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Recurrent Rearrangements in Synaptic and Neurodevelopmental Genes and Shared Biologic Pathways in Schizophrenia, Autism, and Mental Retardation

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WEB-ONLY CONTENT Recurrent Rearrangements in Synaptic and Neurodevelopmental Genes and Shared Biologic Pathways in Schizophrenia, Autism, and Mental Retardation Audrey Guilmatre, PhD; Christèle Dubourg, PhD; Anne-Laure Mosca, MD; Solenn Legallic, BSc; Alice Goldenberg, MD; Vale´rie Drouin-Garraud, MD; Vale´rie Layet, MD; Antoine Rosier, MD; Sylvain Briault, MD; Fre´de´rique Bonnet-Brilhault, MD, PhD; Fre´de´ric Laumonnier, PhD; Sylvie Odent, MD, PhD; Gael Le Vacon, MD; Ge´raldine Joly-Helas, MD; Ve´ronique David, MD; Claude Bendavid, MD; Jean-Michel Pinoit, MD; Ce´line Henry, MD; Caterina Impallomeni, MD; Eva Germano, MD; Gaetano Tortorella, MD; Gabriella Di Rosa, MD; Catherine Barthelemy, MD; Christian Andres, MD; Laurence Faivre, MD, PhD; Thierry Fre´bourg, MD, PhD; Pascale Saugier Veber, PhD; Dominique Campion, MD, PhD Arch Gen Psychiatry. 2009;66(9):947-956 eTable 1. Polymerase Chain Reaction Primers and Amplification Conditionsa Gene Forward Primer Reverse Primer Amplicon Size, bp NRXN1␣ exon 1 CGTTAGATAGTCGGGACCCTTATTTCTTCG GATAGGGTTA GCAGCAGGCGTTCCACTT 258 NRXN1␣ exon 5 CGTTAGATAGTAGTGGAGCCTGTGAATGGAAAG GATAGGGTTAGAGGAGCCCTGTATCATGTTGTT 192 NRXN1␤ exon 4 CGTTAGATAGGCCTGGCCCTGCTTTGG GATAGGGTTAGGAAATGGTGGATGTGGTGC 119 DPP10 CGTTAGATAGCAGATAAGTTCCATATTGACTGGG GATAGGGTTAGCTGTTATTTGGTCCTTTACTTCT 180 ERBB4 CGTTAGATAGCCGAGGATGAGTATGTGAATGA GATAGGGTTAGAAGGGTGCTCCGAGGTG 188 CNTN4 CGTTAGATAGGATCTTCAATGAATACCCTTCC GATAGGGTTACCCAGGACCTTGTGGTTTGT 170 GRM7 CGTTAGATAGTGTGAGCCTTGCGATGGTTA GATAGGGTTAGGGCGTGTCATTGTAGCG 245 NLGN1 CGTTAGATAGGATAAGAGGGATTAAGAAGGAACTCA GATAGGGTTAAGGCAGTCTTCGCTCTGGTCT 299 GABRG1 CGTTAGATAGATGACTCCTGGTCTCCATCCT GATAGGGTTAAAGATAGCCAACCCAATAAACCA 278 SLC1A3 CGTTAGATAGGCCAACGAAACGCTTGTG GATAGGGTTAGGAGAAGACAACTAGACCCAGG 158 ST7 CGTTAGATAGCATGTTTTATGGGCATGTGTAC GATAGGGTTAGGAATCTGAGTCCCCGTTAC 236 CNTNAP2 CGTTAGATAGATTTGGGCAATGTGGAGATT GATAGGGTTATTTGGCTCATCTTGGTCTGTG 101 NRG1 CGTTAGATAGTGCGGGAGGCTCAAGGA GATAGGGTTAGGGAAAGAGGCTCGGAA 118 DLGAP2 CGTTAGATAGCAAAAGCAACGCCAACGG GATAGGGTTATGGAGGTCTTGAGGGACAGG 301 PTK2 CGTTAGATAGCCTGGGTACTGGTATGGAACG GATAGGGTTAGTGGTTGGCTCACTATTGCTTT 110 DLG2 CGTTAGATAGAGTAAAGCGGTGGAAGCCCT GATAGGGTTAGCCTTTGAACAGTTTGATTTC 128 GRIP1 CGTTAGATAGACCTTGTGCAGCTCCACAGGA GATAGGGTTATAAAAATTGTCAATGCCAC 277 GABRA5 CGTTAGATAGCAGACCTACCTTCCCTGCATAA GATAGGGTTAAGAGGCAGCACTAGAAGTTTCG 214 APBA2 CGTTAGATAGGAAGCACAAGGGCGAGATC GATAGGGTTAGTGCCTACCTTGATGATGCC 230 CHRNA7 CGTTAGATAG GGACAAGGAGCTGGTCAAGAACT GATAGGGTTA CTGGGGCCAACTAGAGTGC 226 DOC2A CGTTAGATAGCCCTGCAGCCCTCCTTG GATAGGGTTAACTCACTGGCATCATCCGA 100 MAPT CGTTAGATAGAGCCTGGGCGATAGAGCAA GATAGGGTTACTGAGATGCCGTGGAGACG 281 PRODH CGTTAGATAGGGCTTCCCTTTGCCTTTCAG GATAGGGTTAGCCTTACTCCATCTCCTTGTGCT 256 SHANK3 CGTTAGATAGCTCCACCGCAGCCATCTTC GATAGGGTTATGCTCAGACGCACCCAGTT 183 NLGN4 CGTTAGATAGAAGAAGCCCGTCATGGTCTATAT GATAGGGTTATTCCTCTTGCTCAGTCATTCACA 192 TSPAN7 CGTTAGATAGGGATGCTGAAACTGGTGAGTATG GATAGGGTTATTGTTTTTACCTCTAGGGGATTAA 198 CASK CGTTAGATAGGGGTCCCTTCAGTGTTGTACGA GATAGGGTTAATGGAATAAAGCCAGACA 182 IL1RAPL1 CGTTAGATAGAGCCGATGGATGCACTGACT GATAGGGTTACACTTTGGGCAAGGGAGTAAT 148 GRIA3 CGTTAGATAGGCAGTTATACAACACCAACCAGAA GATAGGGTTACTACTTACAAGCATTTGTCACGGA 132 MECP2 CGTTAGATAGTCAAGGACAAACCCCTCAAGT GATAGGGTTAGCCTGACCCTTCTGATGTCTC 166 a Quantitative multiplex polymerase chain reaction of short fluorescent fragments (QMPSF) included the following: QMPSF 1 (23 cycles at 94°C for 5 minutes, 94°C for 30 seconds, 57°C for 1 minute, 72°C for 30 seconds, and 72°C for 5 minutes), QMPSF 2 (23 cycles at 94°C for 5 minutes, 94°C for 30 seconds, 56°C for 1 minute, 72°C for 30 seconds, and 72°C for 5 minutes), and QMPSF 3 (24 cycles at 94°C for 5 minutes, 94°C for 30 seconds, 58°C for 1 minute, 72°C for 30 seconds, and 72°C for 5 minutes). (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 66 (NO. 9), SEP 2009 WWW.ARCHGENPSYCHIATRY.COM E1 ©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 eTable 2. Other Copy Number Variations Chromosomal Case Diagnosis Location Genes Involved Type Confirmation 1003 Control 22q11 PRODH, DGCR6 Dup QMPSF 1060 Control 22q11 PRODH, DGCR6 Dup QMPSF 1069 Control 22q11 PRODH, DGCR6 Dup QMPSF 1136 Control 22q11 PRODH, DGCR6 Dup QMPSF 1182 Control 22q11 PRODH, DGCR6 Dup QMPSF 292/002 Control 22q11 PRODH, DGCR6 Dup QMPSF 1 SZ AFF 22q11 PRODH, DGCR6 Dup QMPSF 99 SZ 22q11 PRODH, DGCR6 Dup QMPSF 136 SZ 22q11 PRODH, DGCR6 Dup QMPSF 189 SZ 22q11 PRODH, DGCR6 Dup QMPSF 236 SZ 22q11 PRODH, DGCR6 Dup QMPSF 244 SZ 22q11 PRODH, DGCR6 Dup QMPSF 280 SZ AFF 22q11 PRODH, DGCR6 Dup QMPSF 44 544 ASDs 22q11 PRODH, DGCR6 Dup QMPSF 44 743 ASDs 22q11 PRODH, DGCR6 Dup QMPSF 44 822 ASDs 22q11 PRODH, DGCR6 Dup QMPSF 46 658 ASDs 22q11 PRODH, DGCR6 Dup QMPSF 11 198 MR 22q11 PRODH, DGCR6 Dup QMPSF 11 984 MR 22q11 PRODH, DGCR6 Dup QMPSF 14 150 MR 22q11 PRODH, DGCR6 Dup QMPSF 14 260 MR 22q11 PRODH, DGCR6 Dup QMPSF 15 051 MR 22q11 PRODH, DGCR6 Dup QMPSF 6355.002 MR 22q11 PRODH, DGCR6 Dup QMPSF 8635 MR 22q11 PRODH, DGCR6 Dup QMPSF 9930 MR 22q11 PRODH, DGCR6 Dup QMPSF 10 403 MR 22q11 PRODH, DGCR6 Dup QMPSF 1050 Control 15q13 CHRNA7 Dup QMPSF, array-CGH 1067 Control 15q13 CHRNA7 Dup QMPSF SDI013 SZ 15q13 CHRNA7 Dup QMPSF 16 144 ASDs 15q13 CHRNA7 Dup QMPSF 14 522 MR 15q13 CHRNA7 Dup QMPSF Abbreviations: array-CGH, microarray-based technologies for comparative genomic hybridization; ASDs, autism spectrum disorders; Dup, duplication; MR, mental retardation; QMPSF, quantitative multiplex polymerase chain reaction of short fluorescent fragments; SZ, schizophrenia; SZ AFF, schizoaffective disorder. (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 66 (NO. 9), SEP 2009 WWW.ARCHGENPSYCHIATRY.COM E2 ©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 eTable 3. Copy Number Variation (CNV) Margins and Confirmation Methods Margin, bp Case CNV Last Outer First Inner Last Inner First Outer Confirmation 113 Dup (Xp11.4) 38 326 267 38 376 483 38 432 836 38 549 143 QMPSF, array-CGH 313 Dup (8p23) 1 436 299 1 481 035 1 590 831 1 642 837 QMPSF, array-CGH 185 Dup (15q13) 26 999 744 27 000 694 27 994 706 28 109 371 QMPSF, array-CCH 144.1 Del (22q11) . QMPSF 223 Del (2p16.3) 50 704 195 51 006 556 51 114 057 51 433 167 QMPSF, array-CGH 220 Del (2p16.3) 50 172 024 50 420 164 50 420 164 50 704 195 QMPSF, array-CGH 33 Dup (16p11) . QMPSF 136 Dup (16p11) . QMPSF 146 Dup (16p11) . QMPSF 151 Dup (17q21) 40 869 151 41 073 486 41 700 762 42 143 048 QMPSF, array-CGH T35 Del (2p16.3) 51 006 556 51 114 057 51 114 057 51 433 167 QMPSF, array-CGH, FISH 45 431 Del (2p16.3) 50 704 195 51 006 556 51 114 057 51 433 167 QMPSF, array-CGH 47 604 Del (22q13) 47 124 905 47 265 476 49 525 071 . QMPSF, array-CGH Si22 Del (22q13) . QMPSF, MLPA 60 478 Dup (15q11-q13) . QMPSF, FISH T34 Dup (Xq25) 120 669 107 120 746 477 122 166 142 122 316 448 QMPSF, array-CGH, FISH 12 746 Del (22q11) . QMPSF 12 452 Del (22q11) . QMPSF 13 899 Del (22q11) . QMPSF 44 737 Del (22q11) . QMPSF 45 435 Del (22q11) . QMPSF 45 856 Del (22q11) . QMPSF 46 261 Del (22q11) . QMPSF 47 766 Del (22q11) . QMPSF Si30 Del (22q11) . QMPSF 44 813 Dup (15q13) 26 198 996 26 999 744 30 796 716 30 812 300 QMPSF, array-CGH 12 363 Del (22q11) . QMPSF 11 780 Del (22q11) . QMPSF 9680 Del (22q11) . QMPSF 14 684 Del (22q11) . QMPSF 11 695 Del (2p16.3) 51 006 556 51 114 057 51 114 057 51 433 167 QMPSF, array-CGH 14 921 Del (16p11) . QMPSF, FISH 10 417 Del (16p11) . QMPSF, FISH 13 165 Dup (16p11) . QMPSF, FISH 14 390 Del (16p11) . QMPSF, FISH 13 907 Del (15q13) 28 109 371 28 725 507 30 298 096 30 701 373 QMPSF, array-CGH 11 919 Del (15q13) 28 109 371 28 725 507 30 298 096 30 701 373 QMPSF, array-CGH 9930 Del (15q13) 28 109 371 28 725 507 30 298 096 30 701 373 QMPSF, array-CGH 12 988 Del (8p23) . QMPSF, HRK 011/003 Del (22q11) . QMPSF Abbreviations: array-CGH, microarray-based technologies for comparative genomic hybridization; bp, base pair; Del, deletion; Dup, duplication; ellipsis, not applicable; FISH, fluorescence in situ hybridization; HRK, high-resolution karyotype; MLPA, multiplex ligation-dependent probe amplification; QMPSF, quantitative multiplex polymerase chain reaction of short fluorescent fragments. (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 66 (NO. 9), SEP 2009 WWW.ARCHGENPSYCHIATRY.COM E3 ©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 A 90 120 150 180 210 240 270 300 MAPK3 2700 2400 DOC2A 2100 NLGN4 1800 QPRT 1500 PBGD 1200 900 600 300 0 B 150 180 210 240 270 300 2700 2400 ARVCF USP18 PRODH SNAP29 2100 DGCR6 UFD1L DGCR2 1800 1500 DGSA 1200 MSH2 900 600 300 0 eFigure 1. A, Detection by a dedicated quantitative multiplex polymerase chain reaction of short fluorescent fragments (QMPSF) of a 16p11 duplication. The electropherogram of subject 136 with schizophrenia (red) was superimposed on that of a healthy control subject (blue) by adjusting to the same level the peaks obtained from the amplicon PBGD located on chromosome 11. The vertical axis shows fluorescence in arbitrary units and the horizontal axis indicates the size of the amplicon in base pairs. Horizontal bars indicate heterozygous duplications of the amplicons detected by a 1.5-fold increase of the corresponding peaks. This QMPSF covers 5 genes located at 16p11.2 (DOC2A, QPRT, and MAPK3), Xp22.3 (NLGN4), and 11q23.3 (PBGD). NLGN4 located on the X chromosome was used as a control and shows a 2-fold heightening in the female patient compared with the male control. B, Detection by a dedicated QMPSF of a 22q11 deletion. The electropherogram of subject 9680 with mental retardation
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  • Nicotinic Receptors Atlas in the Adult Human Lung

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    bioRxiv preprint doi: https://doi.org/10.1101/2020.06.29.176750; this version posted August 13, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Nicotinic receptors atlas in the adult human lung 2 3 Zania Diabasana1, Jeanne-Marie Perotin1,2, Randa Belgacemi1, Julien Ancel1,2, Pauline 4 Mulette1,2, Gonzague Delepine3, Philippe Gosset4, Uwe Maskos5, Myriam Polette1,6, Gaëtan 5 Deslée1,2, Valérian Dormoy1 6 7 1University of Reims Champagne-Ardenne, Inserm, P3Cell UMR-S1250, SFR CAP-SANTE, 8 51092 Reims, France 9 2CHU of Reims, Hôpital Maison Blanche, Department of respiratory diseases, 51092 Reims, 10 France 11 3CHU of Reims, Hôpital Maison Blanche, Department of thoracic surgery, 51092 Reims, 12 France 13 4University of Lille, CNRS UMR9017, Inserm U1019, CHRU Lille, Pasteur Institute of Lille, 14 CIIL - Center for Infection and Immunity of Lille, 59000 Lille, France 15 5Pasteur Institute of Paris, Integrative Neurobiology of Cholinergic Systems, CNRS UMR 16 3571, Paris, France. 17 6CHU Reims, Hôpital Maison Blanche, Department of biopathology, 51092 Reims, France 18 19 Correspondence to: 20 Dr Valérian Dormoy 21 Inserm UMR-S 1250 22 University of Reims Champagne-Ardenne 23 CHU Maison Blanche 24 45 rue Cognacq-Jay 25 51092 Reims 26 Phone +33 (0)3 10 73 62 28; Fax +33 (0)3 26 06 58 61 27 e-mail: [email protected] 28 29 Short title: lung nicotinic receptors 30 31 32 33 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.29.176750; this version posted August 13, 2020.
  • Structure, Dynamics, and Ligand Recognition of Human-Specific CHRFAM7A (Dup7) Nicotinic Receptor Linked to Neuropsychiatric Diso

    Structure, Dynamics, and Ligand Recognition of Human-Specific CHRFAM7A (Dup7) Nicotinic Receptor Linked to Neuropsychiatric Diso

    International Journal of Molecular Sciences Article Structure, Dynamics, and Ligand Recognition of Human-Specific CHRFAM7A (Dupα7) Nicotinic Receptor Linked to Neuropsychiatric Disorders Danlin Liu 1,†, João V. de Souza 1,†, Ayaz Ahmad 1 and Agnieszka K. Bronowska 1,2,* 1 Chemistry—School of Natural and Environmental Sciences, Newcastle University, Newcastle NE1 7RU, UK; [email protected] (D.L.); [email protected] (J.V.d.S.); [email protected] (A.A.) 2 Newcastle University Centre for Cancer, Newcastle University, Newcastle NE1 7RU, UK * Correspondence: [email protected] † Equal contribution. Abstract: Cholinergic α7 nicotinic receptors encoded by the CHRNA7 gene are ligand-gated ion chan- nels directly related to memory and immunomodulation. Exons 5–7 in CHRNA7 can be duplicated and fused to exons A-E of FAR7a, resulting in a hybrid gene known as CHRFAM7A, unique to humans. Its product, denoted herein as Dupα7, is a truncated subunit where the N-terminal 146 residues of the ligand binding domain of the α7 receptor have been replaced by 27 residues from FAM7. Dupα7 negatively affects the functioning of α7 receptors associated with neurological disorders, including Alzheimer’s diseases and schizophrenia. However, the stoichiometry for the α7 nicotinic receptor containing dupα7 monomers remains unknown. In this work, we developed computational models Citation: Liu, D.; de Souza, J.V.; of all possible combinations of wild-type α7 and dupα7 pentamers and evaluated their stability via Ahmad, A.; Bronowska, A.K. atomistic molecular dynamics and coarse-grain simulations. We assessed the effect of dupα7 subunits Structure, Dynamics, and Ligand on the Ca2+ conductance using free energy calculations.
  • A Human-Specific A7-Nicotinic Acetylcholine Receptor Gene In

    A Human-Specific A7-Nicotinic Acetylcholine Receptor Gene In

    A Human-Specific α7-Nicotinic Acetylcholine Receptor Gene in Human Leukocytes: Identification, Regulation and the Consequences of CHRFAM7A Expression Todd W Costantini,1* Xitong Dang,1,2* Maryana V Yurchyshyna,1 Raul Coimbra,1 Brian P Eliceiri,1 and Andrew Baird1 1Department of Surgery, University of California San Diego Health Sciences, San Diego, California, United States of America; and 2Cardiovascular Research Center, Luzhou Medical College, Luzhou, Sichuan, China The human genome contains a variant form of the α7-nicotinic acetylcholine receptor (α7nAChR) gene that is uniquely human. This CHRFAM7A gene arose during human speciation and recent data suggests that its expression alters ligand tropism of the normally homopentameric human α7-AChR ligand-gated cell surface ion channel that is found on the surface of many dif- ferent cell types. To understand its possible significance in regulating inflammation in humans, we investigated its expression in nor- mal human leukocytes and leukocyte cell lines, compared CHRFAM7A expression to that of the CHRNA7 gene, mapped its pro- moter and characterized the effects of stable CHRFAM7A overexpression. We report here that CHRFAM7A is highly expressed in human leukocytes but that the levels of both CHRFAM7A and CHRNA7 mRNAs were independent and varied widely. To this end, mapping of the CHRFAM7A promoter in its 5′-untranslated region (UTR) identified a unique 1-kb sequence that independently reg- ulates CHRFAM7A gene expression. Because overexpression of CHRFAM7A in THP1 cells altered the cell phenotype and modified the expression of genes associated with focal adhesion (for example, FAK, P13K, Akt, rho, GEF, Elk1, CycD), leukocyte transepithe- lial migration (Nox, ITG, MMPs, PKC) and cancer (kit, kitL, ras, cFos cyclinD1, Frizzled and GPCR), we conclude that CHRFAM7A is bi- ologically active.
  • Genetic Mapping of Putative Chrna7 and Luzp2 Neuronal Transcriptional

    Genetic Mapping of Putative Chrna7 and Luzp2 Neuronal Transcriptional

    BMC Genomics 2005, 6:157 http://www.biomedcentral.com/1471-2164/6/157 Research article Genetic mapping of putative Chrna7 and Luzp2 neuronal transcriptional enhancers due to impact of a transgene-insertion and 6.8 Mb deletion in a mouse model of Prader-Willi and Angelman syndromes Mihaela Stefan1,7, Kathryn C Claiborn1, Edyta Stasiek3, Jing-Hua Chai1, Tohru Ohta1,6, Richard Longnecker4, John M Greally3 and Robert D Nicholls*1,2,5,7 Address: 1Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA, 2Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA, 3Division of Hematology, Department of Medicine, Albert Einstein College of Medicine, The Bronx, USA, 4Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Ward 6-231, 303 East Chicago Ave, Chicago, IL 60611, USA, 5Birth Defects Laboratories, Children's Hospital of Pittsburgh, Room 2109 Rangos Research Center, 3460 Fifth Avenue, Pittsburgh, PA 15213, USA, 6Health Science University of Hokkaido, Hokkaido, Japan and 7Department of Pediatrics, Children's Hospital of Pittsburgh, 3460 Fifth Avenue, Pittsburgh, PA 15213 Email: Mihaela Stefan - [email protected]; Kathryn C Claiborn - [email protected]; Edyta Stasiek - [email protected]; Jing- Hua Chai - [email protected]; Tohru Ohta - [email protected]; Richard Longnecker - [email protected]; John M Greally - [email protected]; Robert D Nicholls* - [email protected] * Corresponding author Published: 09 November 2005 Received: 14 July 2005 Accepted: 09 November 2005 BMC Genomics 2005, 6:157 doi:10.1186/1471-2164-6-157 This article is available from: http://www.biomedcentral.com/1471-2164/6/157 © 2005 Stefan et al; licensee BioMed Central Ltd.