Disruption at the PTCHD1 Locus on Xp22.11 in Autism Spectrum Disorder and Intellectual Disability — Sci TM

Sci Transl Med 15 September 2010:
Vol. 2, Issue 49, p. 49ra68
DOI: 10.1126/scitranslmed.3001267
Research Article
Disruption at the PTCHD1 Locus on Xp22.11 in Autism Spectrum Disorder and Intellectual Disability
Abdul Noor1, Annabel Whibley2,*, Christian R. Marshall3, Peter J. Gianakopoulos1, Amelie Piton4,5, Andrew R. Carson3, Marija Orlic-Milacic1, Anath C. Lionel3, Daisuke Sato3, Dalila Pinto3, Irene Drmic6, Carolyn Noakes6, Lili Senman6, Xiaoyun Zhang7, Rong Mo7, Julie Gauthier4,5, Jennifer Crosbie8, Alistair T. Pagnamenta9, Jeffrey Munson10, Annette M. Estes11, Andreas Fiebig12,13, Andre Franke12,13, Stefan Schreiber12,13,14, Alexandre F. R. Stewart15, Robert Roberts15, Ruth McPherson15, Stephen J. Guter16, Edwin H. Cook Jr.16, Geraldine Dawson17,18,19, Gerard D. Schellenberg20, Agatino Battaglia21, Elena Maestrini22, Autism Genome Project Consortium†, Linda Jeng23, Terry Hutchison24, Evica Rajcan-Separovic25, Albert E. Chudley26, Suzanne M. E. Lewis27, Xudong Liu28,29, Jeanette J. Holden28,29, Bridget Fernandez30,31, Lonnie Zwaigenbaum32, Susan E. Bryson33, Wendy Roberts6, Peter Szatmari34, Louise Gallagher35, Michael R. Stratton36, Jozef Gecz37,38, Angela F. Brady39, Charles E. Schwartz40, Russell J. Schachar8, Anthony P. Monaco9, Guy A. Rouleau4,5, Chi-chung Hui7,41, F. Lucy Raymond2, Stephen W. Scherer3,41,‡ and John B. Vincent1,42,43,‡
+ Author Affiliations

1Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada M5T 1R8.
2Cambridge Institute of Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
3Program in Genetics and Genome Biology and The Centre for Applied Genomics, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
4Center of Excellence in Neuromics, Centre Hospitalier de l’Université de Montréal, Montreal, Quebec, Canada H2L 4M1.
5Department of Medicine, University of Montreal, Montreal, Quebec, Canada H3T 1J4.
6Autism Research Unit, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
7Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
8Department of Psychiatry, Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
9Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX1 2JD, UK.
10Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98133, USA.
11Department of Speech and Hearing Sciences, University of Washington, Seattle, WA 98133, USA.
12Institute for Clinical Molecular Biology, Christian-Albrechts University, Kiel 24098, Germany.
13Biobank PopGen, Kiel 24098, Germany.
14Department of Internal Medicine, University of Kiel, Kiel 24118, Germany.
15University of Ottawa Heart Institute, Ottawa, Ontario, Canada K1Y 4W7.
16Laboratory of Developmental Neuroscience, University of Illinois, Chicago, IL 60612, USA.
17Autism Speaks, New York, NY 10016, USA.
18Department of Psychology, University of Washington, Seattle, WA 98133, USA.
19Department of Psychiatry, University of North Carolina, Chapel Hill, NC 28372, USA.
20Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
21Stella Maris Institute for Child and Adolescent Neuropsychiatry, Pisa 56128, Italy.
22Department of Biology, University of Bologna, Bologna 40126, Italy.
23Department of Laboratory Medicine, University of California, San Francisco, CA 90095, USA.
24Department of Neurology, University of California, San Francisco, CA 90095, USA.
25Department of Pathology (Cytogenetics), Children’s and Women’s Health Centre of British Columbia, Vancouver, British Columbia, Canada V6H 3V5.
26Program in Genetics and Metabolism, Children’s Hospital, Winnipeg, Manitoba, Canada R3C 1T5.
27Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z4.
28Departments of Psychiatry and Physiology, Queen’s University, Kingston, Ontario, Canada K7L 3N6.
29Autism Research Program and Genomics Research Laboratory, Kingston, Ontario, Canada K7L 3N6.
30Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada L7G 2B8.
31Provincial Medical Genetics Program, Health Sciences Center, Eastern Health, St. John’s, Newfoundland, Canada L7G 2B8.
32Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada T6B 2H3.
33Departments of Pediatrics and Psychology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 3J5.
34Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada L8S 4L8.
35Neuropsychiatric Genetics Research Group, Trinity Centre for Health Sciences, Trinity College Dublin, Dublin 6793657, Ireland.
36Wellcome Trust Sanger Institute, Cambridge CB10 1SD, UK.
37SA Pathology, Women’s and Children’s Hospital, North Adelaide, South Australia 5006, Australia.
38University of Adelaide, Adelaide, South Australia 5005, Australia.
39North West Thames Regional Genetic Centre, Northwick Park Hospital, Harrow HA1 3UJ, UK.
40JC Self Research Institute, Greenwood Genetic Center, Greenwood, SC 29646, USA.
41Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
42Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada M5T 1R8.
43Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada M5T 1R8.
‡To whom correspondence should be addressed. E-mail: john_vincent@camh.net (J.B.V.); stephen.scherer@sickkids.ca (S.W.S.)

Abstract
Autism is a common neurodevelopmental disorder with a complex mode of inheritance. It is one of the most highly heritable of the complex disorders, although the underlying genetic factors remain largely unknown. Here, we report mutations in the X-chromosome PTCHD1 (patched-related) gene in seven families with autism spectrum disorder (ASD) and in three families with intellectual disability. A 167-kilobase microdeletion spanning exon 1 was found in two brothers, one with ASD and the other with a learning disability and ASD features; a 90-kilobase microdeletion spanning the entire gene was found in three males with intellectual disability in a second family. In 900 probands with ASD and 208 male probands with intellectual disability, we identified seven different missense changes (in eight male probands) that were inherited from unaffected mothers and not found in controls. Two of the ASD individuals with missense changes also carried a de novo deletion at another ASD susceptibility locus (DPYD and DPP6), suggesting complex genetic contributions. In additional males with ASD, we identified deletions in the 5′ flanking region of PTCHD1 that disrupted a complex noncoding RNA and potential regulatory elements; equivalent changes were not found in male control individuals. Thus, our systematic screen of PTCHD1 and its 5′ flanking regions suggests that this locus is involved in ~1% of individuals with ASD and intellectual disability.

Footnotes
↵* Present address: CNRS/Museum National d’Histoire Naturelle, Paris 75005, France.

↵† See supplementary material for full list of names and affiliations.

Citation: A. Noor, A.Whibley, C. R.Marshall, P. J. Gianakopoulos, A. Piton, A. R. Carson, M. Orlic-Milacic, A. Lionel, D. Sato, D. Pinto, I. Drmic, C. Noakes, L. Senman, X. Zhang, R. Mo, J. Gauthier, J. Crosbie, A. T. Pagnamenta, J. Munson, A. M. Estes, A. Fiebig, A. Franke, S. Schreiber, A. F. R. Stewart, R. Roberts, R. McPherson, S. J. Guter, E. H. Cook Jr., G. Dawson, G. D. Schellenberg, A. Battaglia, E. Maestrini, Autism Genome Project Consortium, L. Jeng, T.Hutchison, E. Rajcan-Separovic, A. E. Chudley, S. M. E. Lewis, X. Liu, J. Holden, B. Fernandez, L. Zwaigenbaum, S. E. Bryson, W. Roberts, P. Szatmari, L. Gallagher, M. R. Stratton, J. Gecz, A. F. Brady, C. E. Schwartz, R. J. Schachar, A. P.Monaco, G. A. Rouleau, C. Hui, F. L. Raymond, S. W. Scherer, J. B. Vincent, Disruption at the PTCHD1 locus on Xp22.11 in autism spectrum disorder and intellectual disability. Sci. Transl. Med. 2, 49ra68 (2010).

Copyright © 2010, American Association for the Advancement of Science
Disruption at the PTCHD1 Locus on Xp22.11 in Autism Spectrum Disorder and Intellectual Disability — Sci TM




GENÉTICA
Actualidad Ultimas noticias - JANOes -
Asocian mutaciones genéticas con el autismo y la discapacidad intelectual
JANO.es · 16 Septiembre 2010 09:45

Aunque no se ha descubierto un único gen responsable, la detección de las alteraciones en un gen parche podría ayudar a comprender y diagnosticar mejor el trastorno.


Investigadores del Centro sobre Adicción y Salud Mental en Toronto, Canadá, han identificado mutaciones genéticas asociadas con el autismo y la discapacidad intelectual. Los resultados del estudio se publican en la revista Science Translational Medicine.

Un análisis genético de miles de pacientes autistas muestra que las mutaciones en el gen parche PTCHD1 están asociadas con la herencia del autismo y la discapacidad intelectual en una pequeña fracción de casos. Aunque no se ha descubierto un único gen responsable del autismo, la detección genética de las alteraciones en el gen parche podría ayudar a los médicos y los asesores genéticos a comprender y diagnosticar mejor la enfermedad.

Los científicos desconocen aún las causas del autismo y la explicación más prometedora es que tanto genética como ambiente interactúan para producir el trastorno, ahora caracterizado bajo el término paraguas trastorno del espectro autista o TEA.

Aunque los síntomas varían de ligeros a graves, las personas con TEA suelen no responder a los estímulos sociales y tienen las habilidades sociales y del lenguaje infradesarrolladas. Ningún gen puede explicar la predisposición a la TEA, pero en algunos individuos estos trastornos se conocen por tener un componente genético fuerte.

Heredabilidad del TEA
Los científicos, dirigidos por John Vincent, muestran que en una pequeña fracción de casos, diferentes tipos de mutaciones en el gen parche están vinculadas a la heredabilidad del TEA y a la discapacidad intelectual.

Así, los autores analizaron la secuencia del gen parche de casi 3.000 pacientes con TEA y 246 con discapacidad intelectual y compararon estos datos con los de más de 10.000 individuos control. Descubrieron mutaciones en el gen parche en un 1% de los pacientes, pero no en los controles. Dado que el gen parche se localiza en el cromosoma X, casi todos los pacientes afectados eran mujeres y la mayoría tenían madres y otras familiares femeninas no afectadas. Sin embargo, los hijos de madres portadoras de una mutación en PTCHD1 podrían tener un mayor riesgo de desarrollar TEA.

Los investigadores también descubrieron que el gen parche es parte de un mecanismo neurobiológico llamado mecanismo de señalización Hedgehog, que proporciona a las células información necesaria para el correcto desarrollo de los embriones humanos.

Los autores del estudio creen que posteriores investigaciones sobre cómo se relaciona el gen parche con el mecanismo Hedgehog podrían proporcionar pistas sobre las posibles causas del TEA y la discapacidad intelectual.


Sci Transl Med 15 September 2010, Vol. 2, Issue 49, p. 49ra68; doi: 10.1126/scitranslmed.3001267
Disruption at the PTCHD1 Locus on Xp22.11 in Autism Spectrum Disorder and Intellectual Disability — Sci TM

Centro sobre Adicción y Salud Mental en Toronto
http://www.camh.net/

Science Translational Medicine
http://stm.sciencemag.org/

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