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1.
Genomic imprinting: potential function and mechanisms revealed by the Prader-Willi and Angelman syndromes 总被引:4,自引:0,他引:4
The Prader-Willi (PWS) and Angelman (AS) syndromes are two clinically
distinct syndromes which result from lack of expression of imprinted genes
within chromosome 15q11-q13. These two syndromes result from 15q11-q13
deletions, chromosome 15 uniparental disomy (UPD), imprinting centre
mutations and, for AS, probable mutations in a single gene. The
differential phenotype results from a paternal genetic deficiency in PWS
patients and a maternal genetic deficiency in AS patients. Within
15q11-q13, four genes (SNRPN, IPW, ZNF127, FNZ127) and two expressed
sequence tags (PAR1 and PAR5) have been found to be expressed only from the
paternally inherited chromosome, and therefore all must be considered
candidate genes involved in the pathogenesis of PWS. A candidate AS gene
(UBE3A) has very recently been identified. The mechanisms of imprinted gene
expression are not yet understood, but it is clear that DNA methylation is
involved in both somatic cell expression and inheritance of the imprint.
The presence of DNA methylation imprints that distinguish the paternally
and maternally inherited alleles is a common characteristic of all known
imprinted genes which have been studied extensively, including SNRPN and
ZNF127. Recently, several PWS and AS patients have been found that have
microdeletions in a region upstream of the SNRPN gene referred to as the
imprinting centre, or IC. Paternal IC deletions in PWS patients and
maternal IC deletions in AS patients result in uniparental DNA methylation
and uniparental gene expression at biparentally inherited loci. The IC is a
novel genetic element which controls initial resetting of the parental
imprint in the germline for all imprinted gene expression over a 1.5-2.5 Mb
region within chromosome 15q11-q13.
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2.
Karthik Muthusamy Erica L. Macke Eric W. Klee Peter J. Tebben Jennifer L. Hand Linda Hasadsri Cherisse A. Marcou Lisa A. Schimmenti 《American journal of medical genetics. Part A》2020,182(10):2442-2449
Prader–Willi syndrome (PWS) is a prototypic genetic condition related to imprinting. Causative mechanisms include paternal 15q11‐q13 deletion, maternal chromosome 15 uniparental disomy (UPD15), Prader–Willi Syndrome/Angelman Syndrome (PWS/AS) critical region imprinting defects, and complex chromosomal rearrangements. Maternal UPD15‐related PWS poses risks of concomitant autosomal recessive (AR) disorders when the mother carries a pathogenic variant in one of the genes on chromosome 15 associated with autosomal recessive inherited disease. Co‐occurrence of autosomal recessive conditions in the setting of UPD leads to increased complexity of the clinical phenotype, and may delay the diagnosis of PWS. We report a patient with PWS and associated congenital ichthyosis due to maternal UPD15, and a homozygous novel pathogenic variant in ceramide synthase 3 (CERS3). We also review the literature of associated disorders reported in the setting of maternal UPD15‐related PWS and provide a summary of the previously described CERS3 variants. This represents the second case of autosomal recessive congenital ichthyosis (ARCI) in the setting of PWS and UPD15. There needs to be a high index of suspicion of this genetic mechanism when there is unexpected phenotype or evolution of the clinical course in a patient with PWS. 相似文献
3.
Klein OD Cotter PD Albertson DG Pinkel D Tidyman WE Moore MW Rauen KA 《Clinical genetics》2004,65(6):477-482
Prader-Willi syndrome (PWS) is caused by lack of expression of paternally inherited genes on chromosome 15q11-->15q13. Most cases result from microdeletions in proximal chromosome 15q. The remainder results from maternal uniparental disomy of chromosome 15, imprinting center defects, and rarely from balanced or unbalanced chromosome rearrangements involving chromosome 15. We report a patient with multiple congenital anomalies, including craniofacial dysmorphology, microcephaly, bilateral cryptorchidism, and developmental delay. Cytogenetic analysis showed a de novo 45,XY,der(5)t(5;15)(p15.2;q13), -15 karyotype. In effect, the proband had monosomies of 5p15.2-->pter and 15pter-->15q13. Methylation polymerase chain reaction analysis of the promoter region of the SNRPN gene showed only the maternal allele, consistent with the PWS phenotype. The proband's expanded phenotype was similar to other patients who have PWS as a result of unbalanced translocations and likely reflects the contribution of the associated monosomy. Array comparative genomic hybridization (array CGH) confirmed deletions of both distal 5p and proximal 15q and provided more accurate information as to the size of the deletions and the molecular breakpoints. This case illustrates the utility of array CGH in characterizing complex constitutional structural chromosome abnormalities at the molecular level. 相似文献
4.
Robert D. Nicholls 《American journal of medical genetics. Part A》1993,46(1):16-25
Although Angelman (AS) and Prader-Willi (PWS) syndromes are human genetic disorders with distinctly different developmental and neurobehavioural phenotypes, they both have abnormalities in inheritance of chromosome 15q11–q13. Whether AS or PWS arises depends on the parental origin of a deletion or uniparental disomy (the inheritance of 2 copies of a genetic locus from only one parent) for 15q11–q13. Normal development requires a genetic contribution for this genetic region from both a male and female parent. The dependence on parental origin implies that genes in human 15q11–q13 have distinct functions depending upon epigenetic, parent-of-origin differences, known as genomic imprinting. Here, I review the role of uniparental disomy and genomic imprinting in the pathogenesis of AS and PWS, and briefly discuss phenotype-genotype correlations using candidate genes and mouse models, in particular for hypopigmentation. © 1993 Wiley-Liss, Inc. 相似文献
5.
Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are two distinct neurodevelopmental disorders, each caused by several genetic and epigenetic mechanisms involving the proximal long arm of chromosome 15. Lack of a functional paternal copy of 15q11-q13 causes PWS; lack of a functional maternal copy of UBE3A, a gene within 15q11-q13, causes AS. This region of chromosome 15 contains a number of imprinted genes that are coordinately regulated by an imprinting center (PWS/AS-IC) that contains two functional elements, the PWS-SRO and the AS-SRO. A chromosome lacking the PWS-SRO has the maternal state of gene activity and epigenetic modification after either maternal or paternal transmission; a chromosome lacking the AS-SRO but containing the PWS-SRO has the paternal state of gene activity and epigenetic modification after either maternal or paternal transmission. The maternal state of chromosome 15q11-q13 is associated with methylation of the PWS-SRO, while the paternal state is associated with lack of methylation of the PWS-SRO. Although most models of PWS/AS region imprinting assume that the PWS-SRO is methylated during oogenesis and that this methylation of the maternal PWS-SRO is maintained after fertilization, several lines of evidence suggest that the maternal PWS-SRO is in fact not methylated until after fertilization. Imprinting defects affecting the PWS/AS region can arise from failure to demethylate the PWS-SRO in the male germ line, from failure to methylate the maternal PWS-SRO, or from failure to maintain PWS-SRO methylation after fertilization. 相似文献
6.
Prader–Willi syndrome and early‐onset morbid obesity NIH rare disease consortium: A review of natural history study
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Merlin G. Butler Virginia Kimonis Elisabeth Dykens June A. Gold Jennifer Miller Roy Tamura Daniel J. Driscoll 《American journal of medical genetics. Part A》2018,176(2):368-375
7.
Flori E Biancalana V Girard-Lemaire F Favre R Flori J Doray B Mandel JL 《European journal of human genetics : EJHG》2004,12(3):181-186
Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are associated with a loss of function of imprinted genes in the 15q11-q13 region mostly due to deletions or uniparental disomies (UPD). These anomalies usually occur de novo with a very low recurrence risk. However, in rare cases, familial translocations are observed, giving rise to a high recurrence risk. We report on the difficulties of genetic counseling and prenatal diagnosis in a family segregating for a translocation (14;15)(q11;q13) where two consanguineous parents carry the same familial translocation in this chromosome 15 imprinting region. Both children of the couple inherited a chromosomal anomaly leading to PWS. However, a paternal 15q11-q13 deletion was responsible for PWS in the first child, whereas prenatal diagnosis demonstrated that PWS was associated with a maternal 15q11-q13 UPD in the fetus. This report demonstrates that both conventional and molecular cytogenetic parental analyses have to be performed when a deletion is responsible for PWS or AS in order not to overlook a familial translocation and to insure reliable diagnosis and genetic counseling. 相似文献
8.
Maina EN Webb T Soni S Whittington J Boer H Clarke D Holland A 《Journal of human genetics》2007,52(4):297-307
Prader-Willi syndrome (PWS) is a neurodevelopmental disorder associated with abnormalities of chromosome 15q11q13. The majority
of cases result either from a deletion approximately 4 Mb in size, affecting chromosome 15 of paternal origin or from UPD(15)mat;
these account for ~70 and ~20–25% of PWS cases, respectively. In the remaining 3–5% of PWS cases where neither the deletion
nor UPD is detectable, PWS is thought to be caused either by a defect in the imprinting centre resulting in a failure to reset
the paternally inherited chromosome 15 derived from the paternal grandmother or, very occasionally, from a balanced translocation
involving a breakpoint in 15q11q13. Nine probands with a firm clinical diagnosis of PWS but who had neither a typical deletion
in the PWS region nor UPD(15)mat were investigated for inactivating mutations in 11 genes located in the PWS region, including
SNURF and SNRPN, which are associated with the imprinting centre. Other genes studied for mutations included MKRN3, NDN, IPW, HBII-85, HBII-13, HBII-436, HBII-438a, PAR1 and PAR5. A possibly inactivating mutation in the SNRPN minimal promoter region was identified. No other inactivating mutations were found in the remainder of our panel of PWS subjects
with atypical genetics. Expression levels of several of the candidate genes for PWS were also investigated in this series
of probands. The results indicate that PWS may result from a stochastic partial inactivation of important genes. 相似文献
9.
Natalie Blagowidow Joan H.M. Knoll Lori Rollings Paolo Fortina Donna M. McDonald‐McGinn Nancy B. Spinner Elaine H. Zackai 《American journal of medical genetics. Part A》2000,92(1):19-24
The Prader‐Willi syndrome (PWS) critical region on 15q11–q13 is subject to imprinting. PWS becomes apparent when genes on the paternally inherited chromosome are not expressed. Familial PWS is rare. We report on a family in which a male and a female paternal first cousin both have PWS with cytogenetically normal karyotypes. Fluorescence in situ hybridization (FISH) analysis shows a submicroscopic deletion of SNRPN, but not the closely associated loci D15S10, D15S11, D15S63, and GABRB3. The cousins' fathers and two paternal aunts have the same deletion and are clinically normal. The grandmother of the cousins is deceased and not available for study, and their grandfather is not deleted for SNRPN. DNA methylation analysis of D15S63 is consistent with an abnormality of the imprinting center associated with PWS. “Grandmatrilineal” inheritance occurs when a woman with deletion of an imprinted, paternally expressed gene is at risk of having affected grandchildren through her sons. In this case, PWS does not become evident as long as the deletion is passed through the matrilineal line. This represents a unique inheritance pattern due to imprinting. Am. J. Med. Genet. 92:19–24, 2000. © 2000 Wiley‐Liss, Inc. 相似文献
10.
11.
Prader-Willi and Angelman syndromes: sister imprinted disorders 总被引:6,自引:0,他引:6
Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are clinically distinct complex disorders mapped to chromosome 15q11-q13. They both have characteristic neurologic, developmental, and behavioral phenotypes plus other structural and functional abnormalities. However, the cognitive and neurologic impairment is more severe in AS, including seizures and ataxia. The behavioral and endocrine disorders are more severe in PWS, including obsessive-compulsive symptoms and hypothalamic insufficiency. Both disorders can result from microdeletion, uniparental disomy, or an imprinting center defect in 15q11-q13, although the abnormality is on the paternally derived chromosome 15 for PWS and the maternally derived 15 for AS because of genomic imprinting. Although the same gene may control imprinting for both disorders, the gene(s) causing their phenotypes differ. AS results from underexpression of a single gene, UBE3A, which codes for E6-AP, a protein that functions to transfer small ubiquitin molecules to certain target proteins, to enable their degradation. The genes responsible for PWS are not determined, although several maternally imprinted genes in 15q11-q13 are known. The most likely candidate is SNRPN, which codes for a small nuclear ribonucleoprotein, a ribosome-associated protein that controls gene splicing and thus synthesis of critical proteins in the brain. Animal models exist for both disorders. The genetic relationship between PWS and AS makes them unique and potentially highly instructive disorders that contribute substantially to the population burden of cognitive impairment. 相似文献
12.
A population-based cohort of people with a clinical diagnosis of Prader-Willi syndrome (PWS) was genetically assessed using molecular diagnostic methods and subsequently divided into the following genetic subtypes involving chromosome 15: 'deletion', 'disomy' and genetically negative (referred to as 'PWS-like'). The physical and behavioral characteristics of the three groups were compared in order to evaluate the unique characteristics of the phenotype resulting from loss of expression of imprinted genes at 15q11q13 (PWS vs. PWS-like cases), the possible effect of either haploid insufficiency of non-imprinted genes (deletion cases), or gain of function of imprinted genes (disomy cases) located within the PWS critical region at 15q11q13. In this study, the main differences between probands with either a deletion or disomy are considered, and the possible involvement of contributing genes discussed. The differences within the PWS group proved difficult to quantify. It would appear that haploid insufficiency or gain of function are more subtle contributors than gender-specific genomic imprinting in the production of the PWS phenotype. 相似文献
13.
Shinji Saitoh Karin Buiting Suzanne B. Cassidy Jeffrey M. Conroy Daniel J. Driscoll James M. Gabriel Gabriele Gillessen-Kaesbach Christopher C. Glenn Louise R. Greenswag Bernhard Horsthemke Ikuko Kondo Katsuko Kuwajima Norio Niikawa Peter K. Rogan Stuart Schwartz James Seip Charles A. Williams Robert D. Nicholls 《American journal of medical genetics. Part A》1997,68(2):195-206
Recent studies have identified a new class of Prader-Willi syndrome (PWS) and Angelman syndrome (AS) patients who have biparental inheritance, but neither the typical deletion nor uniparental disomy (UPD) or translocation. However, these patients have uniparental DNA methylation throughout 15q11-q13, and thus appear to have a mutation in the imprinting process for this region. Here we describe detailed clinical findings of five AS imprinting mutation patients (three families) and two PWS imprinting mutation patients (one new family). All these patients have essentially the classical clinical phenotype for the respective syndrome, except that the incidence of microcephaly is lower in imprinting mutation AS patients than in deletion AS patients. Furthermore, imprinting mutation AS and PWS patients do not typically have hypopigmentation, which is commonly found in patients with the usual large deletion. Molecular diagnosis of these cases is initially achieved by DNA methylation analyses of the DN34/ZNF127, PW71 (D15S63), and SNRPN loci. The latter two probes have clear advantages in the simple molecular diagnostic analysis of PWS and AS patients with an imprinting mutation, as has been found for typical deletion or UPD PWS and AS cases. With the recent finding of inherited microdeletions in PWS and AS imprinting mutation families, our studies define a new class of these two syndromes. The clinical and molecular identification of these PWS and AS patients has important genetic counseling consequences. Am. J. Med. Genet. 68:195–206, 1997 © 1997 Wiley-Liss, Inc. 相似文献
14.
15.
The necdin gene is deleted in Prader-Willi syndrome and is imprinted in human and mouse 总被引:9,自引:5,他引:9
Human chromosome 15q11-q13 contains genes that are imprinted and expressed
from only one parental allele. Prader-Willi syndrome (PWS) is due to the
loss of expression of one or more paternally expressed genes on proximal
human chromosome 15q, most often by deletion or maternal uniparental
disomy. Several candidate genes and a putative imprinting centre have been
identified in the deletion region. We report that the human necdin-encoding
gene (NDN) is within the centromeric portion of the PWS deletion region,
between the two imprinted genes ZNF127 and SNRPN. Murine necdin is a
nuclear protein expressed exclusively in differentiated neurons in the
brain. Necdin is postulated to govern the permanent arrest of cell growth
of post-mitotic neurons during murine nervous system development. We have
localized the mouse locus Ndn encoding necdin to chromosome 7 in a region
of conserved synteny with human chromosome 15q11-q13, by genetic mapping in
an interspecific backcross panel. Furthermore, we demonstrate that
expression of Ndn is limited to the paternal allele in RNA from newborn
mouse brain. Expression of NDN is detected in many human tissues, with
highest levels of expression in brain and placenta. NDN is expressed
exclusively from the paternally inherited allele in human fibroblasts. Loss
of necdin gene expression may contribute to the disorder of brain
development in individuals with PWS.
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16.
Camprubí C Coll MD Villatoro S Gabau E Kamli A Martínez MJ Poyatos D Guitart M 《European journal of medical genetics》2007,50(1):11-20
Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are genetic disorders caused by a deficiency of imprinted gene expression from the paternal or maternal chromosome 15, respectively. This deficiency is due to the deletion of the 15q11-q13 region, parental uniparental disomy of the chromosome 15, or imprinting defect (ID). Mutation of the UBE3A gene causes approximately 10% of AS cases. In this present study, we describe the molecular analysis and phenotypes of two PWS patients and four AS patients with ID. One of the PWS patients has a non-familial imprinting center (IC) deletion and displayed a severe phenotype with an atypical PWS appearance, hyperactivity and psychiatric vulnerability. The other PWS and AS patients did not present genetic abnormalities in the IC, suggesting an epimutation as the genetic cause. The methylation pattern of two AS patients showed a faint maternal band corresponding to a mosaic ID. One of these mosaic patients displayed a mild AS phenotype while the other displayed a PWS-like phenotype. 相似文献
17.
Haruta M Meguro M Sakamoto YK Hoshiya H Kashiwagi A Kaneko Y Mitsuya K Oshimura M 《Journal of human genetics》2005,50(3):124-132
Human chromosome 15q11–q13 involves a striking imprinted gene cluster of more than 2 Mb that is concomitant with multiple neurological disorders manifested by Prader–Willi syndrome (PWS) and Angelman syndrome (AS). PWS and AS patients with imprinting mutation have microdeletions, which share a 4.3 kb short region of overlap (SRO) at the 5 end of the paternal SNURF-SNRPN gene in PWS, or on the maternal allele, which shares a 880 bp SRO located at the 35 kb upstream of the SNURF-SNRPN promoter in AS. Recent studies have revealed an essential role of PWS-SRO in the postzygotic maintenance of the appropriate epigenotype on the paternal chromosome. For AS-SRO, however, there is insufficient experimental evidence exists to determine the direct functions. Here we show that the complete deletion of AS-SRO does not cause any anomalies of imprinted gene expression or DNA methylation on the mutated human chromosome 15, further supporting the idea that AS-SRO is dispensable for post implantation imprint maintenance. This implies that AS-SRO is not essential for the robust epigenotype preservation in somatic cells. 相似文献
18.
Birgitt Schüle Mohammed Albalwi Emma Northrop David I Francis Margaret Rowell Howard R Slater RJ McKinlay Gardner Uta Francke 《BMC medical genetics》2005,6(1):18
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). 相似文献19.
Linkage analysis with chromosome 15q11-13 markers shows genomic imprinting in familial Angelman syndrome.
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E J Meijers-Heijboer L A Sandkuijl H G Brunner H J Smeets A J Hoogeboom W H Deelen J O van Hemel M R Nelen D F Smeets M F Niermeijer et al. 《Journal of medical genetics》1992,29(12):853-857
Angelman syndrome (AS) and Prader-Willi syndrome (PWS) have become the classical examples of genomic imprinting in man, as completely different phenotypes are generated by the absence of maternal (AS) or paternal (PWS) contributions to the q11-13 region of chromosome 15 as a result of deletion or uniparental disomy. Apparently, most patients are sporadic cases. The genetic mechanism underlying familial AS has remained enigmatic for a long time. Recently, evidence has been emerging suggesting autosomal dominant inheritance of a detectable or undetectable defect in a gene or genes at 15q11-13, subject to genomic imprinting. The present report describes an unusually large pedigree with segregation of AS through maternal inheritance and apparent asymptomatic transmission through several male ancestors. Deletion and paternal disomy at 15q11-13 were excluded. However, the genetic defect is still located in this region, as we obtained a maximum lod score of 5.40 for linkage to the GABA receptor locus GABRB3 and the anonymous DNA marker D15S10, which have been mapped within or adjacent to the AS critical region at 15q11-13. The size of the pedigree allowed calculation of an odds ratio in favour of genomic imprinting of 9.25 x 10(5). This family illustrates the necessity of extensive pedigree analysis when considering recurrence risks for relatives of AS patients, those without detectable deletion or disomy in particular. 相似文献
20.
Merlin G. Butler Virginia Kimonis Elisabeth Dykens June Anne Gold Roy Tamura Jennifer L. Miller Daniel J. Driscoll 《American journal of medical genetics. Part A》2019,179(8):1531-1534
Prader‐Willi syndrome (PWS) is generally due to sporadic paternal deletions of the chromosome 15q11‐q13 region followed by maternal disomy 15. Advanced maternal age is more commonly seen in those with maternal disomy 15. Environmental factors (e.g., drug use, occupational chemical exposure, infectious agents, and irradiation) could account for chromosome changes. Previous evidence of differences in male and female gametogenesis could suggest an environmental role in the causation of the paternal 15q11‐q13 deletion seen in PWS. Certain occupations such as hydrocarbon‐exposing occupations (e.g., landscaping, farming, and painting) and viral exposure (e.g., human coronavirus 229E causing upper respiratory infections in adults with an incorporation site in the human genome at chromosome 15q11) can be seasonal in nature and contribute to chromosome damage. To assess, we reviewed birth seasonality data in a large cohort of individuals with PWS recruited nationally (N = 355) but no significant differences were seen by month between those with the 15q11‐q13 deletion compared with maternal disomy 15 when analyzing quarterly seasonal patterns. Although early evidence supported birth seasonality differences in PWS, a larger number of individuals in our recent study using advanced genetic testing methods did not find this observation. 相似文献