Why is There No Diploid Overdose Effect in Prader-Willi Syndrome Due to Uniparental Disomy?

1996 ◽  
Vol 45 (1-2) ◽  
pp. 179-189 ◽  
Author(s):  
A. Smith
Keyword(s):  
Uniparental Disomy ◽  
Good Evidence ◽  
Monoallelic Expression ◽  
Chromosome 15 ◽  
Prader Willi Syndrome ◽  
Phenotypic Effect ◽  
Biallelic Expression ◽  
Chromosome 11P15 ◽  
Imprinted Gene ◽  
Maternal Imprinting

AbstractDue to DNA technology, it is now apparent that the mechanisms of genetic disease are more complex than the model of a gene with biallelic expression in the diploid state. If a gene is imprinted, monoallelic expression is the norm when the chromosomes of a pair are inherited normally from each parent. Uniparental disomy (UPD) is the abnormal situation where both chromosomes of a pair come from the same parent. When the chromosome contains an imprinted gene, UPD may result in nullisomy or disomy for a functional copy of that gene. If there are two imprinted loci on the same chromosome, UPD for that chromosome results in nullisomy for one imprinted gene but functional disomy for the other a “diploid overdose” (DO). This situation has been well demonstrated in the Prader-Willi syndrome (PWS) which is the nullisomic phenotype for the PWS gene(s) on chromosome 15q 11-13. Chromosome 15q11-13 also contains the gene for Angelman syndrome (AS) which has a phenotype distinct from PWS. Both loci are subject to imprinting – in PWS, the imprint is on the maternal chromosome 15, in AS it is on the paternal chromosome 15. All individuals with PWS due to maternal UPD, while functionally nullisomic for the PWS locus, are functionally disomic for the AS locus – a DO situation. Assuming that biallelic expression of an imprinted gene is harmful, one would expect DO for an imprinted gene to produce a phenotypic effect. Cases of PWS due to UPD do not appear to differ from those due to deletion (hypopigmentation in deletional cases can be explained by loss of D15S12 downstream from the critical region). There is no good evidence of DO for the AS locus in PWS due to UPD. Why then was it ‘necessary’ in evolutionary terms to imprint the AS locus and maintain the imprint faithfully for life. A similar situation of two imprinted genes on the same chromosome occurs with IGF2 and H19 on chromosome 11p15. Maternal imprinting for IGF2 and paternal imprinting for H19 is the norm. Paternal UPD in this situation does lead to a DO effect, namely Beckwith-Wiedemann syndrome. The possibility of a DO effect needs to be considered when assessing the phenotypic spectrum of UPD for other chromosomes currently under investigation.

Molecular Analysis of an Extra inv dup(15)(q13) Chromosome in Two Patients with Angelman Syndrome

1996 ◽  
Vol 45 (1-2) ◽  
pp. 217-220 ◽  
Author(s):  
T. Buchholz ◽  
S. Schuffenhauer ◽  
K. Evans ◽  
L. Robson ◽  
B. Appleton ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Angelman Syndrome ◽  
Uniparental Disomy ◽  
Molecular Data ◽  
Monoallelic Expression ◽  
Chromosome 15 ◽  
Prader Willi Syndrome ◽  
Loss Of Function ◽  
Maternal Allele ◽  
Molecular Defects

Angelman syndrome (AS) is caused by the loss of function of yet unidentified gene(s) which map within 15q 11-13 and show monoallelic expression from the maternal allele. Lack of the maternal allele(s), due to either a deletion on the maternal chromosome 15 (about 70% of AS patients) or a paternal uniparental disomy (UPD)15 (<5%), are the most common molecular defects in AS. Prader-Willi syndrome (PWS) also maps to proximal 15q, but is caused by the loss of function of paternally expressed gen(s) [1]. Here we describe clinical, cytogenetic and molecular data for two non-related patients with AS who carry a nonmosaic extra cromosome inv dup(15).

Safety and effectiveness of growth hormone therapy in infants with Prader-Willi syndrome younger than 2 years: a prospective study

2019 ◽  
Vol 32 (8) ◽  
pp. 879-884 ◽  
Author(s):  
Raquel Corripio ◽  
Carla Tubau ◽  
Laura Calvo ◽  
Carme Brun ◽  
Núria Capdevila ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Prospective Study ◽  
Mixed Model ◽  
Standard Deviation Score ◽  
Uniparental Disomy ◽  
Chromosome 15 ◽  
Prader Willi Syndrome ◽  
Gh Treatment ◽  
Maternal Uniparental Disomy ◽  
A Prospective Study

Abstract Background There is little evidence of the effects of early treatment with growth hormone (GH) in infants with Prader-Willi syndrome (PWS). A prospective study was conducted to assess the safety of GH therapy in infants younger than 2 years of age with PWS. Methods A total of 14 patients with PWS started treatment with GH under the age of 2 years and were followed over a 2-year period. A deletion of chromosome 15 was present in nine infants (64.3%) and maternal uniparental disomy 15 in five infants (35.7%). The median age at start of GH treatment was 9.6 months (interquartile range [IQR] 9.0–18.3 months). Changes in height standard deviation score (SDS), body mass index (BMI) SDS and subcapsular and tricipital skinfolds in the follow-up period were evaluated with a mixed-model regression analysis using the Package R. Results There were no fatal adverse events. A significant decrease (p < 0.001) in tricipital and subcapsular skinfold thickness, with an upward trend of height SDS and a downward trend of BMI SDS, was observed. Infants who started GH before 15 months of age started walking at a median of 18.0 [17.0–19.5] months vs. 36.6 [36.3–37.8] months for those who began treatment with GH after 15 months of age (p = 0.024). Conclusions GH treatment in infants with PWS less than 2 years of age is safe and improved body composition. Infants who received GH before the age of 15 months started to walk earlier.

scholarly journals Quantitative Analysis of SRNPN Gene Methylation by Pyrosequencing as a Diagnostic Test for Prader–Willi Syndrome and Angelman Syndrome

2006 ◽  
Vol 52 (6) ◽  
pp. 1005-1013 ◽  
Author(s):  
Helen E White ◽  
Victoria J Durston ◽  
John F Harvey ◽  
Nicholas CP Cross
Keyword(s):  
Diagnostic Test ◽  
Angelman Syndrome ◽  
Uniparental Disomy ◽  
Chromosome 15 ◽  
Prader Willi Syndrome ◽  
Maternal Uniparental Disomy ◽  
Cpg Sites ◽  
Specific Pcr ◽  
Small Nuclear Ribonucleoprotein ◽  
Maternal Contribution

Abstract 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 (∼70%) or maternal uniparental disomy (UPD; ∼30%). Most cases of AS result from the lack of a maternal contribution from this same region by maternal deletion (∼70%) or by paternal UPD (∼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.

Non-chromosome 15 marker chromosome in a Prader-Willi syndrome patient with uniparental disomy

2006 ◽  
Vol 48 (1) ◽  
pp. 97-99
Author(s):  
MIZUHO ICHIKAWA ◽  
MAKI OKAJIMA ◽  
TAKAHITO WADA ◽  
YUMI GOKAN ◽  
HIROMI SHIMAKAGE ◽  
...  
Keyword(s):  
Marker Chromosome ◽  
Uniparental Disomy ◽  
Chromosome 15 ◽  
Prader Willi Syndrome ◽  
Syndrome Patient

Relative locations of the centromere and imprinted SNRPN gene within chromosome 15 territories during the cell cycle in HL60 cells

2000 ◽  
Vol 113 (12) ◽  
pp. 2157-2165 ◽  
Author(s):  
M. Nogami ◽  
A. Kohda ◽  
H. Taguchi ◽  
M. Nakao ◽  
T. Ikemura ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Mutual Recognition ◽  
Ccd Camera ◽  
S Phase ◽  
Monoallelic Expression ◽  
Chromosome 15 ◽  
Hl60 Cells ◽  
Imprinted Gene ◽  
Centromeric Repeat ◽  
Gene Coding

Investigations of imprinted regions provide clues that increase our understanding of the regulation of gene functions at higher order chromosomal domains. Here, the relative positions of the chromosome 15 centromere and the imprinted SNRPN gene in interphase nuclei of human myeloid leukemia HL60 cells were compared, because the homologous association of this imprinted chromosomal domain was previously observed in lymphocytes and lymphoblasts. Four targets including the chromosome 15 territory, its centromere, the SNRPN gene on this chromosome, and the nucleus, were visualized simultaneously in three-dimensionally preserved nuclei using multicolor fluorescence in situ hybridization, and the spatial distributions of these probes were analyzed with a cooled CCD camera deconvolution system. We found that preferential association of SNRPN interhomologues did not occur during the cell cycle in HL60 cells, although this gene exhibited asynchronous replication and monoallelic expression in this cells. SNRPN was found to localize at the periphery of the chromosome territories, and it preferentially faced the nuclear membrane, unlike the adjacent centromeric repeat. The SNRPN gene and the centromere were located close to each other late in S phase, reflecting that these DNA segments may be compacted into the same intranuclear subcompartments with the progress of S phase and in course of preparation for the following G(2) phase. Our results suggest that, although an imprinted gene has features similar to those observed with intranuclear localization of other gene coding sequences, the characteristic of mutual recognition of imprinted regions is determined by certain cellular regulation, and it is not necessary for the allele-specific features of an imprinted gene.

The phenomenology and diagnosis of psychiatric illness in people with Prader–Willi syndrome

2008 ◽  
Vol 38 (10) ◽  
pp. 1505-1514 ◽  
Author(s):  
S. Soni ◽  
J. Whittington ◽  
A. J. Holland ◽  
T. Webb ◽  
E. N. Maina ◽  
...  
Keyword(s):  
Family History ◽  
Affective Disorder ◽  
Psychiatric Illness ◽  
Uniparental Disomy ◽  
Psychotic Symptoms ◽  
Chromosome 15 ◽  
Prader Willi Syndrome ◽  
Psychotic Illness ◽  
Genetic Subtype ◽  
History Of

BackgroundPsychotic illness is strongly associated with the maternal uniparental disomy (mUPD) genetic subtype of Prader–Willi syndrome (PWS), but not the deletion subtype (delPWS). This study investigates the clinical features of psychiatric illness associated with PWS. We consider possible genetic and other mechanisms that may be responsible for the development of psychotic illness, predominantly in those with mUPD.MethodThe study sample comprised 119 individuals with genetically confirmed PWS, of whom 46 had a history of psychiatric illness. A detailed clinical and family psychiatric history was obtained from these 46 using the PAS-ADD, OPCRIT, Family History and Life Events Questionnaires.ResultsIndividuals with mUPD had a higher rate of psychiatric illness than those with delPWS (22/34 v. 24/85, p<0.001). The profile of psychiatric illness in both genetic subtypes resembled an atypical affective disorder with or without psychotic symptoms. Those with delPWS were more likely to have developed a non-psychotic depressive illness (p=0.005) and those with mUPD a bipolar disorder with psychotic symptoms (p=0.00005). Individuals with delPWS and psychotic illness had an increased family history of affective disorder. This was confined exclusively to their mothers.ConclusionsPsychiatric illness in PWS is predominately affective with atypical features. The prevalence and possibly the severity of illness are greater in those with mUPD. We present a ‘two-hit’ hypothesis, involving imprinted genes on chromosome 15, for the development of affective psychosis in people with PWS, regardless of genetic subtype.

Prader-Willi syndrome due to maternal uniparental disomy of chromosome 15 in a boy with a balanced 3;21 translocation

2001 ◽  
Vol 100 (1) ◽  
pp. 85-86 ◽  
Author(s):  
Lori L. Bassett ◽  
Ron C. Michaelis ◽  
Mary Holland Geiger ◽  
Jack Tarleton ◽  
C. Lynn Moore ◽  
...  
Keyword(s):  
Uniparental Disomy ◽  
Chromosome 15 ◽  
Prader Willi Syndrome ◽  
Maternal Uniparental Disomy

Mosaic maternal uniparental disomy of chromosome 15 in Prader-Willi syndrome: Utility of genome-wide SNP array

2012 ◽  
Vol 161 (1) ◽  
pp. 166-171 ◽  
Author(s):  
Kosuke Izumi ◽  
Avni B. Santani ◽  
Matthew A. Deardorff ◽  
Holly A. Feret ◽  
Tanya Tischler ◽  
...  
Keyword(s):  
Snp Array ◽  
Uniparental Disomy ◽  
Chromosome 15 ◽  
Prader Willi Syndrome ◽  
Maternal Uniparental Disomy ◽  
Genome Wide

scholarly journals Molecular Changes in Prader-Willi Syndrome Neurons Reveals Clues About Increased Autism Susceptibility.

2021 ◽  
Author(s):  
Anna Kaitlyn Victor ◽  
Martin Donaldson ◽  
Daniel Johnson ◽  
Winston Miller ◽  
Lawrence Reiter
Keyword(s):  
Behavioral Problems ◽  
Neurodevelopmental Disorder ◽  
Uniparental Disomy ◽  
Autism Spectrum ◽  
Chromosome 15 ◽  
Prader Willi Syndrome ◽  
Maternal Uniparental Disomy ◽  
Mitochondrial Defects ◽  
Mitochondrial Transcripts ◽  
Global Reduction

Background: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hormonal dysregulation, obesity, intellectual disability, and behavioral problems. Most PWS cases are caused by paternal interstitial deletions of 15q11.2-q13.1, while a smaller number of cases are caused by chromosome 15 maternal uniparental disomy (PW-UPD). Children with PW-UPD are at higher risk for developing autism spectrum disorder (ASD) than the neurotypical population. In this study, we used expression analysis of PW-UPD neurons to try to identify the molecular cause for increased autism risk. Methods: Dental pulp stem cells (DPSC) from neurotypical control and PWS subjects were differentiated to neurons for mRNA sequencing. Significantly differentially expressed transcripts among all groups were identified. Downstream protein analysis including immunocytochemistry and immunoblots were performed to confirm the transcript level data and pathway enrichment findings. Results: We identified 9 transcripts outside of the PWS critical region (15q11.2-q13.1) that may contribute to core PWS phenotypes. Moreover, we discovered a global reduction in mitochondrial transcripts in the PW-UPD +ASD group. We also found decreased mitochondrial abundance along with mitochondrial aggregates in the cell body and neural projections of +ASD neurons. Conclusions: The 9 transcripts we identified common to all PWS subtypes may reveal PWS specific defects during neurodevelopment. Importantly, we found a global reduction in mitochondrial transcripts in PW-UPD +ASD neurons versus control and other PWS subtypes. We then confirmed mitochondrial defects in neurons from individuals with PWS at the cellular level. Quantification of this phenotype supports our hypothesis that the increased incidence of ASD in PW-UPD subjects may arise from mitochondrial defects in developing neurons.

Speech and Language Skills of Individuals With Prader-Willi Syndrome

2002 ◽  
Vol 11 (3) ◽  
pp. 285-294 ◽  
Author(s):  
Barbara A. Lewis ◽  
Lisa Freebairn ◽  
Shauna Heeger ◽  
Suzanne B. Cassidy
Keyword(s):  
Standardized Testing ◽  
Voice Quality ◽  
Speech Sound ◽  
Uniparental Disomy ◽  
Speaking Rate ◽  
Chromosome 15 ◽  
Prader Willi Syndrome ◽  
Speech And Language ◽  
Language Abilities ◽  
Motor Difficulties

The speech and language of 55 individuals (27 males and 28 females) with Prader-Willi syndrome (PWS), aged from 6 months to 42 years, were examined through standardized testing and spontaneous speech sample analysis. While great variability was noted in speech and language abilities, most subjects presented with speech sound errors characterized by imprecise articulation (85%), and oral motor difficulties (91%). Hypernasality was noted in 62% and hyponasality in 14%. Other speech characteristics included a slow speaking rate, flat intonation patterns, abnormal pitch of the voice, and harsh/hoarse voice quality. Narrative retelling abilities were poor, with specific deficits in sequencing of story events. Individuals with PWS as a result of deletions of chromosome 15 did not differ significantly in speech and language from individuals with PWS as a result of uniparental disomy.

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