Epigenetic Inheritance Associated with Human Chromosome 14

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REVIEW ARTICLE Epigenetic inheritance associated with human chromosome 14

Deepak Kamnasaran, BS From the Department of Medical Genetics, University of Alberta, Edmonton, Alta. Medical subject headings: chromosome aberrations; chromosomes, human; genes; genomic imprinting; hereditary diseases; maternal uniparental disomy; mice; paternal uniparental disomy

(Original manuscript submitted Dec. 4, 2000; received in re- vised form Mar. 12, 2001; accepted Apr. 2, 2001.)

Clin Invest Med 2001;24(3):138-46

Abstract Résumé

Within the last decade, there has been sufficient evi- Suffisamment de données probantes ont été mises à jour au dence to support the association of epigenetic inheri- cours de la dernière décennie pour appuyer l’association de tance or genomic imprinting on human chromosome la mémoire épigénétique ou empreinte génomique sur le 14. This has been achieved with studies of imprinting chromosome 14 de l’humain. Il a été possible d’y parvenir on both human chromosome 14 and mouse chromo- à l’aide d’études sur l’empreinte du chromosome 14 de some 12, which has the largest homology to human l’humain et du chromosome 12 de la souris, chromosome chromosome 14. Initial studies with mouse chromo- qui présente le plus grand degré d’homologie avec le chro- some 12 aberrations suggested that specific phenotypes mosome 14 de l’humain. Les premières études qui por- due to genomic imprinting were confined to the mater- taient sur les aberrations du chromosome 12 de la souris in- nal or paternal mouse chromosome 12, depending on diquaient que les phénotypes spécifiquement attribuables à the parent from which the chromosome was inherited. l’empreinte génomique se limitaient chez la souris au chro- Such findings were later supplemented with human mosome 12 maternel ou paternel, suivant de quel parent le chromosome 14 aberrations that had provided evidence chromosome avait été hérité. Ces constatations ont été for imprinted intervals on this chromosome, and possi- complétées plus tard par des données sur les aberrations du bly 2 syndromes associated with a maternal or paternal chromosome 14 de l’humain qui révélaient la présence sur uniparental disomy affecting chromosome 14. The re- ce chromosome d’intervalles portant l’empreinte de même cent discovery of 2 imprinted genes on human chromo- que la possibilité que deux syndromes découlent d’une dis- some 14 and mouse chromosome 12 has confirmed omie uniparentale maternelle ou paternelle du chromosome genomic imprinting on these chromosomes. These 14. La découverte récente de deux gènes marqués de l’em- findings will refine our understanding of the clinical preinte sur le chromosome 14 de l’humain et sur le chro- consequences of human chromosome 14 aberrations mosome 12 de la souris a confirmé que ces chromosomes and of the causes of the disease phenotype associated sont soumis à l’empreinte génomique. Ces résultats nous with defective imprinted genes. This article reviews permettront de mieux comprendre les séquelles cliniques evidence in mice and humans, and the clinical implica- des anomalies du chromosome 14 de l’humain et les causes tions for genomic imprinting associated with human du phénotype morbide associé aux gènes défectueux chromosome 14. soumis à l’empreinte. Le présent article examine les don- nées probantes relatives aux souris et aux humains ainsi que les répercussions cliniques de l’empreinte génomique associée au chromosome 14 de l’humain.

138 Clin Invest Med ¥ Vol 24, no 3, juin 2001 Imprinting on chromosome 14

Glossary of terms used in the text Term Definition Aneuploid An extra or missing copy of a chromosome in a cell Asynchronous DNA replication Differences in the timing of DNA replication between the maternal and paternal chromosomes in the case of imprinted chromosomes Biallelic expression Expression of a gene from both parental chromosomes Centromere A primary constriction of a chromosome required for its segregation during mitosis and meiosis Chromatid A newly replicated DNA molecule Chromatin A complex of DNA and proteins cM CentiMorgan — a measure of genetic distance CpG rich A segment of DNA sequence that usually comprises over 60% deoxycytidine and deoxyguanidine nucleotides Epigenetic A factor that affects the phenotype without alterations in the genotype Genomic, gametic or parental Monoallelic expression of a gene depending on the parent of origin imprinting Heterodisomy Both chromosomes of a homologue inherited from a single parent Imprintor A regulator of imprinted genes Interstitial deletion or duplication A deletion or duplication of a region within a chromosome Isodisomy Two identical copies of a chromosome inherited from a single parent Gynogenote A diploid cell with 2 maternal genomes Monoallelic expression Expression of a gene from only 1 parental chromosome Orthologue The copy of a gene in another species Partial trisomy Three copies of a specific region on a chromosome Paternal tertiary trisomy The presence of 1 maternal and 2 paternal copies of a chromosome. Here, one of the paternal copies represents only part of the chromosome Paternal tertiary monosomy The presence of only 1 paternal copy of a chromosome Polymorphic heteromorphism A variable amount of DNA present with a frequency of over 1 in a 100 in the population Reciprocal translocation The union of chromosome material between 2 non-homologous chromosomes Recombination The exchange of DNA between 2 homologous chromosomes Robertsonian translocation The fusion of acrocentric chromosomes usually at the short arm. These include human chromosomes 13, 14, 15, 21 and 22 Terminal deletion or duplication A deletion or duplication at the end of a chromosome Transgene locus A stable insertion of foreign DNA into a chromosomal region Trisomy mosaicism A mixture of trisomic and normal diploid cells Uniparental recessive genes A pair of recessive genes of the same locus that are inherited from a single parent

Introduction mated to be approximately 100 to 200 based on studies in mice that have demonstrated abnormal or Classic Mendelian laws of inheritance state that both deleterious phenotypes when parts of homologous maternal and paternal inherited alleles of a gene con- chromosomes are inherited from a single parent.1 tribute equally to the phenotype. One exception to About 40 imprinted genes have been discovered to Mendelian inheritance is a process known as ge- date on human chromosomes 1, 2, 6, 7, 9, 11, 14, 15, nomic, gametic or parental imprinting. Here, specific 19 and X.2 A few of these genes are responsible for regions of a chromosome are said to be imprinted, well-established imprinting disorders such as Rus- when the genes exhibit monoallelic expression, de- sellÐSilver syndrome, Angelman syndrome, pending on the parent from which the chromosome PraderÐWilli syndrome, BeckwithÐWiedemann syn- is inherited. In this manner, only 1 allele of a gene drome and several infantile and adult tumours.3 This contributes to the phenotype; the inactive allele of review will summarize the evidence for genomic im- the gene is denoted as being imprinted. The number printing on human chromosome 14 and the abnor- of imprinted genes in the human genome is esti- malities associated therein.

Clin Invest Med ¥ Vol 24, no 3, June 2001 139 Kamnasaran

Properties of imprinted genes human chromosome 15 are active on the paternal chromosome but silent on the maternal chromo- The process of imprinting is a form of epigenetic in- some. The maternal PraderÐWilli chromosomal heritance since the phenotype of an imprinted gene region is replicated later and undergoes fewer re- is a result of heritable modifications in gene expres- combinations during meiosis than the active paternal sion rather than changes in the gene’s DNA se- chromosomal region.7 quence. Numerous studies have been performed on the spatio-temporal expression patterns of imprinted Mechanisms for generating uniparental genes, which have resulted in the definition of 3 disomy main properties of all imprinted genes. First, the imprint must be established during gametogenesis or at Uniparental disomy refers to a chromosomal abnor- an early post-zygotic developmental stage.2 An ex- mality in which 2 identical copies, or both chromo- ample is the murine “Achaete-scute complex-like II” somes, of a homologue are inherited from a single gene that initially demonstrates biallelic expression parent. The frequency of this occurrence is un- but acquires monoallelic expression later during im- known. When both chromosomes of a homologue plantation of the embryo.4 Second, the imprint must are inherited from a single parent, it is an example be stable after fertilization in all tissues that permit of heterodisomy. When 2 identical chromosomes of the imprint.2 Some imprinted genes such as the a homologue are inherited from a single parent, it is murine “Insulin-like growth factor II” demonstrate an example of isodisomy. The frequency of het- monoallelic expression in most tissues but biallelic erodisomy is higher than isodisomy.9 Moreover, expression in the choroid plexus, leptomeninges, isodisomy can result in 2 copies of a recessive mu- brain, adult liver and chondrocytes.5,6 Third, the im- tation being inherited from a heterozygous carrier print must be erased and reset during gametogenesis parent. Examples of recessive disorders due to or at an early post-zygotic developmental stage so isodisomy are cystic fibrosis on chromosome 7, rod that the sex-specific imprint is transmitted to the monochromacy on chromosome 14 and spinal mus- progeny.2 cular atrophy on chromosome 5.10 Heterodisomy is The subsequent cloning, sequencing and mapping not expected to cause abnormalities unless the of imprinted genes have led to the identification of genes on the heterodisomic chromosome are im- additional common features among them. First, imprinted and there is the absence of a deletion or printed genes are localized in clusters; usually gene mutation. Examples of imprinting defects due among CpG-rich DNA sequences.7 The eutherian to uniparental disomy include chromosome 15 in (placental) mammalian paternal X chromosome is 25% of patients affected with PraderÐWilli syn- an example of the largest cluster of imprinted genes.7 drome and less than 5% of patients affected with Second, within each cluster, both maternal and Angelman syndrome.11 Other chromosomes like 7, paternal imprinted genes are interspersed.7 For 11 and 14 demonstrate a phenotype when associated instance, on human chromosome 11, the paternally with uniparental disomy, whereas other chromo- imprinted H19 gene is localized 90 kb away from somes like 2, 6, 16, 20 and X demonstrate moderate the maternally imprinted “Insulin II” and “Insulin- evidence for an associated uniparental disomic phe- like growth factor II” genes.8 Third, differences in notype.11 The risk for uniparental disomy in general the methylation of DNA and acetylation of DNA is estimated to be high when homologous chromo- histone proteins have been found in the maternal and somes are involved since they are more likely to be paternal alleles of imprinted genes.7 These epigenetic implicated in the formation of aberrant chromo- changes are speculated to mediate the regulation of somes. For instance, the human acrocentric chromo- imprinted genes. Fourth, parent-of-origin differences somes, numbers 13, 14, 15, 21 and 22, have exten- in chromatin structure result in asynchronous DNA sive homologous regions on the short arm. The replication timing and recombination differences.7 short arms of these chromosomes frequently recom- For example, the genes of PraderÐWilli syndrome on bine to form Robertsonian translocation chromo-

140 Clin Invest Med ¥ Vol 24, no 3, juin 2001 Imprinting on chromosome 14

somes. In fact, uniparental disomy involving chro- from this mechanism since there is a mixture of mosomes 13 and any of the acrocentric chromo- normal cells with cells that have undergone gene somes are very common.9 conversion.9 There are 4 proposed mechanisms that generate uniparental disomy and these are described briefly. Chromosome aberration studies in mice

Gametic complementation The mouse genome has initially served as a model for possible imprinted genes and chromosomal re- This represents the union of an oocyte with a sperm gions in human by comparisons of the imprinted in which one gamete has an extra chromosome and maps of mouse chromosomes with the human- the other lacks the same chromosome. This mecha- mouse chromosome homology maps. The genes of nism is suspected when a transmitting parent is a human chromosome 14 are homologous with mouse carrier of a chromosome abnormality such as a reci- genes that map mainly to mouse chromosomes 12 procal or Robertsonian translocation, which in- and 14 (Fig. 1).12 With the use of chromosome aber- creases the likelihood for segregation errors during rations in mice, evidence for genomic imprinting meiosis. Oocytes are more likely to carry the extra was found on mouse chromosome 12 but not on chromosome since 18% of oocytes and only 3% to mouse chromosome 14. Specifically, evidence for 4% of spermatocytes are aneuploid.9 imprinting of the entire mouse chromosome 12 was demonstrated with mouse embryos that had an Trisomic rescue abnormal phenotype when they were carriers of a maternal or paternal uniparental disomy of chromo- This involves the loss of 1 extra chromosome usu- some 12.13 Mouse embryos with a paternal uni- ally before blastulation because of selection against parental disomy of chromosome 12 died at a late trisomic cells. Again, this mechanism is suspected gestational stage.13 Furthermore, these embryos when a transmitting parent is a carrier of a chromo- demonstrated placentomegaly, hypo-ossification of some abnormality. With this mechanism, there is a mesoderm-derived bones, and defects in skeletal 33% chance of obtaining uniparental disomy from muscle maturation and costal cartilage formation.13 trisomic rescue. In 1% to 2% of the cases, trisomic On the other hand, mouse embryos that had a mater- rescue can result in trisomic mosaicism confined to nal uniparental disomy of chromosome 12 survived placental tissues.9 to birth but died perinatally of respiratory distress and exhibited growth retardation and defects in Compensatory uniparental disomy skeletal muscle maturation.13 In order to define selected imprinted intervals on This mechanism involves replacing an abnormal or mouse chromosome 12, abnormal phenotypes can missing chromosome with a copy of the normal be assessed in mice that are carriers of partial aber- homologue either by mis-division of the centromere rations of chromosome 12. With this strategy, evi- or mis-segration of a chromatid.9 dence for imprinted parts of mouse chromosome 12 was initially obtained from a paternal or maternal Gene conversion duplication of the distal region of mouse chromosome 12. The pups that were carriers of such aber- This is a common mechanism proposed for the rant chromosomes had growth retardation and late loss of heterozygosity in the genesis of tumours embryonic or neonatal death.14 Mice that were car- like retinoblastoma and Wilms’ tumour, and many riers of a paternal tertiary trisomy or paternal ter- other forms of cancer.9,10 This mechanism involves tiary monosomy of the distal tip of mouse chromo- the nonreciprocal exchange of DNA between 2 ho- some 12 survived. These findings suggested the mologous chromosomes, resulting in partial or presence of imprinted genes on the distal tip of complete isodisomy. A milder phenotype results mouse chromosome 12.

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Imprinted genes and loci on mouse dence has not yet been found for a locus for acrodys- chromosome 12 plasia on human chromosome 14. A second imprinted gene, known as Maternal Ex- The first imprinted transgene locus reported on pressed Gene III (Meg3), maps to the distal region of mouse chromosome 12 was called Acrodysplasia.15 mouse chromosome 12.16 This gene was identified The inheritance of the transgene locus from the pa- by the use of a technique known as subtractive hy- ternal lineage resulted in pups that were affected bridization to isolate unique maternally expressed with cranial, limb and paw defects.15 From examina- genes from gynogenote embryos.16 Further analysis tion of the human-mouse homology maps, an of Meg3 demonstrated maternal monoallelic expres- acrodysplasia locus was speculated to reside at the sion in mouse embryos staged from 8.5 to 12.5 days medial interval of chromosome 14. However, from and in brain tissues of adult mice. This gene is pro- linkage studies or chromosome aberrations in indi- posed to encode a regulatory RNA molecule.16 viduals affected with isolated acrodysplasia, evi- A third imprinted gene, known as Delta-like I (Dlk1), which maps to the distal region of mouse chromosome 12 about 120 kb away from Meg3,was recently reported by Schmidt and colleagues.17 This gene encodes a transmembrane protein that is prote- olytically modified to produce a secreted peptide, which accumulates in the amniotic fluid and in the fetal and maternal circulation.17 The Dlk1 gene was demonstrated to have paternal monoallelic expression in mice embryonic and placental tissues staged at 12.5 and 18.5 days.17 Furthermore, both Dlk1 and Meg3 genes are expressed in a reciprocal manner in mouse embryos staged at 7 to 11 days, and in the pi- tuitary and adrenal gland of adult mouse brains.17 This expression pattern is similar to that of other imprinted gene clusters such as the genes of Beck- withÐWiedemann syndrome.17 14 Chromosome 14 aberration studies in humans

Genomic imprinting on human chromosome 14 is supported by the fact that people are affected with a spectrum of clinical anomalies when they are carriers of a maternal or paternal uniparental disomy of chromosome 14. In this manner, the phenotype of people who are carriers of a heterodisomic chromosome 14 is concordant with that of people who have an isodis- omic chromosome 14. The similarity in phenotype is due to a defect of imprinting rather than to the pres- Fig. 1: Homology relationships among mouse chro- ence of 2 uniparental recessive genes. Given this, a mosomes and human chromosome 14. The human maternal uniparental disomy 14 syndrome was pro- bone morphogenetic protein IV, GTP cyclohydroxy- posed based on the fact that subjects who are carriers lase I, kinectin I and Drosophila orthodenticle homologue II genes, mapping at the medial region of of maternal heterodisomy or isodisomy for chromo- human chromosome 14, have homologues that map some 14 are affected with distinct phenotypes. Short to mouse chromosome 14. stature and precocious puberty are the most frequent

142 Clin Invest Med ¥ Vol 24, no 3, juin 2001 Imprinting on chromosome 14

phenotypes associated with maternal uniparental dis- to distal regions of the maternal chromosome 14 and omy 14 syndrome.18Ð34 However, these people can individuals affected with low birth weight, short also be affected with more than one of the following: philtrum and small hands, features prevalent in spontaneously arrested hydrocephalus; intrauterine maternal uniparental disomy 14 syndrome.39 A weak growth retardation; hypotonia; feeding problems; association was found between the distal region of mild hypercholesterolemia; obesity; mental and de- the paternal chromosome 14 and a broad neck.39 velopmental delay; recurrent ottis media; scoliosis; A second approach by Sutton and Shaffer40 was small hands; short philtrum; fleshy nasal tip; high, used to confine imprinted intervals on human chro- broad forehead; high, arched palate; micrognathia; mosome 14. The phenotypes of 17 maternal and 4 frontal bossing; undescended testis; and hyperexten- paternal uniparental disomy 14 subjects were com- sible joints.18Ð34 Examples of paternal uniparental dis- pared with 33 subjects who had an assortment of omy of chromosome 14 are very rare, and it is uncer- chromosome 14 deletions that were of either pater- tain whether these cases do constitute a paternal nal or maternal origin.40 With this strategy, im- uniparental disomy 14 syndrome. Nevertheless, those printed regions at the proximal, medial and distal who are carriers of a paternal heterodisomy or isodis- regions of chromosome 14 were suggested (Fig. omy for chromosome 14 tend to manifest one or 2). Here, a loss of monoallelic expression of an more of the following: growth and developmental imprinted gene was a possible cause of the mater- delay; mental retardation; polyhydramnios; small nal or paternal uniparental disomy 14 syndrome thorax; short, webbed neck; depressed nasal bridge; phenotype observed in a person with a chromo- hairy forehead; protruding philtrum; small palpebral some 14 deletion. This is similarly observed in fissures; small ears; joint contractures; campto- PraderÐWilli syndrome3 and Angelman syndrome,3 dactyly; and blepharophimosis.35Ð38 To date, 18 cases of maternal uniparental dis- omy18Ð34 and 4 of paternal uniparental disomy35Ð38 have been reported for human chromosome 14, based on genotyping or the identification of polymorphic heteromorphisms of the centromere, or both. These uniparental disomy studies have suggested the presence of genomic imprinting on human chromosome 14; however, they are uninforma- tive with respect to localizing imprinted intervals on the chromosome. One approach to confine local imprinted regions on chromosome 14 was found in a study by Georgiades and associates.39 Over 50 anomalies were examined in more than 50 people who had a partial trisomy of chromosome 14, to deter- mine whether they demonstrated common phenotypes within the maternal or paternal uniparental disomy 14 syndromes’ spectrum. Here, a region of the chromosome that was trisomic and had associated clinical features within the uniparental disomy 14 syndromes was possibly imprinted. In this manner, a gain of biallelic expression of an imprinted gene, as observed in RussellÐSilver syndrome3 or Beck- Fig. 2: Suggested imprinted cytogenetic intervals on 3 human chromosome 14. Confined to these intervals withÐWiedemann syndrome, was the primary cause are specific clinical features found within the ma- of the phenotype. Using this criterion, these re- ternal and paternal uniparental disomy 14 syn- searchers found an association between the medial dromes.

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where a loss of monoallelic expression of im- in the clinical spectrum of maternal and paternal uni- printed genes in a chromosome 15 deletion is the parental disomy 14 syndromes. predominant cause. A third approach to confine imprinted intervals on Clinical implications human chromosome 14 is to compare the phenotypes of subjects with partial uniparental disomy of Any genetic disorders or chromosome aberration chromosome 14 with the maternal or paternal uni- syndromes that manifest undergrowth, overgrowth or parental disomy 14 syndromes. An example is behaviour abnormalities should have genomic im- found in the study by Martin and colleagues,22 who printing as a suspected cause.10 This is based on the reported a female proband with developmental de- clinical observations of imprinting defects localized lay, generalized hypotonia, macrocephaly and joint to human chromosomes 7, 11, 15, 16 and 20.10 At laxity. Molecular analysis on the proband demon- least, undergrowth and overgrowth anomalies were strated maternal heterodisomy affecting a 2 to 21 observed in the clinical spectrum of the maternal and cM genetic interval at the medial region of chromo- paternal uniparental disomy 14 syndromes. These some 14. A second example is found in the study of suspected imprinted anomalies could be due to mu- Robin and colleagues,41 who reported a father and tations in an imprinted gene or an imprintor, and to daughter who were carriers of a duplication of the chromosome rearrangements as described above. medial to distal region of chromosome 14. The fa- Regardless of the causes of the imprinting defect, it ther was clinically normal; however, the daughter must be considered that the disorder may bypass a was affected with mild developmental delay, micro- generation and only become manifest when trans- cephaly and mild facial anomalies. The proband's mitted by one sex. In this manner, the risk to any off- flat midface, bulbous nose and upslanting palpebral spring of an affected or carrier parent is 50%, if the fissures were the only features in common with defective imprinted gene(s) or deficient imprinted other subjects who had similar inherited duplica- region is not silenced during gametogenesis of the tions of chromosome 14.41 parent. The risk to an offspring is greatly reduced when the imprinting defect is being transmitted by a Human chromosome 14 imprinted genes parent who silences the relevant imprinted gene(s) or deficient imprinted region during gametogenesis. The human orthologue of the mouse Meg3 has been This has been observed in such families affected cloned and mapped to the distal region of human with dominant hereditary glomus43 or PraderÐWilli chromosome 14.16 This gene has maternal monoal- syndrome.10 The carrier status of mutations in im- lelic expression in chorionic villi and human fetal printed genes or imprintors can be identified using tissue, and biallelic expression in adult brain.16 The conventional mutation detection techniques and mouse and human Meg3 are about 67% identical and DNA methylation assays where relevant. may encode a regulatory RNA molecule.16 The hu- An imprinting map of genes and physical regions man orthologue of the mouse Dlk1 gene has also of human chromosome 14 will be of clinical impor- been cloned and mapped to the distal region of hu- tance for the prenatal diagnosis and counselling of man chromosome 14.42 The human Dlk1 gene has people who are carriers of aberrations for this chro- paternal monoallelic expression in several human fe- mosome. For instance, those having uniparental distal tissues such as the heart, kidney and brain, and omy, interstitial or terminal deletions or duplications, DNA sequence properties similar to other imprinted or partial or mosaic trisomy of human chromosome genes.42 It is speculated that these 2 genes may be 14 are at risk of being affected with an imprinted de- regulated in a reciprocal manner similar to the fect. In general, trisomy is prevalent in an estimated mouse orthologues.42 Mutations are yet to be identi- 10% to 15% of all human conceptuses,10 with a rate fied in these imprinted genes of chromosome 14. that increases with maternal age. Since complete hu- Moreover, the functions of these genes need to be man trisomy of chromosome 14 is embryo-lethal,13 correlated with the cause of the phenotype observed only conceptuses with partial and mosaic trisomy of

144 Clin Invest Med ¥ Vol 24, no 3, juin 2001 Imprinting on chromosome 14

chromosome 14 should be considered for further 2. Falls JG, Pulford DJ, Wylie AA, Jirtle RL. Genomic analyses of imprinting defects. This is also applica- imprinting: implications for human disease. Am J Pathol 1999;154:635-47. ble for interstitial and terminal deletions or duplica- 3. Tilghman SM. The sins of the fathers and mothers: ge- tions of human chromosome 14 since they are asso- nomic imprinting in mammalian development. Cell ciated with clinical features within the maternal or 1999;96:185-93. paternal uniparental disomy 14 syndrome. The loss 4. Tanaka M, Puchyr M, Gertsenstein M, Harpal K, Jaenisch R, Rossant J, et al. Parental origin-specific of monoallelic expression of an imprinted gene is a expression of Mash2 is established at the time of im- possible cause of an imprinting defect associated plantation with its imprinting mechanism highly resis- with uniparental disomy or interstitial or terminal tant to genome-wide demethylation. Mech Dev 1999; deletion of human chromosome 14. On the other 87:129-42. 5. Ohlsson R, Nystrom A, Pfeifer-Ohlsson S, Tohonen V, hand, a gain of biallelic expression of an imprinted Hedborg F, Schofield P, et al. IGF2 is parentally im- gene is a possible cause of an imprinting defect asso- printed during human embryogenesis and in the Beck- ciated with partial or mosaic trisomy, interstitial or withÐWiedemann syndrome. Nat Genet 1993;4:94-7. terminal duplication, and uniparental disomy of 6. Ogawa O, Eccles MR, Szeto J, McNoe LA, Yun K, Maw MA, et al. Relaxation of insulin-like growth fac- chromosome 14. Standard cytogenetic analyses and tor II gene imprinting implicated in Wilms’ tumour. genotyping with polymorphic markers are routinely Nature 1993;362:749-51. used to detect these aberrations. 7. Pfeifer K. Mechanisms of genomic imprinting. Am J Hum Genet 2000;67:777-87. 8. Sasaki H, Ishihara K, Kato R. Mechanisms of Igf2/H19 Summary imprinting: DNA methylation, chromatin and long-distance gene regulation. J Biochem (Tokyo) 2000;127: The development of an imprinting map for human 711-5. chromosome 14 is on the verge of being constructed. 9. Robinson WP. Mechanisms leading to uniparental dis- Too few cases are available yet to pinpoint the mini- omy and their clinical consequences. Bioessays 2000;22:452-9. mal imprinted regions of this chromosome. In addi- 10. Hall JG. Human diseases and genomic imprinting. Re- tion, the specific clinical features associated with the sults Probl Cell Differ 1999;25:119-32. maternal and paternal uniparental disomy 14 syn- 11. Engel E, Ledbetter DH. Uniparental disomy in hu- dromes need to be clarified, especially for the pro- mans: development of an imprinting map and its im- plication for prenatal diagnosis. Hum Mol Genet posed paternal uniparental disomy 14 syndrome. 1995;4:1757-64. Recent evidence has suggested imprinted domains at 12. Blake JA, Eppig JT, Richardson JE, Davisson MT. the distal region of human chromosome 14 and pos- The Mouse Genome Database (MGD): expanding ge- sibly at the medial and proximal regions. An im- netic and genomic resources for the laboratory mouse. The Mouse Genome Database Group. Nucleic Acids printing map will be of clinical importance for the Res 2000;28:108-11. counselling and prenatal diagnosis of people who 13. Beechey CV. Appendix: imprinted genes and regions are carriers of chromosome 14 aberrations, by in mouse and human. Results Probl Cell Differ screening for mutations in causative genes or by 1999;25:303-23. 14. Georgiades P, Watkins M, Surani MA, Ferguson- searching for changes in the copy number of the Smith AC. Parental origin-specific developmental de- causative genes. Moreover, it will be important in fects in mice with uniparental disomy for chromosome understanding the cause of disease phenotype by 12. Development 2000;127:4719-28. way of genotype-phenotype correlations. 15. DeLoia JA, Solter D. A transgene insertional mutation at an imprinted locus in the mouse genome. Dev Suppl 1990:73-9. Acknowledgements: D. Kamnasaran is funded by an Alberta 16. Miyoshi N, Wagatsuma H, Wakana S, Shiroishi T, No- Heritage Foundation for Medical Research Scholarship. mura M, Aisaka K, et al. Identification of an imprinted gene, Meg3/Gtl2 and its human homologue MEG3, References first mapped on mouse distal chromosome 12 and human chromosome 14q. Genes Cells 2000;5:211-20. 17. Schmidt JV, Matteson PG, Jones BK, Guan XJ, Tilgh- 1. Barlow DP. Gametic imprinting in mammals. Science man SM. The Dlk1 and Gtl2 genes are linked and reci- 1995;270:1610-3. procally imprinted. Genes Dev 2000;14:1997-2002.

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18. Pentao L, Lewis RA, Ledbetter DH, Patel PI, Lupski 1994;51:147-9. JR. Maternal uniparental isodisomy of chromosome 32. Robinson WP, Bernasconi F, Basaran S, Yuksel-Apak 14: association with autosomal recessive rod mono- M, Neri G, Serville F, et al. A somatic origin of ho- chromacy. Am J Hum Genet 1992;50:690-9. mologous Robertsonian translocations and isochromo- 19. Sanlaville D, Aubry MC, Dumez Y, Nolen MC, Amiel somes. Am J Hum Genet 1994;54:290-302. J, Pinson MP, et al. Maternal uniparental heterodisomy 33. Antonarakis SE, Blouin JL, Maher J, Avramopoulos of chromosome 14: chromosomal mechanism and clin- D, Thomas G, Talbot CC Jr. Maternal uniparental dis- ical follow up. J Med Genet 2000;37:525-8. omy for human chromosome 14, due to loss of a chro- 20. Morichon-Delvallez N, Seques B, Pinson MP, Berube mosome 14 from somatic cells with t(13;14) trisomy D, Dommerques M, Aubry MC, et al. Maternal uni- 14. Am J Hum Genet 1993;52:1145-52. parental disomy for chromosome 14 by secondary 34. Temple IK, Cockwell A, Hassold T, Pettay D, Jacobs non-disjunction of a initial trisomy [abstract]. Am J P. Maternal uniparental disomy for chromosome 14. J Hum Genet 1994;55:379A. Med Genet 1991;28:511-4. 21. Hordijk R, Wierenga H, Scheffer H, Leegte B, Hofstra 35. Cotter PD, Kaffe S, McCurdy LD, Jhaveri M, Willner RM, Stolte-Dijkstra I. Maternal uniparental disomy for JP, Hirschhorn K. Paternal uniparental disomy for chromosome 14 in a boy with a normal karyotype. J chromosome 14: a case report and review. Am J Med Med Genet 1999;36:782-5. Genet 1997;70:74-9. 22. Martin RA, Sabol DW, Rogan PK. Maternal uni- 36. Walter CA, Shaffer LG, Kaye CI, Huff RW, Ghidoni parental disomy of chromosome 14 confined to an in- PD, McCaskill C, et al. Short-limb dwarfism and hy- terstitial segment (14q23Ð14q24.2). J Med Genet pertrophic cardiomyopathy in a patient with paternal 1999;36:633-6. isodisomy 14: 45,XY,idic(14)(p11). Am J Med Genet 23. Ralph A, Scott F, Tiernan C, Caubere M, Kollegger S, 1996;65:259-65. Junio J, et al. Maternal uniparental isodisomy for chro- 37. Wang JC, Passage MB, Yen PH, Shapiro LJ, Mohan- mosome 14 detected prenatally. Prenat Diagn 1999;9: das TK. Uniparental heterodisomy for chromosome 14 681-4. in a phenotypically abnormal familial balanced 13/14 24. Fokstuen S, Ginsburg C, Zachmann M, Schinzel A. Robertsonian translocation carrier. Am J Hum Genet Maternal uniparental disomy 14 as a cause of intrauter- 1991;48:1069-74. ine growth retardation and early onset of puberty. J 38. Papenhausen PR, Mueller OT, Johnson VP, Sutcliffe Pediatr 1999;134:689-95. M, Diamond TM, Kousseff BG. Uniparental isodisomy 25. Berends MJ, Hordijk R, Scheffer H, Oosterwijk JC, of chromosome 14 in two cases: an abnormal child and Halley DJ, Sorgedrager N. Two cases of maternal uni- a normal adult. Am J Med Genet 1995; 59:271-5. parental disomy 14 with a phenotype overlapping with 39. Georgiades P, Chierakul C, Ferguson-Smith AC. the PraderÐWilli phenotype. Am J Med Genet Parental origin effects in human trisomy for chromo- 1999;84:76-9. some 14q: implications for genomic imprinting. J Med 26. Miyoshi O, Hayashi S, Fujimoto M, Tomita H, Sohda Genet 1998;5:821-4. M, Niikawa N. Maternal uniparental disomy for chro- 40. Sutton VR, Shaffer LG. Search for imprinted regions mosome 14 in a boy with intrauterine growth retarda- on chromosome 14: comparison of maternal and pater- tion. J Hum Genet 1998;43:138-42. nal UPD cases with cases of chromosome 14 deletion. 27. Splitt MP, Goodship JA. Another case of maternal uni- Am J Med Genet 2000;93:381-7. parental disomy chromosome 14 syndrome. Am J Med 41. Robin NH, Harari-Shacham A, Schwartz S, Wolff DJ. Genet 1997;72:239-40. Duplication 14(q24.3q31) in a father and daughter: de- 28. Coviello DA, Panucci E, Mantero MM, Perfumo C, lineation of a possible imprinted region. Am J Med Guelfi M, Borrone C, et al. Maternal uniparental dis- Genet 1997;71:361-5. omy for chromosome 14. Acta Genet Med Gemellol 42. Wylie AA, Murphy SK, Orton TC, Jirtle RL. Novel (Roma) 1996;45:169-72. imprinted DLK1/GTL2 domain on human chromo- 29. Tomkins DJ, Roux AF, Waye J, Freeman VC, Cox some 14 contains motifs that mimic those implicated DW, Whelan DT. Maternal uniparental isodisomy of in IGF2/H19 regulation. Genome Res 2000;10:1711-8. human chromosome 14 associated with a paternal 43. van der Mey AG, Maaswinkel-Mooy PD, Cornelisse t(13q14q) and precocious puberty. Eur J Hum Genet CJ, Schmidt PH, van de Kamp JJ. Genomic imprinting 1996;4:153-9. in hereditary glomus tumours: evidence for new ge- 30. Sirchia SM, De Andreis C, Pariani S, Grimoldi MG, netic theory. Lancet 1989;2:1291-4. Molinari A, Buscaglia M, et al. Chromosome 14 maternal uniparental disomy in the euploid cell line of a fetus with mosaic 46,XX/47,XX,+14 karyotype. Hum Reprint requests to: Deepak Kamnasaran, BS, 8-43 Genet 1994;94:355-8. 31. Healey S, Powell F, Battersby M, Chenevix-Trench Medical Sciences Bldg., University of Alberta, Ed- G, McGill J. Distinct phenotype in maternal uni- monton AB T6G 2H7; fax 780 492-1998, dkam- parental disomy of chromosome 14. Am J Med Genet [email protected]

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