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PubMed2006

Imprinted genes in placental growth and obstetric disorders.

Genomic imprinting has a special role in placental biology. Imprinted genes are often strongly expressed in the placenta, and the allelic expression bias due to imprinting is sometimes stronger in this extraembryonic organ than in the embryo and adult. Mutations, epimutations, and uniparental disomies affecting imprinted loci cause placental stunting or overgrowth in mice and humans, and placental neoplasms (complete hydatidiform moles) are androgenetic. Whether imprinted genes might also play a role in the more common medical conditions that affect the placenta, including preeclampsia and intrauterine growth restriction (IUGR), is an important question that is now receiving some attention. Here we review this area and describe recent data indicating altered expression of imprinted genes in the placental response to maternal vascular underperfusion associated with IUGR.

Female↗
PubMed2006

New chromosome 11p15 epigenotypes identified in male monozygotic twins with Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome demonstrating heterogeneous molecular alterations of two imprinted domains on chromosome 11p15. The most common molecular alterations include loss of methylation at the proximal imprinting center, IC2, paternal uniparental disomy (UPD) of chromosome 11p15 and hypermethylation at the distal imprinting center, IC1. An increased incidence of female monozygotic twins discordant for BWS has been reported. The molecular basis for eleven such female twin pairs has been demonstrated to be a loss of methylation at IC2, whereas only one male monozygotic twin pair has been reported with this molecular defect. We report here two new pairs of male monozygotic twins. One pair is discordant for BWS; the affected twin exhibits paternal UPD for chromosome 11p15 whereas the unaffected twin does not. The second male twin pair is concordant for BWS and both twins of the pair demonstrate hypermethylation at IC1. Thus, this report expands the known molecular etiologies for BWS twins. Interestingly, these findings demonstrate a new epigenotype-phenotype correlation in BWS twins. That is, while female monozygotic twins with BWS are likely to show loss of imprinting at IC2, male monozygotic twins with BWS reflect the molecular heterogeneity seen in BWS singletons. These data underscore the need for molecular testing in BWS twins, especially in view of the known differences among 11p15 epigenotypes with respect to tumor risk.

Beckwith-Wiedemann Syndrome↗
PubMed2006

Multicolor FISH used for the characterization of small supernumerary marker chromosomes (sSMC) in commercially available immortalized cell lines.

There are only about 30 commercially available cell lines which include small supernumerary marker chromosomes (sSMC). As approximately 2.5 million people worldwide are carriers of an sSMC, this small number of immortalized cell lines is hard to understand. sSMC cell lines provide practically unlimited material for continuing studies e.g. to learn more about marker chromosome formation, or karyotypic evolution. To obtain information about their genetic content, in the present study we analyzed by FISH and multicolor-FISH approaches 19 sSMC cell lines obtained from the European Collection of Cell Cultures (ECACC). Microdissection and reverse painting, (sub-) centromere-specific multicolor-FISH (sub-)cenM-FISH, multicolor banding (MCB) and selected locus-specific FISH probes were applied. Thus, we were able to characterize comprehensively 14 out of 19 sSMC carrying cell lines; in the remaining five cases an sSMC could not be detected. Surprisingly, in six of the nine cell lines with sSMC previously characterized for their chromosomal origin by others, those results had to be revised. This has impact on the conclusions of previous studies, e.g. for uniparental disomy (UPD) in connection with sSMC.

Cell Line↗
PubMed2006

Supernumerary marker chromosome 5 diagnosed by M-FISH in a child with congenital heart defect and unusual face.

We describe a female patient with a small supernumerary marker chromosome (sSMC) present in mosaic and characterized in detail by fluorescence in situ hybridization (FISH) using all 24 human whole chromosome painting probes, multicolor banding (MCB) and subcentromere specific multicolor FISH (subcenM-FISH). The sSMC was demonstrated to be derived from chromosome 5 and the karyotype of our patient was as follows: 47,XX,+mar.ish r(5)(::p13.2 approximately p13.3-->q11.2::) [60%]/46,XX [40%]. Partial trisomy for the proximal 5p and q chromosomal regions is a rare event. A critical region exists at 5p13 for the phenotype associated with duplication 5p. As far as we know, eight similar cases have been published up to now. We describe a new case which, to our knowledge, is the first characterized in such detail. The role of uniparental disomy (UPD) in cases of SMC is also discussed.

Abnormalities, Multiple↗
PubMed1997

Molecular markers for malignancy in adrenocortical tumors.

Little is known about the pathophysiology of sporadic adrenocortical tumors. Benign and malignant adrenocortical tumors are often difficult to distinguish by conventional histology. We tested 38 adrenocortical tumors (23 benign and 15 malignant) for loss of heterozygosity (LOH) at 17p13 and abnormalities in the 11p15 region (uniparental disomy, UPD, and overexpression of the IGF II gene). We showed that 17p13 LOH, 11p15 UPD and overexpression of the IFG II gene are frequent in adrenocortical tumors, occurring in 40% of them. These genetic changes are associated with the malignant phenotype and thus could be used for diagnostic evaluation of adrenocortical tumors.

Adolescent↗
PubMed1996

Maternal uniparental isodisomy of human chromosome 14 associated with a paternal t(13q14q) and precocious puberty.

Cytogenetic and molecular investigation of a boy with precocious puberty and motor developmental delay revealed a 45,XY,t(14q14q) or i(14q) karyotype with no paternal chromosome 14 contribution. VNTR analysis of loci on four other chromosomes excluded non-paternity with greater than 99% confidence. Results of VNTR and CA repeat analyses of ten loci along the entire length of chromosome 14 were consistent with homozygosity at all loci, suggesting that the chromosomal rearrangement was a maternal isochromosome for 14q. As the proband's father had a balanced Robertsonian translocation, t(13q14q), we suggest that the origin of the maternal uniparental disomy (UPD) was fertilization by a nullisomy 14 sperm with formation of the isochromosome in the early embryo. Also, the proband has several clinical features in common with six previously reported liveborn cases of maternal UPD 14: hypotonia and motor developmental delay, mild dysmorphic facial features, low birth weight and growth abnormalities, and, more specifically, precocious puberty among the four cases old enough to assess. The emergence of a syndrome associated with maternal UPD 14 suggests the possibility of genomic imprinting of regions of chromosome 14, especially a gene involved in the onset of puberty.

Adolescent↗
PubMed1993

Somatic mosaicism for partial paternal isodisomy in Wiedemann-Beckwith syndrome: a post-fertilization event.

Genomic imprinting has been implicated in the aetiology of an overgrowth cancer-prone syndrome, the Wiedemann-Beck-with syndrome (WBS). We have demonstrated uniparental disomy (UPD) for paternal chromosome 11p markers in 5 out of 25 sporadic cases (20%). Delineation of the extent of the disomy region may help in understanding the mechanism and the stage, meiotic or mitotic, of disomy formation in this disease and in associated tumours. Our current studies in WBS patients with seventeen 11p and one 11q markers reveal paternal isodisomy, not heterodisomy, in the five cases. For one case we demonstrate unambiguously that partial isodisomy for 11p and somatic mosaicism for UPD resulted from a post-fertilization event. The restriction of isodisomy to part of 11p in another case, and somatic mosaicism for UPD in three other cases, suggest a mitotic recombinational event that must have occurred after fertilization. Mosaic phenotypes reflect the timing of their origin and the fate of the cells involved, as well as the cell-specific pattern of imprinting. Somatic mosaicism for UPD in four cases may thus explain the incomplete forms of WBS. The association of hemihypertrophy in sporadic WBS and even some cases of isolated hemihypertrophy. This is in agreement with a recent report of paternal isodisomy for 11p markers in a patient with hemihypertrophy, Wilms' tumour and adrenocortical carcinoma. Moreover, the risk of developing a tumour seems higher (50%) for patients with paternal 11p UPD than for WBS patients in general (7.5%).

Adult↗
PubMed1993

Molecular investigation of familial Beckwith-Wiedemann syndrome: a model for paternal imprinting.

In familial Beckwith-Wiedemann syndrome (BWS), the mode of inheritance is uncertain and possible patterns include autosomal dominant, multifactorial and autosomal dominant sex-dependent inheritance. Genomic imprinting has recently been invoked to explain the unusual inheritance patterns in several disorders. We have previously reviewed 28 published kindreds of BWS and shown that paternal imprinting is probably responsible for familial BWS. In the present paper, highly informative RFLP markers in the 11p15.5 region have been shown to segregate with the disease gene as an autosomal dominant, but phenotypic manifestations in an offspring are dependent on the sex of the parent contributing the defective gene. In contrast to previous reports in which imprinting of the growth stimulator gene, IGF2, has been invoked as the mechanism explaining sporadic cases of BWS (especially in situations where uniparental disomy and trisomy of the 11p15.5 region has occurred), it is suggested that paternal imprinting of a growth suppressor gene, e.g., H19, may be one of the causes of familial BWS.

Alleles↗
PubMed1999

Abetalipoproteinemia caused by maternal isodisomy of chromosome 4q containing an intron 9 splice acceptor mutation in the microsomal triglyceride transfer protein gene.

Uniparental disomy (UPD), a rare inheritance of 2 copies of a single chromosome homolog or a region of a chromosome from one parent, can result in various autosomal recessive diseases. Abetalipoproteinemia (ABL) is a rare autosomal recessive deficiency of apoB-containing lipoproteins caused by a microsomal triglyceride transfer protein (MTP) deficiency. In this study, we describe a patient with ABL inherited as a homozygous intron 9 splice acceptor G(-1)-to-A mutation of the transfer protein gene. This mutation alters the splicing of the mRNA, resulting in a 36 amino acids, in-frame deletion of sequence encoded by exon 10. We analyzed chromosome 4, including MTP gene (4q22-24), using short tandem repeat markers. The proband has only his mother's genes in chromosome 4q spanning a 150-centimorgan region; ie, segmental maternal isodisomy 4q21-35, probably due to mitotic recombination. Nonpaternity between the proband and his father was excluded using 6 polymorphic markers from different chromosomes (paternity probability, 0.999). Maternal isodisomy (maternal UPD 4q) was the basis for homozygosity of the MTP gene mutation in this patient.

Abetalipoproteinemia↗
PubMed1998

Paternal mutation of the sulfonylurea receptor (SUR1) gene and maternal loss of 11p15 imprinted genes lead to persistent hyperinsulinism in focal adenomatous hyperplasia.

Congenital hyperinsulinism, or persistent hyperinsulinemic hypoglycemia of infancy (PHHI), is a glucose metabolism disorder characterized by unregulated secretion of insulin and profound hypoglycemia. From a morphological standpoint, there are two types of histopathological lesions, a focal adenomatous hyperplasia of islet cells of the pancreas in approximately 30% of operated sporadic cases, and a diffuse form. In sporadic focal forms, specific losses of maternal alleles (LOH) of the imprinted chromosomal region 11p15, restricted to the hyperplastic area of the pancreas, were observed. Similar mechanisms are observed in embryonal tumors and in the Beckwith-Wiedemann syndrome (BWS), also associated with neonatal but transient hyperinsulinism. However, this region also contains the sulfonylurea receptor (SUR1) gene and the inward rectifying potassium channel subunit (KIR6.2) gene, involved in recessive familial forms of PHHI, but not known to be imprinted. Although the parental bias in loss of maternal alleles did not argue in favor of their direct involvement, the LOH may also unmask a recessive mutation leading to persistent hyperinsulinism. We now report somatic reduction to hemizygosity or homozygosity of a paternal SUR1 constitutional heterozygous mutation in four patients with a focal form of PHHI. Thus, this somatic event which leads both to beta cell proliferation and to hyperinsulinism can be considered as the somatic equivalent, restricted to a microscopic focal lesion, of constitutional uniparental disomy associated with unmasking of a heterozygous parental mutation leading to a somatic recessive disorder.

ATP-Binding Cassette Transporters↗
PubMed2006

Familial robertsonian 13;14 translocation with mental retardation and epilepsy.

Familial reports of a robertsonian translocation in more than two generations are rare. We report three generations (a daughter, the mother, and the mother's father) with a heterozygous, balanced robertsonian translocation t(13;14)(q11;q11). Central nervous system disease was present, but differentially expressed, in generations I and III. The daughter presented with mental delay and epilepsy, and the mother was apparently healthy, whereas the mother's father was again symptomatic, with borderline intelligence. Fluorescent in situ hybridization analysis was performed to exclude a loss or gain of chromosomal material. No uniparental disomy was present. We concluded that genetic counseling in the presence of this rearrangement was extremely difficult, independent of the affected parent being symptomatic or asymptomatic.

Adult↗
PubMed2005

Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders.

The analysis of rare chromosomal translocations in myeloproliferative disorders has highlighted the importance of aberrant tyrosine kinase signaling in the pathogenesis of these diseases. Here we have investigated samples from 679 patients and controls for the nonreceptor tyrosine kinase JAK2 V617F mutation. Of the 480 myeloproliferative disorder (MPD) samples, the proportion of positive cases per disease subtype was 30 (20%) of 152 for atypical or unclassified MPD, 2 of 134 (2%) for idiopathic hypereosinophilic syndrome, 58 of 72 (81%) for polycythemia vera, 24 of 59 (41%) essential thrombocythemia (ET), and 15 of 35 (43%) for idiopathic myelofibrosis. V617F was not identified in patients with systemic mastocytosis (n = 28), chronic or acute myeloid leukemia (n = 35), secondary erythrocytosis (n = 4), or healthy controls (n = 160). Homozygosity for V617F was seen in 43% of mutant samples and was closely correlated with chromosome 9p uniparental disomy. Homozygosity was significantly less common in ET compared with other MPD subtypes. In 53 cases analyzed, the median level of PRV1 expression was significantly higher in V617F-positive cases compared with cases without the mutation. We conclude that V617F is widespread in MPDs. Detection of this acquired mutation is likely to have a major impact on the way patients with MPD are diagnosed, as well as serving as an obvious target for signal transduction therapy.

Case-Control Studies↗
PubMed2005

Molecular breakpoint cloning and gene expression studies of a novel translocation t(4;15)(q27;q11.2) associated with Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (MIM #176270; PWS) is caused by lack of the paternally-derived copies, or their expression, of multiple genes in a 4 Mb region on chromosome 15q11.2. Known mechanisms include large deletions, maternal uniparental disomy or mutations involving the imprinting center. De novo balanced reciprocal translocations in 5 reported individuals had breakpoints clustering in SNRPN intron 2 or exon 20/intron 20. To further dissect the PWS phenotype and define the minimal critical region for PWS features, we have studied a 22 year old male with a milder PWS phenotype and a de novo translocation t(4;15)(q27;q11.2). METHODS: We used metaphase FISH to narrow the breakpoint region and molecular analyses to map the breakpoints on both chromosomes at the nucleotide level. The expression of genes on chromosome 15 on both sides of the breakpoint was determined by RT-PCR analyses. RESULTS: Pertinent clinical features include neonatal hypotonia with feeding difficulties, hypogonadism, short stature, late-onset obesity, learning difficulties, abnormal social behavior and marked tolerance to pain, as well as sticky saliva and narcolepsy. Relative macrocephaly and facial features are not typical for PWS. The translocation breakpoints were identified within SNRPN intron 17 and intron 10 of a spliced non-coding transcript in band 4q27. LINE and SINE sequences at the exchange points may have contributed to the translocation event. By RT-PCR of lymphoblasts and fibroblasts, we find that upstream SNURF/SNRPN exons and snoRNAs HBII-437 and HBII-13 are expressed, but the downstream snoRNAs PWCR1/HBII-85 and HBII-438A/B snoRNAs are not. CONCLUSION: As part of the PWCR1/HBII-85 snoRNA cluster is highly conserved between human and mice, while no copy of HBII-438 has been found in mouse, we conclude that PWCR1/HBII-85 snoRNAs is likely to play a major role in the PWS- phenotype.

Adult↗
PubMed2002

The gene locus encoding iodothyronine deiodinase type 3 (Dio3) is imprinted in the fetus and expresses antisense transcripts.

The mouse Dio3 gene codes for the type 3 iodothyronine deiodinase (D3), a conserved selenocysteine-containing enzyme that inactivates thyroid hormones and is highly expressed during early development. The mouse Dio3 gene and its human homolog map to chromosomal regions that are known to contain imprinted genes. We assessed the allelic expression of the Dio3 using a mouse model in which the gene had been inactivated by the introduction of a critical mutation in the selenocysteine codon. We compared Dio3 gene expression in fetuses that were either wild type or heterozygous (+/-Dio3) for the mutation. D3 enzymatic activities in the head, limbs, liver and body of heterozygous fetuses (E14 to E18) that inherited the mutation from the mother were no different from those found in their wild type littermates. However, D3 activities in heterozygous animals that inherited the mutation from the father were only 18 to 28% of the activities of their wild type littermates in these same tissues. No detectable activity was found in fetuses homozygous for the mutation indicating full inactivation of the enzyme. Northern analysis of mRNA from E15 fetuses showed that the Dio3 mRNA transcripts generated from the paternal allele were at least 5 times more abundant than the transcripts originated from the maternal allele. We conclude that the Dio3 gene is subject to genomic imprinting and preferentially expressed from the paternal allele in the mouse fetus. We also identified a gene that is transcribed antisense from the Dio3 locus. The Dio3 gene likely belongs to the same cluster of imprinted genes detected in mouse chromosome 12 and human chromosome 14 and should be considered as a candidate gene that might play a role in the phenotypic abnormalities associated with uniparental disomy of those chromosomes, a condition in which gene expression is altered due to abnormal genomic imprinting.

Alleles↗
PubMed2003

A case report in favor of a multistep adrenocortical tumorigenesis.

The mechanisms of adrenocortical tumorigenesis are still not fully understood. Data from clonal analysis, comparative genomic hybridization, and allelotyping suggest that it involves a multistep process during which several genetic defects are progressively acquired, leading to the malignant transformation. The events involved in the first steps of this process are not well known, and most of the abnormalities described in adrenocortical tumors to date are associated with the malignant phenotype. We report a case that suggests that adrenocortical tumorigenesis may be a multistep process. A 43-yr-old patient underwent surgery for an incidentally discovered adrenal mass. Pathological analysis showed that this tumor consisted of two parts: a central part with features of malignancy surrounded by another part with a strictly benign appearance. These data were confirmed by molecular analysis and comparative genomic hybridization that were consistent with either a malignant or benign presentation. The apparently malignant part of the tumor exhibited molecular abnormalities [17p13 loss of heterozygosity (LOH), 11p15 uniparental disomy and overexpression of the IGF-II gene] as well as chromosomal gains and losses (comparative genomic hybridization) that have been previously described in malignant tumors. No abnormalities were found in the surrounding benign tissues. Although this observation is not definitive proof that adrenocortical tumorigenesis occurs via a multistep process, it suggests that there is a progressive change from the benign to the malignant state in some adrenocortical tumors.

Adrenal Cortex Neoplasms↗
PubMed2006

IGF-II serum levels are normal in children with Silver-Russell syndrome who frequently carry epimutations at the IGF2 locus.

CONTEXT: Epigenetic mutations of 11p15 encompassing IGF2 are present in short children with Silver-Russell syndrome (SRS) with high frequency (31-50%). It has been speculated that these mutations characterized by demethylation of ICR1 cause diminished IGF2 expression. OBJECTIVE: We aimed to determine the prevalence of pathologically low IGF-II serum levels in children with SRS. SUBJECTS: SRS was defined by birth weight or length below the 3rd percentile, lack of postnatal catch-up growth, and the presence of two of the following characteristics: typical face, relative macrocephaly, and skeletal asymmetry. Serum samples of 30 patients were available. Mean age was 5.4 +/- 2.1 yr. METHODS: The serum levels of IGF-I, IGF-II, IGF binding protein (IGFBP)-2, and IGFBP-3 were measured by RIA and compared with age-related reference values and with serum concentrations measured in age- and gender-matched controls born small for gestational age (SGA), but lacking major dysmorphic features. Analysis of genomic DNA was possible in a subgroup of children with SRS: the methylation status of the ICR1 locus on 11p15 and the parental origin of chromosome 7 were analyzed in 9 and 23 children, respectively. RESULTS: Demethylation of ICR1 was found in 44% and uniparental disomy in 17% of the tested children with SRS. The median IGF-II serum level in SRS was 441 microg/liter (range, 238-875). This was significantly higher than in the SGA controls: 387 microg/liter (range, 265-596) (P < 0.03), but below the median value of the age-related reference, which was 532 microg/liter. The four children with SRS and ICR1 demethylation had high-normal and normal IGF-II serum levels that were higher than the levels of their SGA controls. IGF-I, IGFBP-2, and IGFBP-3 serum levels were not different between the SRS children and their SGA controls. CONCLUSIONS: Our data render it unlikely that demethylation of ICR1 on 11p15 does cause diminished IGF-II serum levels in children with SRS. This observation does not exclude deficient IGF-II action before birth.

Case-Control Studies↗
PubMed2006

Quantitative analysis of SNRPN(correction of SRNPN) gene methylation by pyrosequencing as a diagnostic test for Prader-Willi syndrome and Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are 2 distinct neurodevelopmental disorders caused primarily by deficiency of specific parental contributions at an imprinted domain within the chromosomal region 15q11.2-13. In most cases, lack of paternal contribution leads to PWS either by paternal deletion (approximately 70%) or maternal uniparental disomy (UPD; approximately 30%). Most cases of AS result from the lack of a maternal contribution from this same region by maternal deletion (approximately 70%) or by paternal UPD (approximately 5%). Analysis of allelic methylation differences at the small nuclear ribonucleoprotein polypeptide N (SNRPN) locus can differentiate the maternally and paternally inherited chromosome 15 and can be used as a diagnostic test for AS and PWS. METHODS: Sodium bisulfite-treated genomic DNA was PCR-amplified for the SNRPN gene. We used pyrosequencing to individually quantify the resulting artificial C/T sequence variation at CpG sites. Anonymized DNA samples from PWS patients (n = 40), AS patients (n = 31), and controls (n = 81) were analyzed in a blinded fashion with 2 PCR and 3 pyrosequencing reactions. We compared results from the pyrosequencing assays with those obtained with a commonly used methylation-specific PCR (MS-PCR) diagnostic protocol. RESULTS: The pyrosequencing assays had a sensitivity and specificity of 100% and provided quantification of methylation at 12 CpG sites within the SNRPN locus. The resulting diagnoses were 100% concordant with those obtained from the MS-PCR protocol. CONCLUSIONS: Pyrosequencing is a rapid and robust method for quantitative methylation analysis of the SNRPN locus and can be used as a diagnostic test for PWS and AS.

Angelman Syndrome↗
PubMedDate not supplied

Screening for insulin-like growth factor-I receptor mutations in patients with Silver-Russell syndrome.

Individuals with a deletion of 15q26.1-->qter which contains the insulin-like growth factor-I (IGF-I) receptor gene exhibit phenotypical similarities to patients with Silver-Russell syndrome (SRS) who represent a group of short children affected by pre- and postnatal growth failure and several dysmorphic features. The genetic basis of SRS is presumably heterogeneous. The IGF-I receptor gene is a good SRS candidate gene because the biological effects of the major growth factors IGF-I and -II are transmitted through the IGF-I receptor during pre- and postnatal growth. All 12 patients studied exhibited the classical SRS phenotype with low birth weight, connatal macrocephaly, typical facial features and short stature at presentation. Klinodactyly of the fifth finger was found in ten patients, and skeletal asymmetry in seven. Chromosomal analysis gave normal results. Uniparental disomy of chromosome 7 was excluded. After reverse transcription of RNA, 19 overlapping cDNA fragments encompassing the whole IGF-I receptor coding sequence were PCR-amplified and screened for mutations by single strand conformation analysis (SSCP). In eight of 12 patients studied, we detected four SSCP polymorphisms which were directly sequenced. All single base exchanges (C948A, C2343T, G3174A and G3915A) were silent variants of the IGF-I receptor gene, two of which were also present in control individuals. In conclusion, for the first time, the complete coding region of the IGF-I receptor gene was screened for mutations in patients with SRS. Our data do not support the suggestion that the IGF-I receptor is frequently involved in the pathogenesis of SRS.

Abnormalities, Multiple↗