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Auteur Nora URRACA |
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Increased copy number for methylated maternal 15q duplications leads to changes in gene and protein expression in human cortical samples / Haley SCOLES in Molecular Autism, (December 2011)
[article]
Titre : Increased copy number for methylated maternal 15q duplications leads to changes in gene and protein expression in human cortical samples Type de document : Texte imprimé et/ou numérique Auteurs : Haley SCOLES, Auteur ; Nora URRACA, Auteur ; Samuel CHADWICK, Auteur ; Lawrence REITER, Auteur ; Janine M. LASALLE, Auteur Année de publication : 2011 Article en page(s) : 41 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : BACKGROUND:Duplications of chromosome 15q11-q13 account for ~3% of autism cases. Chromosome 15q11-q13 contains imprinted genes necessary for normal mammalian neurodevelopment controlled by a differentially methylated imprinting center (PWS-IC). Maternal duplications of 15q11-q13 (dup15q) occur as both interstitial duplications (int dup(15)) and isodicentric chromosome 15 (idic15). Over-expression of the maternally expressed gene UBE3A is predicted to be the primary cause of the autistic features associated with dup15q. Previous analysis of two post-mortem dup15q frontal cortical samples showed heterogeneity between the two cases, with one showing levels of GABAA receptor genes, UBE3A, and SNRPN in a manner not predicted by copy number or parental imprint.METHODS:Postmortem human brain tissue (BA19, extrastriate visual cortex) was obtained from 8 dup15q, 10 idiopathic autism and 21 typical control samples. Quantitative PCR was used to confirm duplication status. Quantitative reverse transcriptase PCR and Western blot analyses were performed to measure 15q11-q13 transcript and protein levels, respectively. Methylation-sensitive high resolution melt curve analysis was performed on brain genomic DNA to identify the maternal:paternal ratio of methylation at PWS-IC.RESULTS:Dup15q brain samples showed a higher level of PWS-IC methylation than control or autism samples, indicating that the duplication of 15q was maternal in origin. UBE3A transcript and protein levels were significantly higher in dup15q than control and autism, as expected, although levels were variable and lower than expected based on copy number in some samples. In contrast, this increase in copy number did not result in consistently increased GABRB3 transcript or protein levels for dup15q samples. Furthermore, SNRPN was expected to be unchanged in expression in dup15q because it is expressed from the single unmethylated paternal allele, yet SNRPN levels were significantly reduced in dup15q samples compared to controls. PWS-IC methylation positively correlated with UBE3A and GABRB3, but negatively correlated with SNRPN levels. Idiopathic autism samples exhibited significantly lower GABRB3 and significantly more variable SNRPN levels compared to controls.CONCLUSIONS:While these results show that increased UBE3A/UBE3A is a consistent feature of dup15q syndrome, they also suggest that gene expression within 15q11-q13 is not based entirely on copy number but can be influenced by epigenetic mechanisms in brain. En ligne : http://dx.doi.org/10.1186/2040-2392-2-19 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=149
in Molecular Autism > (December 2011) . - 41 p.[article] Increased copy number for methylated maternal 15q duplications leads to changes in gene and protein expression in human cortical samples [Texte imprimé et/ou numérique] / Haley SCOLES, Auteur ; Nora URRACA, Auteur ; Samuel CHADWICK, Auteur ; Lawrence REITER, Auteur ; Janine M. LASALLE, Auteur . - 2011 . - 41 p.
Langues : Anglais (eng)
in Molecular Autism > (December 2011) . - 41 p.
Index. décimale : PER Périodiques Résumé : BACKGROUND:Duplications of chromosome 15q11-q13 account for ~3% of autism cases. Chromosome 15q11-q13 contains imprinted genes necessary for normal mammalian neurodevelopment controlled by a differentially methylated imprinting center (PWS-IC). Maternal duplications of 15q11-q13 (dup15q) occur as both interstitial duplications (int dup(15)) and isodicentric chromosome 15 (idic15). Over-expression of the maternally expressed gene UBE3A is predicted to be the primary cause of the autistic features associated with dup15q. Previous analysis of two post-mortem dup15q frontal cortical samples showed heterogeneity between the two cases, with one showing levels of GABAA receptor genes, UBE3A, and SNRPN in a manner not predicted by copy number or parental imprint.METHODS:Postmortem human brain tissue (BA19, extrastriate visual cortex) was obtained from 8 dup15q, 10 idiopathic autism and 21 typical control samples. Quantitative PCR was used to confirm duplication status. Quantitative reverse transcriptase PCR and Western blot analyses were performed to measure 15q11-q13 transcript and protein levels, respectively. Methylation-sensitive high resolution melt curve analysis was performed on brain genomic DNA to identify the maternal:paternal ratio of methylation at PWS-IC.RESULTS:Dup15q brain samples showed a higher level of PWS-IC methylation than control or autism samples, indicating that the duplication of 15q was maternal in origin. UBE3A transcript and protein levels were significantly higher in dup15q than control and autism, as expected, although levels were variable and lower than expected based on copy number in some samples. In contrast, this increase in copy number did not result in consistently increased GABRB3 transcript or protein levels for dup15q samples. Furthermore, SNRPN was expected to be unchanged in expression in dup15q because it is expressed from the single unmethylated paternal allele, yet SNRPN levels were significantly reduced in dup15q samples compared to controls. PWS-IC methylation positively correlated with UBE3A and GABRB3, but negatively correlated with SNRPN levels. Idiopathic autism samples exhibited significantly lower GABRB3 and significantly more variable SNRPN levels compared to controls.CONCLUSIONS:While these results show that increased UBE3A/UBE3A is a consistent feature of dup15q syndrome, they also suggest that gene expression within 15q11-q13 is not based entirely on copy number but can be influenced by epigenetic mechanisms in brain. En ligne : http://dx.doi.org/10.1186/2040-2392-2-19 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=149 The Interstitial Duplication 15q11.2-q13 Syndrome Includes Autism, Mild Facial Anomalies and a Characteristic EEG Signature / Nora URRACA in Autism Research, 6-4 (August 2013)
[article]
Titre : The Interstitial Duplication 15q11.2-q13 Syndrome Includes Autism, Mild Facial Anomalies and a Characteristic EEG Signature Type de document : Texte imprimé et/ou numérique Auteurs : Nora URRACA, Auteur ; Julie CLEARY, Auteur ; Victoria BREWER, Auteur ; Eniko K. PIVNICK, Auteur ; Kathryn MCVICAR, Auteur ; Ronald L. THIBERT, Auteur ; N. Carolyn SCHANEN, Auteur ; Carmen ESMER, Auteur ; Dustin LAMPORT, Auteur ; Lawrence T. REITER, Auteur Article en page(s) : p.268-279 Langues : Anglais (eng) Mots-clés : autism 15q duplication imprinting copy number variation UBE3A Index. décimale : PER Périodiques Résumé : Chromosomal copy number variants (CNV) are the most common genetic lesion found in autism. Many autism-associated CNVs are duplications of chromosome 15q. Although most cases of interstitial (int) dup(15) that present clinically are de novo and maternally derived or inherited, both pathogenic and unaffected paternal duplications of 15q have been identified. We performed a phenotype/genotype analysis of individuals with interstitial 15q duplications to broaden our understanding of the 15q syndrome and investigate the contribution of 15q duplication to increased autism risk. All subjects were recruited solely on the basis of interstitial duplication 15q11.2-q13 status. Comparative array genome hybridization was used to determine the duplication size and boundaries while the methylation status of the maternally methylated small nuclear ribonucleoprotein polypeptide N gene was used to determine the parent of origin of the duplication. We determined the duplication size and parental origin for 14 int dup(15) subjects: 10 maternal and 4 paternal cases. The majority of int dup(15) cases recruited were maternal in origin, most likely due to our finding that maternal duplication was coincident with autism spectrum disorder. The size of the duplication did not correlate with the severity of the phenotype as established by Autism Diagnostic Observation Scale calibrated severity score. We identified phenotypes not comprehensively described before in this cohort including mild facial dysmorphism, sleep problems and an unusual electroencephalogram variant. Our results are consistent with the hypothesis that the maternally expressed ubiquitin protein ligase E3A gene is primarily responsible for the autism phenotype in int dup(15) since all maternal cases tested presented on the autism spectrum. En ligne : http://dx.doi.org/10.1002/aur.1284 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=212
in Autism Research > 6-4 (August 2013) . - p.268-279[article] The Interstitial Duplication 15q11.2-q13 Syndrome Includes Autism, Mild Facial Anomalies and a Characteristic EEG Signature [Texte imprimé et/ou numérique] / Nora URRACA, Auteur ; Julie CLEARY, Auteur ; Victoria BREWER, Auteur ; Eniko K. PIVNICK, Auteur ; Kathryn MCVICAR, Auteur ; Ronald L. THIBERT, Auteur ; N. Carolyn SCHANEN, Auteur ; Carmen ESMER, Auteur ; Dustin LAMPORT, Auteur ; Lawrence T. REITER, Auteur . - p.268-279.
Langues : Anglais (eng)
in Autism Research > 6-4 (August 2013) . - p.268-279
Mots-clés : autism 15q duplication imprinting copy number variation UBE3A Index. décimale : PER Périodiques Résumé : Chromosomal copy number variants (CNV) are the most common genetic lesion found in autism. Many autism-associated CNVs are duplications of chromosome 15q. Although most cases of interstitial (int) dup(15) that present clinically are de novo and maternally derived or inherited, both pathogenic and unaffected paternal duplications of 15q have been identified. We performed a phenotype/genotype analysis of individuals with interstitial 15q duplications to broaden our understanding of the 15q syndrome and investigate the contribution of 15q duplication to increased autism risk. All subjects were recruited solely on the basis of interstitial duplication 15q11.2-q13 status. Comparative array genome hybridization was used to determine the duplication size and boundaries while the methylation status of the maternally methylated small nuclear ribonucleoprotein polypeptide N gene was used to determine the parent of origin of the duplication. We determined the duplication size and parental origin for 14 int dup(15) subjects: 10 maternal and 4 paternal cases. The majority of int dup(15) cases recruited were maternal in origin, most likely due to our finding that maternal duplication was coincident with autism spectrum disorder. The size of the duplication did not correlate with the severity of the phenotype as established by Autism Diagnostic Observation Scale calibrated severity score. We identified phenotypes not comprehensively described before in this cohort including mild facial dysmorphism, sleep problems and an unusual electroencephalogram variant. Our results are consistent with the hypothesis that the maternally expressed ubiquitin protein ligase E3A gene is primarily responsible for the autism phenotype in int dup(15) since all maternal cases tested presented on the autism spectrum. En ligne : http://dx.doi.org/10.1002/aur.1284 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=212