xu F, Peng H, Fang X, Zhao S, Li Y, Cuevas B, Kuo WL, Gray JW, Siciliano M, Mills GB, Bast RC, Jr: NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian, and breast carcinomas. Proc Natl Acad Sci USA 1999, 96:214-219[Abstract/Free Full Text]
130. Korner C, Nurnberg B, Uhde M, Braulke T: Mannose 6-phosphate/insulin-like growth factor II receptor fails to interact with G-proteins: analysis of mutant cytoplasmic receptor domains. J Biol Chem 1995, 270:287-295[Abstract/Free Full Text]
131. Souza RF, Appel R, Yin J, Wang S, Smolinski KN, Abraham JM, Zou T-T, Shi Y-Q, Lei J, Cottrell J, Cymes K, Biden K, Simms L, Leggett B, Lynch PM, Frazier M, Powell SM, Harpaz N, Sugimura H, Young J, Meltzer SJ: The insulin-like growth factor II receptor gene is a target of microsatellite instability in human gastrointestinal tumours. Nat Genet 1996, 14:255-257[Medline]
132. Ouyang H, Shiwaku HO, Hagiwara H, Miura K, Abe T, Kato Y, Ohtani H, Shiiba K, Souza RF, Meltzer SJ, Horii A: The insulin-like growth factor II receptor gene is mutated in genetically unstable cancers of the endometrium, stomach, and colorectum. Cancer Res 1997, 57:1851-1854[Abstract/Free Full Text]
133. Leung SY, Chan TL, Chung LP, Chan AS, Fan YW, Hung KN, Kwong WK, Ho JW, Yuen ST: Microsatellite instability and mutation of DNA mismatch repair genes in gliomas. Am J Pathol 1998, 153:1181-1188[Abstract/Free Full Text]
134. Chappell SA, Walsh T, Walker RA, Shaw JA: Loss of heterozygosity at the mannose 6-phosphate insulin-like growth factor 2 receptor gene correlates with poor differentiation in early breast carcinomas. Br J Cancer 1997, 76:1558-1561[Medline]
135. Mills JJ, Falls JG, De Souza AT, Jirtle RL: Imprinted M6p/Igf2 receptor is mutated in rat liver tumors. Oncogene 1998, 16:2797-2802[Medline]
136. Xu Y, Goodyer CG, Deal C, Polychronakos C: Functional polymorphism in the parental imprinting of the human IGF2R gene. Biochem Biophys Res Commun 1993, 197:747-754[Medline]
137. Ogawa O, McNoe LA, Eccles MR, Morison IM, Reeve AE: Human insulin-like growth factor type I and type II receptors are not imprinted. Hum Mol Genet 1993, 2:2163-2165<