DOCSLIB.ORG

Bilateral Striatal Necrosis Due to Homoplasmic Mitochondrial 3697G>A Mutation Presents with Incomplete Penetrance and Sex Bias

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Bilateral Striatal Necrosis Due to Homoplasmic Mitochondrial 3697G>A Mutation Presents with Incomplete Penetrance and Sex Bias University of Mississippi eGrove Health, Exercise Science, and Recreation Faculty and Student Publications Management, Department of 3-1-2019 Bilateral striatal necrosis due to homoplasmic mitochondrial 3697G>A mutation presents with incomplete penetrance and sex bias Shanshan Zhong Peking University People's Hospital Shumeng Wen Wenzhou Medical University Yusen Qiu Nanchang University Yanyan Yu Nanchang University Ling Xin University of Mississippi Follow this and additional works at: https://egrove.olemiss.edu/hesrm_facpubs See next page for additional authors Part of the Exercise Physiology Commons, Leisure Studies Commons, Recreation Business Commons, Sports Management Commons, Sports Sciences Commons, and the Sports Studies Commons Recommended Citation Zhong, S., Wen, S., Qiu, Y., Yu, Y., Xin, L., He, Y., Gao, X., Fang, H., Hong, D., & Zhang, J. (2019). Bilateral striatal necrosis due to homoplasmic mitochondrial 3697G>A mutation presents with incomplete penetrance and sex bias. Molecular Genetics & Genomic Medicine, 7(3), e541. https://doi.org/10.1002/ mgg3.541 This Article is brought to you for free and open access by the Health, Exercise Science, and Recreation Management, Department of at eGrove. It has been accepted for inclusion in Faculty and Student Publications by an authorized administrator of eGrove. For more information, please contact [email protected]. Authors Shanshan Zhong, Shumeng Wen, Yusen Qiu, Yanyan Yu, Ling Xin, Yang He, Xuguang Gao, Hezhi Fang, Daojun Hong, and Jun Zhang This article is available at eGrove: https://egrove.olemiss.edu/hesrm_facpubs/27 Received: 24 September 2018 | Revised: 9 November 2018 | Accepted: 2 December 2018 DOI: 10.1002/mgg3.541 ORIGINAL ARTICLE Bilateral striatal necrosis due to homoplasmic mitochondrial 3697G>A mutation presents with incomplete penetrance and sex bias Shanshan Zhong1* | Shumeng Wen2* | Yusen Qiu3 | Yanyan Yu3 | Ling Xin4 | Yang He1 | Xuguang Gao1 | Hezhi Fang2 | Daojun Hong1 | Jun Zhang1 1Department of Neurology, Peking University People’s Hospital, Beijing, China Abstract 2Key Laboratory of Laboratory Medicine, Background: Heteroplasmic mitochondrial 3697G>A mutation has been associated College of Laboratory Medicine and Life with leber hereditary optic neuropathy (LHON), mitochondrial encephalopathy, lac- Science, Wenzhou Medical University, tic acidosis and stroke‐like episodes (MELAS), and LHON/MELAS overlap syn- Wenzhou, China drome. However, homoplasmic m.3697G>A mutation was only found in a family 3Department of Neurology, The First Affiliated Hospital of Nanchang University, with Leigh syndrome, and the phenotype and pathogenicity of this homoplasmic Nanchang, China mutation still need to be investigated in new patients. 4 Department of Health, Exercise Science, Methods: The clinical interviews were conducted in 12 individuals from a multiple‐ and Recreation Management, University of generation inherited family. Mutations were screened through exome next‐genera- Mississippi, University, Mississippi tion sequencing and subsequently confirmed by PCR‐restriction fragment length Correspondence polymorphism. Mitochondrial complex activities and ATP production rate were Daojun Hong and Jun Zhang, Department of Neurology, Peking University People’s measured by biochemical analysis. Hospital, Beijing, China. Results: The male offspring with bilateral striatal necrosis (BSN) were characterized Emails: [email protected] (DH); by severe spastic dystonia and complete penetrance, while the female offspring pre- [email protected] (JZ) sented with mild symptom and low penetrance. All offspring carried homoplasmic mutation of NC_012920.1: m.3697G>A, p.(Gly131Ser). Biochemical analysis re- Funding information This work was supported by the National vealed an isolated defect of complex I, but the magnitude of the defect was higher in Natural Science Foundation of China the male patients than that in the female ones. The ATP production rate also exhib- (81460199 and 81870996); and Peking University People’s Hospital Research and ited a similar pattern. However, no possible modifier genes on the X chromosome Development Funds (RDX 2018‐08). were identified. Conclusion: Homoplasmic m.3697G>A mutation could be associated with BSN, which expanded the clinical spectrum of m.3697G>A. Our preliminary investiga- tions had not found the underlying modifiers to support the double hit hypothesis, while the high level of estrogens in the female patients might exert a potential com- pensatory effect on mutant cell metabolism. KEYWORDS bilateral striatal necrosis, homoplasmy, mitochondrial DNA mutation, sex bias *The authors had equal contribution to this work. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. Mol Genet Genomic Med. 2019;7:e541. wileyonlinelibrary.com/journal/mgg3 | 1 of 9 https://doi.org/10.1002/mgg3.541 2 of 9 | ZHONG ET AL. 1 | INTRODUCTION provided by every examined individual according to the Declaration of Helsinki. The study was approved by the Bilateral striatal necrosis (BSN) is a heterogeneous group of institutional ethical review board of the Peking University neurodegenerative diseases named after the distinctive neu- People's Hospital. roradiological features (Lim, 2009). The main neurological findings are characterized by symmetrical degeneration of putamen, caudate nucleus, and globus pallidus occasionally. 2.2 | Patients The pathogenesis of BSN is heterogeneous and has been asso- The index patient was a 20‐year‐old man (III3) from a non- ciated with various acquired and hereditary causes (Chokshi, consanguineous family (Figure 1). He had rigidity on the left Aygun, & Mullins, 2014). Hereditary striatal degeneration can limbs since he was 6 years old. The dystonia insidiously pro- be inherited as an autosomal dominant, autosomal recessive, or gressed and resulted in clumsy movements of the left limbs, mitochondrial disorder (Tonduti et al., 2016). Adult‐onset auto- but the symptoms maintained a stable condition since the age somal‐dominant BSN is caused by mutations in the phosphodi- of eight. Eight months ago, the right limbs started exhibiting esterase 8B (PDE8B, OMIM #603390) gene on chromosome similar rigidity. He presented with dysarthria, dysphagia, and 5q13 (Appenzeller et al., 2010). Autosomal‐recessive BSNs are difficulty of standing steadily. The patient had no complaints associated with mutations in several genes such as solute carrier about muscle weakness, myalgia, or numbness. Mini‐mental family 25 member 19 (SLC25A19, OMIM #606521) (Spiegel state examination (MMSE) revealed a moderate cognitive et al., 2009), nucleoporin 62 (NUP62, OMIM #605815) disability (17/30). Physical examination revealed scoliosis, (Bianciardi et al., 2016), adenosine deaminase RNA specific finger joint contracture, left ankle deformity, and an in- (ADAR1, OMIM: 146920) (La Piana et al., 2014), and protein creased muscle tone of the neck and all of the limbs. Muscle Vac14 homolog (VAC14, OMIM #604632) (Stutterd et al., strength graded 5/5 in the right limbs and 4/5 in the left limbs 2017). Mitochondrial BSNs are caused by mutations in both mi- (Medical Research Council Scale). The deep tendon reflexes tochondrial and nuclear genes associated with the maintenance of the lower limbs were enhanced. The Babinski sign was of mitochondrial function (Binder et al., 2003; Thyagarajan, positive on the left side. His visual acuity and auditory ability Shanske, Vazquez‐Memije, Vivo, & DiMauro, 1995). were unimpaired. The pinprick, position, and vibration sen- Several mitochondrial DNA (mtDNA) mutations associ- sations were normal. ated with defects of oxidative respiratory chain enzymes were The elder aunt's son (III2) was 23 years old, and he dis- linked with infantile‐onset BSNs (Hirayanagi et al., 2017; played spastic gait at the age of five. He developed upper limb Tarnopolsky, Meaney, Robinson, Sheldon, & Boles, 2013). spasticity, lower limb tightness, and walking difficulty at the The heteroplasmic mutation of NC_012920.1: m.3697G>A, age of 10. He was wheelchair‐bound when he was referred p.(Gly131Ser) in the mitochondrial NADH dehydrogenase to our clinic at the age of 26. His cognitive performance was subunit 1 (MTND1, OMIM #516000) gene was identified in mildly decreased (MMSE: 20/30). Physical examination re- patients with mitochondrial encephalomyopathy, lactic aci- vealed enhanced muscle tone. The sensations were intact, and dosis and stroke‐like episodes (MELAS) (Kirby et al., 2004), the optic neuropathy was not detected. Leber's hereditary optic neuropathy (LHON) (Spruijt et al., The index patient's young brother (III5) was 16 years 2007), LHON/MELAS overlap syndrome (Blakely et al., old. He had similar symptoms with the index patient. The 2005), and Stüve‐Wiedemann syndrome (Morava, Hamel, Hol, age of onset was four. Clinical symptoms included moder- Rodenburg, & Smeitink, 2006). In contrast, the homoplas- ate cognitive ability (MMSE: 17/30), scoliosis, finger joint mic m.3697G>A mutation was found as a causation of Leigh syndrome (LS) in a Japanese family (Negishi et al., 2014), in which the affected individuals exhibited early childhood‐onset rigidity of the upper and lower limbs due to bilateral basal ganglion and brainstem degeneration. Herein, we investigated the clinical features, brain MRI changes,
Load more

Recommended publications
  • Supplementary Data
    Figure 2S 4 7 A - C 080125 CSCs 080418 CSCs - + IFN-a 48 h + IFN-a 48 h + IFN-a 72 h 6 + IFN-a 72 h 3 5 MRFI 4 2 3 2 1 1 0 0 MHC I MHC II MICA MICB ULBP-1 ULBP-2 ULBP-3 ULBP-4 MHC I MHC II MICA MICB ULBP-1 ULBP-2 ULBP-3 ULBP-4 7 B 13 080125 FBS - D 080418 FBS - + IFN-a 48 h 12 + IFN-a 48 h + IFN-a 72 h + IFN-a 72 h 6 080125 FBS 11 10 5 9 8 4 7 6 3 MRFI 5 4 2 3 2 1 1 0 0 MHC I MHC II MICA MICB ULBP-1 ULBP-2 ULBP-3 ULBP-4 MHC I MHC II MICA MICB ULBP-1 ULBP-2 ULBP-3 ULBP-4 Molecule Molecule FIGURE 4S FIGURE 5S Panel A Panel B FIGURE 6S A B C D Supplemental Results Table 1S. Modulation by IFN-α of APM in GBM CSC and FBS tumor cell lines. Molecule * Cell line IFN-α‡ HLA β2-m# HLA LMP TAP1 TAP2 class II A A HC§ 2 7 10 080125 CSCs - 1∞ (1) 3 (65) 2 (91) 1 (2) 6 (47) 2 (61) 1 (3) 1 (2) 1 (3) + 2 (81) 11 (80) 13 (99) 1 (3) 8 (88) 4 (91) 1 (2) 1 (3) 2 (68) 080125 FBS - 2 (81) 4 (63) 4 (83) 1 (3) 6 (80) 3 (67) 2 (86) 1 (3) 2 (75) + 2 (99) 14 (90) 7 (97) 5 (75) 7 (100) 6 (98) 2 (90) 1 (4) 3 (87) 080418 CSCs - 2 (51) 1 (1) 1 (3) 2 (47) 2 (83) 2 (54) 1 (4) 1 (2) 1 (3) + 2 (81) 3 (76) 5 (75) 2 (50) 2 (83) 3 (71) 1 (3) 2 (87) 1 (2) 080418 FBS - 1 (3) 3 (70) 2 (88) 1 (4) 3 (87) 2 (76) 1 (3) 1 (3) 1 (2) + 2 (78) 7 (98) 5 (99) 2 (94) 5 (100) 3 (100) 1 (4) 2 (100) 1 (2) 070104 CSCs - 1 (2) 1 (3) 1 (3) 2 (78) 1 (3) 1 (2) 1 (3) 1 (3) 1 (2) + 2 (98) 8 (100) 10 (88) 4 (89) 3 (98) 3 (94) 1 (4) 2 (86) 2 (79) * expression of APM molecules was evaluated by intracellular staining and cytofluorimetric analysis; ‡ cells were treatead or not (+/-) for 72 h with 1000 IU/ml of IFN-α; # β-2 microglobulin; § β-2 microglobulin-free HLA-A heavy chain; ∞ values are indicated as ratio between the mean of fluorescence intensity of cells stained with the selected mAb and that of the negative control; bold values indicate significant MRFI (≥ 2).
    [Show full text]
  • The Direction of Cross Affects Obesity After Puberty in Male but Not Female
    Kärst et al. BMC Genomics (2015) 16:904 DOI 10.1186/s12864-015-2164-2 RESEARCH ARTICLE Open Access The direction of cross affects obesity after puberty in male but not female offspring Stefan Kärst1†, Danny Arends1†, Sebastian Heise1†, Jan Trost1, Marie-Laure Yaspo2, Vyacheslav Amstislavskiy2, Thomas Risch2, Hans Lehrach2 and Gudrun A. Brockmann1* Abstract Background: We investigated parent-of-origin and allele-specific expression effects on obesity and hepatic gene expression in reciprocal crosses between the Berlin Fat Mouse Inbred line (BFMI) and C57Bl/6NCrl (B6N). Results: We found that F1-males with a BFMI mother developed 1.8 times more fat mass on a high fat diet at 10 weeks than F1-males of a BFMI father. The phenotype was detectable from six weeks on and was preserved after cross-fostering. RNA-seq data of liver provided evidence for higher biosynthesis and elongation of fatty acids (p = 0.00635) in obese male offspring of a BFMI mother versus lean offspring of a BFMI father. Furthermore, fatty acid degradation (p = 0.00198) and the peroxisome pathway were impaired (p = 0.00094). The circadian rhythm was affected as well (p = 0.00087). Among the highest up-regulated protein coding genes in obese males were Acot4 (1.82 fold, p = 0.022), Cyp4a10 (1.35 fold, p = 0.026) and Cyp4a14 (1.32 fold, p = 0.012), which hydroxylize fatty acids and which are known to be increased in liver steatosis. Obese males showed lower expression of the genetically imprinted and paternally expressed 3 (Peg3) gene (0.31 fold, p = 0.046) and higher expression of the androgen receptor (Ar) gene (2.38 fold, p = 0.068).
    [Show full text]
  • Investigation of Candidate Genes and Mechanisms Underlying Obesity
    Prashanth et al. BMC Endocrine Disorders (2021) 21:80 https://doi.org/10.1186/s12902-021-00718-5 RESEARCH ARTICLE Open Access Investigation of candidate genes and mechanisms underlying obesity associated type 2 diabetes mellitus using bioinformatics analysis and screening of small drug molecules G. Prashanth1 , Basavaraj Vastrad2 , Anandkumar Tengli3 , Chanabasayya Vastrad4* and Iranna Kotturshetti5 Abstract Background: Obesity associated type 2 diabetes mellitus is a metabolic disorder ; however, the etiology of obesity associated type 2 diabetes mellitus remains largely unknown. There is an urgent need to further broaden the understanding of the molecular mechanism associated in obesity associated type 2 diabetes mellitus. Methods: To screen the differentially expressed genes (DEGs) that might play essential roles in obesity associated type 2 diabetes mellitus, the publicly available expression profiling by high throughput sequencing data (GSE143319) was downloaded and screened for DEGs. Then, Gene Ontology (GO) and REACTOME pathway enrichment analysis were performed. The protein - protein interaction network, miRNA - target genes regulatory network and TF-target gene regulatory network were constructed and analyzed for identification of hub and target genes. The hub genes were validated by receiver operating characteristic (ROC) curve analysis and RT- PCR analysis. Finally, a molecular docking study was performed on over expressed proteins to predict the target small drug molecules. Results: A total of 820 DEGs were identified between
    [Show full text]
  • 140503 IPF Signatures Supplement Withfigs Thorax
    Supplementary material for Heterogeneous gene expression signatures correspond to distinct lung pathologies and biomarkers of disease severity in idiopathic pulmonary fibrosis Daryle J. DePianto1*, Sanjay Chandriani1⌘*, Alexander R. Abbas1, Guiquan Jia1, Elsa N. N’Diaye1, Patrick Caplazi1, Steven E. Kauder1, Sabyasachi Biswas1, Satyajit K. Karnik1#, Connie Ha1, Zora Modrusan1, Michael A. Matthay2, Jasleen Kukreja3, Harold R. Collard2, Jackson G. Egen1, Paul J. Wolters2§, and Joseph R. Arron1§ 1Genentech Research and Early Development, South San Francisco, CA 2Department of Medicine, University of California, San Francisco, CA 3Department of Surgery, University of California, San Francisco, CA ⌘Current address: Novartis Institutes for Biomedical Research, Emeryville, CA. #Current address: Gilead Sciences, Foster City, CA. *DJD and SC contributed equally to this manuscript §PJW and JRA co-directed this project Address correspondence to Paul J. Wolters, MD University of California, San Francisco Department of Medicine Box 0111 San Francisco, CA 94143-0111 [email protected] or Joseph R. Arron, MD, PhD Genentech, Inc. MS 231C 1 DNA Way South San Francisco, CA 94080 [email protected] 1 METHODS Human lung tissue samples Tissues were obtained at UCSF from clinical samples from IPF patients at the time of biopsy or lung transplantation. All patients were seen at UCSF and the diagnosis of IPF was established through multidisciplinary review of clinical, radiological, and pathological data according to criteria established by the consensus classification of the American Thoracic Society (ATS) and European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and the Latin American Thoracic Association (ALAT) (ref. 5 in main text). Non-diseased normal lung tissues were procured from lungs not used by the Northern California Transplant Donor Network.
    [Show full text]
  • Analysis of the Indacaterol-Regulated Transcriptome in Human Airway
    Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2018/04/13/jpet.118.249292.DC1 1521-0103/366/1/220–236$35.00 https://doi.org/10.1124/jpet.118.249292 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 366:220–236, July 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Analysis of the Indacaterol-Regulated Transcriptome in Human Airway Epithelial Cells Implicates Gene Expression Changes in the s Adverse and Therapeutic Effects of b2-Adrenoceptor Agonists Dong Yan, Omar Hamed, Taruna Joshi,1 Mahmoud M. Mostafa, Kyla C. Jamieson, Radhika Joshi, Robert Newton, and Mark A. Giembycz Departments of Physiology and Pharmacology (D.Y., O.H., T.J., K.C.J., R.J., M.A.G.) and Cell Biology and Anatomy (M.M.M., R.N.), Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Received March 22, 2018; accepted April 11, 2018 Downloaded from ABSTRACT The contribution of gene expression changes to the adverse and activity, and positive regulation of neutrophil chemotaxis. The therapeutic effects of b2-adrenoceptor agonists in asthma was general enriched GO term extracellular space was also associ- investigated using human airway epithelial cells as a therapeu- ated with indacaterol-induced genes, and many of those, in- tically relevant target. Operational model-fitting established that cluding CRISPLD2, DMBT1, GAS1, and SOCS3, have putative jpet.aspetjournals.org the long-acting b2-adrenoceptor agonists (LABA) indacaterol, anti-inflammatory, antibacterial, and/or antiviral activity. Numer- salmeterol, formoterol, and picumeterol were full agonists on ous indacaterol-regulated genes were also induced or repressed BEAS-2B cells transfected with a cAMP-response element in BEAS-2B cells and human primary bronchial epithelial cells by reporter but differed in efficacy (indacaterol $ formoterol .
    [Show full text]
  • Comparative Transcriptomics Reveals Similarities and Differences
    Seifert et al. BMC Cancer (2015) 15:952 DOI 10.1186/s12885-015-1939-9 RESEARCH ARTICLE Open Access Comparative transcriptomics reveals similarities and differences between astrocytoma grades Michael Seifert1,2,5*, Martin Garbe1, Betty Friedrich1,3, Michel Mittelbronn4 and Barbara Klink5,6,7 Abstract Background: Astrocytomas are the most common primary brain tumors distinguished into four histological grades. Molecular analyses of individual astrocytoma grades have revealed detailed insights into genetic, transcriptomic and epigenetic alterations. This provides an excellent basis to identify similarities and differences between astrocytoma grades. Methods: We utilized public omics data of all four astrocytoma grades focusing on pilocytic astrocytomas (PA I), diffuse astrocytomas (AS II), anaplastic astrocytomas (AS III) and glioblastomas (GBM IV) to identify similarities and differences using well-established bioinformatics and systems biology approaches. We further validated the expression and localization of Ang2 involved in angiogenesis using immunohistochemistry. Results: Our analyses show similarities and differences between astrocytoma grades at the level of individual genes, signaling pathways and regulatory networks. We identified many differentially expressed genes that were either exclusively observed in a specific astrocytoma grade or commonly affected in specific subsets of astrocytoma grades in comparison to normal brain. Further, the number of differentially expressed genes generally increased with the astrocytoma grade with one major exception. The cytokine receptor pathway showed nearly the same number of differentially expressed genes in PA I and GBM IV and was further characterized by a significant overlap of commonly altered genes and an exclusive enrichment of overexpressed cancer genes in GBM IV. Additional analyses revealed a strong exclusive overexpression of CX3CL1 (fractalkine) and its receptor CX3CR1 in PA I possibly contributing to the absence of invasive growth.
    [Show full text]
  • Supplemetary Table 2. List of Genes Down-Regulated in LPAR6 Knocked Down Cells
    Supplemetary Table 2. List of genes down-regulated in LPAR6 knocked down cells g# initial alias c# converted alias name description namespace 1 NM_002317.5 1.1 ENSG00000113083 LOX lysyl oxidase [Source:HGNC Symbol;Acc:6664] REFSEQ_MRNA 2 NM_006183.4 2.1 ENSG00000133636 NTS neurotensin [Source:HGNC Symbol;Acc:8038] REFSEQ_MRNA 3 NM_005213.3 3.1 ENSG00000121552 CSTA cystatin A (stefin A) [Source:HGNC Symbol;Acc:2481] REFSEQ_MRNA 4 NM_007231.3 4.1 ENSG00000087916 SLC6A14 solute carrier family 6 (amino acid transporter), member 14 [Source:HGNC Symbol;Acc:11047] REFSEQ_MRNA 5 NM_001873.2 5.1 ENSG00000109472 CPE carboxypeptidase E [Source:HGNC Symbol;Acc:2303] REFSEQ_MRNA 6 NM_019856.1 6.1 ENSG00000101605 MYOM1 myomesin 1, 185kDa [Source:HGNC Symbol;Acc:7613] REFSEQ_MRNA 7 NM_032590.4 7.1 ENSG00000089094 KDM2B lysine (K)-specific demethylase 2B [Source:HGNC Symbol;Acc:13610] REFSEQ_MRNA 8 NM_001901.2 8.1 ENSG00000118523 CTGF connective tissue growth factor [Source:HGNC Symbol;Acc:2500] REFSEQ_MRNA 9 NM_007183.2 9.1 ENSG00000184363 PKP3 plakophilin 3 [Source:HGNC Symbol;Acc:9025] REFSEQ_MRNA 10 NM_182965.2 10.1 ENSG00000176170 SPHK1 sphingosine kinase 1 [Source:HGNC Symbol;Acc:11240] REFSEQ_MRNA 11 NM_152423.4 11.1 ENSG00000157502 MUM1L1 melanoma associated antigen (mutated) 1-like 1 [Source:HGNC Symbol;Acc:26583] REFSEQ_MRNA 12 NM_002923.3 12.1 ENSG00000116741 RGS2 regulator of G-protein signaling 2, 24kDa [Source:HGNC Symbol;Acc:9998] REFSEQ_MRNA 13 NR_003038.2 13.1 N/A N/A N/A N/A 14 NM_080862.1 14.1 ENSG00000175093 SPSB4 splA/ryanodine receptor
    [Show full text]
  • Estudo Da Deficiência Mental De Herança Ligada Ao Cromossomo X
    JOSÉ OLIVEIRA DOS SANTOS ESTUDO DA DEFICIÊNCIA MENTAL DE HERANÇA LIGADA AO CROMOSSOMO X (Versão Corrigida) Tese apresentada ao Instituto de Biociências da Universidade de São Paulo, para a obtenção de Título de Doutor em Ciências, na Área de Biologia/Genética São Paulo 2013 Orientadora: Angela M. Vianna Morgante OLIVEIRA DOS SANTOS, JOSÉ ESTUDO DA DEFICIÊNCIA MENTAL DE HERANÇA LIGADA AO CROMOSSOMO X Tese (Doutorado) - Instituto de Biociências da Universidade de São Paulo, Departamento de Genética e Biologia Evolutiva 1. Deficiência Mental 2. Deficiência Mental com Herança Ligada ao X 3. Microrrearranjos Cromossômicos 4. Inativação do Cromossomo X Universidade de São Paulo. Instituto de Biociências. Departamento de Genética e Biologia Evolutiva COMISSÃO JULGADORA _____________________________ ____________________________ _____________________________ ____________________________ __________________________________ Orientadora Este trabalho foi realizado com auxílio financeiro da FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo) concedido à orientadora (FAPESP-CEPID 98/14254- 2) e bolsa da CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) concedida ao aluno (CAPES-DS). AGRADECIMENTOS Os meus sinceros agradecimentos a todos que de alguma forma contribuíram para a realização deste trabalho. Ao Departamento de Genética e Biologia Evolutiva do Instituto e Biociências da Universidade de São Paulo, pela infraestrutura que permitiu a realização deste trabalho. À Dra. Angela M. Vianna-Morgante, pela orientação neste projeto, por permitir que eu fizesse parte deste excelente grupo de pesquisa, pelos ensinamentos e pela confiança depositada em mim. Ao Dr. Paulo Alberto Otto, pelos ensinamentos, pelo auxílio nas análises e por estar sempre disposto a ajudar no que fosse necessário. O exame clínico que realizou nos pacientes foi fundamental para este trabalho.
    [Show full text]
  • Supplementary Table 1 Double Treatment Vs Single Treatment
    Supplementary table 1 Double treatment vs single treatment Probe ID Symbol Gene name P value Fold change TC0500007292.hg.1 NIM1K NIM1 serine/threonine protein kinase 1.05E-04 5.02 HTA2-neg-47424007_st NA NA 3.44E-03 4.11 HTA2-pos-3475282_st NA NA 3.30E-03 3.24 TC0X00007013.hg.1 MPC1L mitochondrial pyruvate carrier 1-like 5.22E-03 3.21 TC0200010447.hg.1 CASP8 caspase 8, apoptosis-related cysteine peptidase 3.54E-03 2.46 TC0400008390.hg.1 LRIT3 leucine-rich repeat, immunoglobulin-like and transmembrane domains 3 1.86E-03 2.41 TC1700011905.hg.1 DNAH17 dynein, axonemal, heavy chain 17 1.81E-04 2.40 TC0600012064.hg.1 GCM1 glial cells missing homolog 1 (Drosophila) 2.81E-03 2.39 TC0100015789.hg.1 POGZ Transcript Identified by AceView, Entrez Gene ID(s) 23126 3.64E-04 2.38 TC1300010039.hg.1 NEK5 NIMA-related kinase 5 3.39E-03 2.36 TC0900008222.hg.1 STX17 syntaxin 17 1.08E-03 2.29 TC1700012355.hg.1 KRBA2 KRAB-A domain containing 2 5.98E-03 2.28 HTA2-neg-47424044_st NA NA 5.94E-03 2.24 HTA2-neg-47424360_st NA NA 2.12E-03 2.22 TC0800010802.hg.1 C8orf89 chromosome 8 open reading frame 89 6.51E-04 2.20 TC1500010745.hg.1 POLR2M polymerase (RNA) II (DNA directed) polypeptide M 5.19E-03 2.20 TC1500007409.hg.1 GCNT3 glucosaminyl (N-acetyl) transferase 3, mucin type 6.48E-03 2.17 TC2200007132.hg.1 RFPL3 ret finger protein-like 3 5.91E-05 2.17 HTA2-neg-47424024_st NA NA 2.45E-03 2.16 TC0200010474.hg.1 KIAA2012 KIAA2012 5.20E-03 2.16 TC1100007216.hg.1 PRRG4 proline rich Gla (G-carboxyglutamic acid) 4 (transmembrane) 7.43E-03 2.15 TC0400012977.hg.1 SH3D19
    [Show full text]
  • Differences in MWCNT- and SWCNT-Induced DNA Methylation
    Öner et al. Particle and Fibre Toxicology (2018) 15:11 DOI 10.1186/s12989-018-0244-6 RESEARCH Open Access Differences in MWCNT- and SWCNT- induced DNA methylation alterations in association with the nuclear deposition Deniz Öner1†, Manosij Ghosh1†, Hannelore Bové2,3, Matthieu Moisse4,5, Bram Boeckx4,5, Radu C. Duca6,KatrienPoels6, Katrien Luyts1, Eveline Putzeys1,7, Kirsten Van Landuydt7, Jeroen AJ Vanoirbeek1,6,MarcelAmeloot3, Diether Lambrechts4,5, Lode Godderis6,8 and Peter HM Hoet1* Abstract Background: Subtle DNA methylation alterations mediated by carbon nanotubes (CNTs) exposure might contribute to pathogenesis and disease susceptibility. It is known that both multi-walled carbon nanotubes (MWCNTs) and single-walled carbon nanotubes (SWCNTs) interact with nucleus. Such, nuclear-CNT interaction may affect the DNA methylation effects. In order to understand the epigenetic toxicity, in particular DNA methylation alterations, of SWCNTs and short MWCNTs, we performed global/genome-wide, gene-specific DNA methylation and RNA-expression analyses after exposing human bronchial epithelial cells (16HBE14o- cell line). In addition, the presence of CNTs on/in the cell nucleus was evaluated in a label-free way using femtosecond pulsed laser microscopy. Results: Generally, a higher number of SWCNTs, compared to MWCNTs, was deposited at both the cellular and nuclear level after exposure. Nonetheless, both CNT types were in physical contact with the nuclei. While particle type dependency was noticed for the identified genome-wide and gene-specific alterations, no global DNA methylation alteration on 5- methylcytosine (5-mC) sites was observed for both CNTs. After exposure to MWCNTs, 2398 genes were hypomethylated (at gene promoters), and after exposure to SWCNTs, 589 CpG sites (located on 501 genes) were either hypo- (N = 493 CpG sites) or hypermethylated (N = 96 CpG sites).
    [Show full text]
  • STAT3 Expression, Activity and Functional Consequences of STAT3 Inhibition in Esophageal Squamous Cell Carcinomas and Barrett’S Adenocarcinomas
    Oncogene (2014) 33, 3256–3266 & 2014 Macmillan Publishers Limited All rights reserved 0950-9232/14 www.nature.com/onc ORIGINAL ARTICLE STAT3 expression, activity and functional consequences of STAT3 inhibition in esophageal squamous cell carcinomas and Barrett’s adenocarcinomas S Timme1,11, S Ihde1,11, CD Fichter1,2,11, V Waehle1, L Bogatyreva3, K Atanasov1, I Kohler1, A Scho¨ pflin1, H Geddert4, G Faller4, D Klimstra5, L Tang5, T Reinheckel6,7,8, D Hauschke3, H Busch6,9,10, M Boerries6,9,10, M Werner1,8,9,10 and S Lassmann1,7,8,9,10 Signal transducer and activator of transcription 3 (STAT3) is altered in several epithelial cancers and represents a potential therapeutic target. Here, STAT3 expression, activity and cellular functions were examined in two main histotypes of esophageal carcinomas. In situ, immunohistochemistry for STAT3 and STAT3-Tyr705 phosphorylation (P-STAT3) in esophageal squamous cell carcinomas (ESCC, n ¼ 49) and Barrett’s adenocarcinomas (BAC, n ¼ 61) revealed similar STAT3 expression in ESCCs and BACs (P ¼ 0.109), but preferentially activated P-STAT3 in ESCCs (P ¼ 0.013). In vitro, strong STAT3 activation was seen by epidermal growth factor (EGF) stimulation in OE21 (ESCC) cells, whereas OE33 (BAC) cells showed constitutive weak STAT3 activation. STAT3 knockdown significantly reduced cell proliferation of OE21 (P ¼ 0.0148) and OE33 (P ¼ 0.0243) cells. Importantly, STAT3 knockdown reduced cell migration of OE33 cells by 2.5-fold in two types of migration assays (P ¼ 0.073, P ¼ 0.015), but not in OE21 cells (P ¼ 0.1079, P ¼ 0.386). Investigation of transcriptome analysis of STAT3 knockdown revealed a reduced STAT3 level associated with significant downregulation of cell cycle genes in both OE21 (Po0.0001) and OE33 (P ¼ 0.01) cells.
    [Show full text]
  • Validation of Genes Sensitive to P23 Levels in a Different MCF-7 Cell Line Overexpressing P23 [Clone #8]
    Supplementary Figure 1 – Validation of genes sensitive to p23 levels in a different MCF-7 cell line overexpressing p23 [clone #8]. qRT-PCR experiments were performed to show the relative fold-change (RFC) in the expression of six genes from Figure 1c between MCF-7 control (white bars) and MCF-7+p23 (#8) cells (black bars). Data are means of three independent experiments, normalized to GAPDH, and presented as RFC from that of MCF-7 control cells, set to 1. Error bars represent standard deviation. Supplementary Figure 2 – Genes most upregulated or downregulated by p23 overexpression are also overexpressed or under- expressed in invasive breast cancers Differential analyses of microarray datasets from invasive breast cancer subgroups (listed in the Legend) were performed using the Oncomine database (www.oncomine.org) to determine if the ten genes most upregulated or the eighteen genes most downregulated ( > 5-fold, Tables S5-6) by p23 overexpression are also over- or under-expressed in invasive breast cancers. Shown are five of the 10 upregulated and 11 of the 18 downregulated genes that are significantly over- or under-expressed in at least one invasive breast cancer dataset (p-value < 0.05) (* designates those genes that are not considered significant using Oncomine differential analysis, but are associated with invasive cancers in referenced literature). Over-expressed genes ranked highest, based on significance, within a particular dataset are designated with red boxes (or dark blue boxes for under-expressed genes). Pink and light blue boxes indicate genes that are statistically significant, but with lower gene rank. White boxes designate genes that are not statistically significant within a given dataset.
    [Show full text]