Identification of a PTEN mutation with reduced protein stability, phosphatase activity, and nuclear localization in Hong Kong patients with autistic features, neurodevelopmental delays, and macrocephaly / C. W. WONG in Autism Research, 11-8 (August 2018)  

Public ISBD [article]  inAutism Research > 11-8 (August 2018) . - p.1098-1109 Titre : Identification of a PTEN mutation with reduced protein stability, phosphatase activity, and nuclear localization in Hong Kong patients with autistic features, neurodevelopmental delays, and macrocephaly Type de document : Texte imprimé et/ou numérique Auteurs : C. W. WONG, Auteur ; P. M. Y. OR, Auteur ; Y. WANG, Auteur ; L. LI, Auteur ; J. LI, Auteur ; M. YAN, Auteur ; Y. CAO, Auteur ; H. M. LUK, Auteur ; T. M. F. TONG, Auteur ; N. R. LESLIE, Auteur ; I. F. LO, Auteur ; K. W. CHOY, Auteur ; A. M. L. CHAN, Auteur Article en page(s) : p.1098-1109 Langues : Anglais (eng) Mots-clés : Hong Kong  Pten  PTEN hamartoma tumor syndrome  autism spectrum disorders  macrocephaly Index. décimale : PER Périodiques Résumé : PTEN is a tumor suppressor gene inactivated in over 30% of human cancers. It encodes a lipid phosphatase that serves as a gatekeeper of the phosphoinositide 3-kinase signaling pathway. Germline mutation frequently occurs in this gene in patients diagnosed with PTEN Hamartoma Tumor Syndrome (PHTS). PHTS individuals are characterized by macrocephaly, benign growth of multiple tissues and increased tumor risk. In addition, autistic phenotypes are found in 10-20% of individuals carrying the germline PTEN mutation with macrocephaly. In this report, 13 suspected PHTS patients were screened for mutation in the PTEN gene. A missense variant (c. 302T > C) substituting the isoleucine at codon 101 to a threonine, a single nucleotide insertion (c. 327-328insC) causing a frame shift mutation and termination at codon 109, and a nonsense variant (c. 1003C > T) truncated the protein at codon 335 were identified. The I101T mutation significantly reduced PTEN protein expression levels by 2.5- to 4.0-fold. Mechanistically, I101T reduced the protein half-life of PTEN possibly due to enhanced polyubiquitination at Lysine 13. However, the I101T mutant retained almost 30% of the lipid phosphatase activity of the wild-type protein. Finally, the I101T mutant has reduced phosphorylation at a PTEN auto-dephosphorylation site at Threonine 366 and a lowered ratio of nuclear to cytosolic protein level. These partial losses of multiple PTEN biochemical functions may contribute to the tissue overgrowth and autistic features of this PHTS patient. Autism Res 2018, 11: 1098-1109. (c) 2018 The Authors Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc. LAY SUMMARY: The genetics of autism spectrum disorders is highly complex with individual risk influenced by both genetic and environmental factors. Mutation in the human PTEN gene confers a high risk of developing autistic behavior. This report revealed that PTEN mutations occurred in 23% of a selected group of Hong Kong patients harboring autistic features with gross overgrowth symptoms. Detailed characterization of a PTEN mutation revealed reduced protein stability as one of the underlying mechanisms responsible for reduced PTEN activity. En ligne : http://dx.doi.org/10.1002/aur.1950 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=369 [article] Identification of a PTEN mutation with reduced protein stability, phosphatase activity, and nuclear localization in Hong Kong patients with autistic features, neurodevelopmental delays, and macrocephaly [Texte imprimé et/ou numérique] / C. W. WONG, Auteur ; P. M. Y. OR, Auteur ; Y. WANG, Auteur ; L. LI, Auteur ; J. LI, Auteur ; M. YAN, Auteur ; Y. CAO, Auteur ; H. M. LUK, Auteur ; T. M. F. TONG, Auteur ; N. R. LESLIE, Auteur ; I. F. LO, Auteur ; K. W. CHOY, Auteur ; A. M. L. CHAN, Auteur . - p.1098-1109. Langues : Anglais (eng) in Autism Research > 11-8 (August 2018) . - p.1098-1109 Mots-clés : Hong Kong  Pten  PTEN hamartoma tumor syndrome  autism spectrum disorders  macrocephaly Index. décimale : PER Périodiques Résumé : PTEN is a tumor suppressor gene inactivated in over 30% of human cancers. It encodes a lipid phosphatase that serves as a gatekeeper of the phosphoinositide 3-kinase signaling pathway. Germline mutation frequently occurs in this gene in patients diagnosed with PTEN Hamartoma Tumor Syndrome (PHTS). PHTS individuals are characterized by macrocephaly, benign growth of multiple tissues and increased tumor risk. In addition, autistic phenotypes are found in 10-20% of individuals carrying the germline PTEN mutation with macrocephaly. In this report, 13 suspected PHTS patients were screened for mutation in the PTEN gene. A missense variant (c. 302T > C) substituting the isoleucine at codon 101 to a threonine, a single nucleotide insertion (c. 327-328insC) causing a frame shift mutation and termination at codon 109, and a nonsense variant (c. 1003C > T) truncated the protein at codon 335 were identified. The I101T mutation significantly reduced PTEN protein expression levels by 2.5- to 4.0-fold. Mechanistically, I101T reduced the protein half-life of PTEN possibly due to enhanced polyubiquitination at Lysine 13. However, the I101T mutant retained almost 30% of the lipid phosphatase activity of the wild-type protein. Finally, the I101T mutant has reduced phosphorylation at a PTEN auto-dephosphorylation site at Threonine 366 and a lowered ratio of nuclear to cytosolic protein level. These partial losses of multiple PTEN biochemical functions may contribute to the tissue overgrowth and autistic features of this PHTS patient. Autism Res 2018, 11: 1098-1109. (c) 2018 The Authors Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc. LAY SUMMARY: The genetics of autism spectrum disorders is highly complex with individual risk influenced by both genetic and environmental factors. Mutation in the human PTEN gene confers a high risk of developing autistic behavior. This report revealed that PTEN mutations occurred in 23% of a selected group of Hong Kong patients harboring autistic features with gross overgrowth symptoms. Detailed characterization of a PTEN mutation revealed reduced protein stability as one of the underlying mechanisms responsible for reduced PTEN activity. En ligne : http://dx.doi.org/10.1002/aur.1950 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=369

Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERbeta activation / W. XIE in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 43p. Titre : Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERbeta activation Type de document : Texte imprimé et/ou numérique Auteurs : W. XIE, Auteur ; X. GE, Auteur ; L. LI, Auteur ; A. YAO, Auteur ; X. WANG, Auteur ; M. LI, Auteur ; X. GONG, Auteur ; Z. CHU, Auteur ; Z. LU, Auteur ; X. HUANG, Auteur ; Y. JIAO, Auteur ; Y. WANG, Auteur ; M. XIAO, Auteur ; H. CHEN, Auteur ; W. XIANG, Auteur ; P. YAO, Auteur Article en page(s) : 43p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Estrogen receptor beta  Lipid metabolism  Mitochondria  Oxidative stress  Progestin  Resveratrol Index. décimale : PER Périodiques Résumé : Background: Recent literatures indicate that maternal hormone exposure is a risk factor for autism spectrum disorder (ASD). We hypothesize that prenatal progestin exposure may counteract the neuroprotective effect of estrogen and contribute to ASD development, and we aim to develop a method to ameliorate prenatal progestin exposure-induced autism-like behavior. Methods: Experiment 1: Prenatal progestin exposure-induced offspring are treated with resveratrol (RSV) through either prenatal or postnatal exposure and then used for autism-like behavior testing and other biomedical analyses. Experiment 2: Prenatal norethindrone (NET) exposure-induced offspring are treated with ERbeta knockdown lentivirus together with RSV for further testing. Experiment 3: Pregnant dams are treated with prenatal NET exposure together with RSV, and the offspring are used for further testing. Results: Eight kinds of clinically relevant progestins were used for prenatal exposure in pregnant dams, and the offspring showed decreased ERbeta expression in the amygdala with autism-like behavior. Oral administration of either postnatal or prenatal RSV treatment significantly reversed this effect with ERbeta activation and ameliorated autism-like behavior. Further investigation showed that RSV activates ERbeta and its target genes by demethylation of DNA and histone on the ERbeta promoter, and then minimizes progestin-induced oxidative stress as well as the dysfunction of mitochondria and lipid metabolism in the brain, subsequently ameliorating autism-like behavior. Conclusions: We conclude that resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERbeta activation. Our data suggest that prenatal progestin exposure is a strong risk factor for autism-like behavior. Many potential clinical progestin applications, including oral contraceptive pills, preterm birth drugs, and progestin-contaminated drinking water or seafood, may be risk factors for ASD. In addition, RSV may be a good candidate for clinically rescuing or preventing ASD symptoms in humans, while high doses of resveratrol used in the animals may be a potential limitation for human application. En ligne : https://dx.doi.org/10.1186/s13229-018-0225-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERbeta activation [Texte imprimé et/ou numérique] / W. XIE, Auteur ; X. GE, Auteur ; L. LI, Auteur ; A. YAO, Auteur ; X. WANG, Auteur ; M. LI, Auteur ; X. GONG, Auteur ; Z. CHU, Auteur ; Z. LU, Auteur ; X. HUANG, Auteur ; Y. JIAO, Auteur ; Y. WANG, Auteur ; M. XIAO, Auteur ; H. CHEN, Auteur ; W. XIANG, Auteur ; P. YAO, Auteur . - 43p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 43p. Mots-clés : Autism spectrum disorder  Estrogen receptor beta  Lipid metabolism  Mitochondria  Oxidative stress  Progestin  Resveratrol Index. décimale : PER Périodiques Résumé : Background: Recent literatures indicate that maternal hormone exposure is a risk factor for autism spectrum disorder (ASD). We hypothesize that prenatal progestin exposure may counteract the neuroprotective effect of estrogen and contribute to ASD development, and we aim to develop a method to ameliorate prenatal progestin exposure-induced autism-like behavior. Methods: Experiment 1: Prenatal progestin exposure-induced offspring are treated with resveratrol (RSV) through either prenatal or postnatal exposure and then used for autism-like behavior testing and other biomedical analyses. Experiment 2: Prenatal norethindrone (NET) exposure-induced offspring are treated with ERbeta knockdown lentivirus together with RSV for further testing. Experiment 3: Pregnant dams are treated with prenatal NET exposure together with RSV, and the offspring are used for further testing. Results: Eight kinds of clinically relevant progestins were used for prenatal exposure in pregnant dams, and the offspring showed decreased ERbeta expression in the amygdala with autism-like behavior. Oral administration of either postnatal or prenatal RSV treatment significantly reversed this effect with ERbeta activation and ameliorated autism-like behavior. Further investigation showed that RSV activates ERbeta and its target genes by demethylation of DNA and histone on the ERbeta promoter, and then minimizes progestin-induced oxidative stress as well as the dysfunction of mitochondria and lipid metabolism in the brain, subsequently ameliorating autism-like behavior. Conclusions: We conclude that resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERbeta activation. Our data suggest that prenatal progestin exposure is a strong risk factor for autism-like behavior. Many potential clinical progestin applications, including oral contraceptive pills, preterm birth drugs, and progestin-contaminated drinking water or seafood, may be risk factors for ASD. In addition, RSV may be a good candidate for clinically rescuing or preventing ASD symptoms in humans, while high doses of resveratrol used in the animals may be a potential limitation for human application. En ligne : https://dx.doi.org/10.1186/s13229-018-0225-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

The association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders in children: a meta-analysis / M. WANG in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 51p. Titre : The association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders in children: a meta-analysis Type de document : Texte imprimé et/ou numérique Auteurs : M. WANG, Auteur ; K. LI, Auteur ; D. ZHAO, Auteur ; L. LI, Auteur Article en page(s) : 51p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorders  Children  Folic acid supplements  Maternal  Meta-analysis Index. décimale : PER Périodiques Résumé : Previous reviews have been conducted to evaluate the association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders (ASD) in children, with no definitive conclusion. We therefore conducted a more comprehensive meta-analysis to reassess the relationship between folic acid and the risk of ASD. The electronic databases PubMed, Web of Knowledge, and Wanfang Data were carefully searched to find eligible studies as recent as March 2017. A random effects model was used to combine the relative risk (RR) with 95% confidence intervals (CI). Sensitivity analysis and publication bias were conducted. A total of 12 articles with 16 studies comprising 4514 ASD cases were included in this report. It was found that supplementation with folic acid during pregnancy could reduce the risk of ASD [RR = 0.771, 95% CI = 0.641-0.928, I(2) = 59.7%, Pheterogeneity = 0.001] as compared to those women without folic acid supplementation. The associations were significant among Asian, European, and American populations. In summary, this comprehensive meta-analysis suggested that maternal use of folic acid supplements during pregnancy could significantly reduce the risk of ASD in children regardless of ethnicity, as compared to those women who did not supplement with folic acid. En ligne : http://dx.doi.org/10.1186/s13229-017-0170-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] The association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders in children: a meta-analysis [Texte imprimé et/ou numérique] / M. WANG, Auteur ; K. LI, Auteur ; D. ZHAO, Auteur ; L. LI, Auteur . - 51p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 51p. Mots-clés : Autism spectrum disorders  Children  Folic acid supplements  Maternal  Meta-analysis Index. décimale : PER Périodiques Résumé : Previous reviews have been conducted to evaluate the association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders (ASD) in children, with no definitive conclusion. We therefore conducted a more comprehensive meta-analysis to reassess the relationship between folic acid and the risk of ASD. The electronic databases PubMed, Web of Knowledge, and Wanfang Data were carefully searched to find eligible studies as recent as March 2017. A random effects model was used to combine the relative risk (RR) with 95% confidence intervals (CI). Sensitivity analysis and publication bias were conducted. A total of 12 articles with 16 studies comprising 4514 ASD cases were included in this report. It was found that supplementation with folic acid during pregnancy could reduce the risk of ASD [RR = 0.771, 95% CI = 0.641-0.928, I(2) = 59.7%, Pheterogeneity = 0.001] as compared to those women without folic acid supplementation. The associations were significant among Asian, European, and American populations. In summary, this comprehensive meta-analysis suggested that maternal use of folic acid supplements during pregnancy could significantly reduce the risk of ASD in children regardless of ethnicity, as compared to those women who did not supplement with folic acid. En ligne : http://dx.doi.org/10.1186/s13229-017-0170-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

---

1 (1 - 3 / 3)