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Übersichtsarbeit/Overview article

Genetische Analysen zur Identifizierung molekularer Mechanismen bei Autismus-Spektrum-Störungen

Published Online:March 25, 2011https://doi.org/10.1024/1422-4917/a000096

Abstract

Autismus-Spektrum-Störungen (ASS) sind neuronale Entwicklungsstörungen mit Auswirkung auf Kommunikation, Sprachentwicklung und Verhalten. Der komplexe Phänotyp und die starke klinische Heterogenität lassen bei erhöhter Disposition von ASS unter Geschwistern auf einen multifaktoriellen genetischen Hintergrund schließen. Neben einzelnen seltenen Mutationen werden auch Genkopie-Varianten und Einzelnukleotid-Polymorphismen immer mehr als Risikofaktoren in Betracht gezogen. Zur Identifizierung zentraler Schlüsselmechanismen werden im Rahmen von Konsortien Kopplungsanalysen und genomweite Assoziationsstudien durchgeführt. Außer polygenen bzw. genetisch komplexen Modellen, denen ASS zugrunde liegt, gibt es auch monogenetisch bedingte Formen. Dabei kommt es durch Aberrationen an einzelnen Genen zu einem autistischen Phänotyp, wie z. B. beim Fragilen-X-Syndrom. Knockout-Tiermodelle für monogenetischen Autismus wie FMRP–/– oder für neurodegenerative Erkrankungen wie MeCP2–/– werden häufig zur Untersuchung der molekularen Mechanismen herangezogen, welche bei ASS gestört sein könnten. Hier geben wir einen Einblick in den Stand der aktuellen Forschung im Bereich der Genomanalyse und beschreiben die wichtigsten Mausmodelle im Hinblick auf die Erkenntnisse bei poly- und monogenetischem Autismus. Grundsätzlich kann man erkennen, dass die meisten assoziierten Genomregionen und Gene im Zusammenhang mit der Ausbildung des synaptischen Spalts, der korrekten Sekretion von Oberflächenmolekülen oder der Translation stehen. Dies lässt vermuten, dass der Phänotyp bei ASS vorrangig durch eine Störung der translationsabhängigen Zell-Zell-Konnektivität und synaptischen Plastizität hervorgerufen wird.


Genetic analyses for identifying molecular mechanisms in autism spectrum disorders

Autism spectrum disorders (ASD) are severe neurodevelopmental disorders with marked deficits in social communication, verbal development, and behaviour. The broad phenotype and the clinical heterogeneity point to a polygenic disorder – despite high heritability among siblings. According to recent findings not only do single-rare mutations but also copy number variations and single nucleotide polymorphisms impact the ASD phenotype. Because of the scope of national and international consortia, many linkage and genome-wide association studies have evolved which elucidate candidate and susceptibility genomic regions and genes relevant for ASD. In contrast to polygenic or genetic complex models for autism, a few monogenetic forms of ASD are known to be caused by single gene defects, e.g., fragile-X syndrome. Knock-out animal models of monogenetic autism (e.g. FMRP–/–) or neurodegenerative disorders (e.g. MeCP2–/–) are often used to analyze the molecular mechanisms underlying ASD. In this review we describe the state of the art of genome analyses in ASD, the most widely used mouse models for polygenic or monogenetic forms of autism and discuss new insights gained from these analyses. The susceptibility genes so far identified seem to be involved in the proper establishment of the synaptic cleft, the secretion of surface proteins, or the overall cellular translation processes. Theses findings suggest that impacting translation-dependent processes like synaptic plasticity or cell-to-cell connectivity may lead to an ASD phenotype.

Literatur

  • Abrahams, B. S. , Geschwind, D. H. (2008). Advances in autism genetics: On the threshold of a new neurobiology. Nature Reviews Genetics, 9, 341–355. First citation in articleCrossref Medline, Google Scholar

  • Alarcon, M. , Abrahams, B. S. , Stone, J. L. , Duvall, J. A. , Perederiy, J. V. , Bomar, J. M. , ... Geschwind, D. H. (2008). Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. American Journal of Human Genetics, 82, 150–159. First citation in articleCrossref Medline, Google Scholar

  • Arking, D. E. , Cutler, D. J. , Brune, C. W. , Teslovich, T. M. , West, K. , Ikeda, M. , ... Chakravarti, A. (2008). A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. American Journal of Human Genetics, 82, 160–164. First citation in articleCrossref Medline, Google Scholar

  • Asperger, H. (1944). Die autistischen Psychopathen im Kindesalter. Archiv Psychiatrischer Nervenkrankheiten, 117, 76–136. First citation in articleCrossref, Google Scholar

  • Bailey, A. , Le Couteur, A. , Gottesman, I. , Bolton, P. , Simonoff, E. , Yuzda, E. , Rutter, M. (1995). Autism as a strongly genetic disorder: Evidence from a british twin study. Psychological Medicine, 25, 63–77. First citation in articleCrossref Medline, Google Scholar

  • Bakkaloglu, B. , O’Roak, B. J. , Louvi, A. , Gupta, A. R. , Abelson, J. F. , Morgan, T. M. , ... State, M. W. (2008). Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. American Journal of Human Genetics, 82, 165–173. First citation in articleCrossref Medline, Google Scholar

  • Betancur, C. , Sakurai, T. , Buxbaum, J. D. (2009). The emerging role of synaptic cell-adhesion pathways in the pathogenesis of autism spectrum disorders. Trends in Neuroscience, 32, 402–412. First citation in articleCrossref Medline, Google Scholar

  • Bucan, M. , Abrahams, B. S. , Wang, K. , Glessner, J. T. , Herman, E. I. , Sonnenblick, L. I. , ... Hakonarson, H. (2009). Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genetics, 5, e1000536. First citation in articleGoogle Scholar

  • Cook, E. H., Jr. , Scherer, S. W. (2008). Copy-number variations associated with neuropsychiatric conditions. Nature, 455, 919–923. First citation in articleCrossref Medline, Google Scholar

  • Crawley, J. N. (2007). Mouse behavioral assays relevant to the symptoms of autism. Brain Pathology, 17, 448–459. First citation in articleCrossref Medline, Google Scholar

  • de Vries, P. J. (2009). Genetics and neuropsychiatric disorders: Genome-wide, yet narrow. Nature Medicine, 15, 850–851. First citation in articleCrossref Medline, Google Scholar

  • Dickson, S. P. , Wang, K. , Krantz, I. , Hakonarson, H. , Goldstein, D. B. (2010). Rare variants create synthetic genome-wide associations. PLoS Biology, 8, e1000294. First citation in articleGoogle Scholar

  • Dobkin, C. , Rabe, A. , Dumas, R. , El Idrissi, A. , Haubenstock, H. , Brown, W. T. (2000). Fmr1 knockout mouse has a distinctive strain-specific learning impairment. Neuroscience, 100, 423–429. First citation in articleCrossref Medline, Google Scholar

  • Dölen, G. , Osterweil, E. , Rao, B. S. , Smith, G. B. , Auerbach, D. , Chattarji, S. , Bear, M. F. (2007). Correction of fragile X syndrome in mice. Neuron, 56, 955–962. First citation in articleCrossref Medline, Google Scholar

  • Durand, C. M. , Betancur, C. , Boeckers, T. M. , Bockmann, J. , Chaste, P. , Fauchereau, F. , ... Bourgeron, T. (2007). Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nature Genetics, 39, 25–27. First citation in articleCrossref Medline, Google Scholar

  • Feng, J. , Schroer, R. , Yan, J. , Song, W. , Yang, C. , Bockholt, A. , ... Sommer, S. S. (2006). High frequency of neurexin 1beta signal peptide structural variants in patients with autism. Neuroscience Letters, 409, 10–13. First citation in articleCrossref Medline, Google Scholar

  • Freitag, C. M. (2007). The genetics of autistic disorders and its clinical relevance: A review of the literature. Molecular Psychiatry, 12, 2–22. First citation in articleCrossref Medline, Google Scholar

  • GAIN Collaborative Research Group . (2007). New models of collaboration in genome-wide association studies: The Genetic Association Information Network. Nature Genetics, 39, 1045–1051. First citation in articleCrossref Medline, Google Scholar

  • Glessner, J. T. , Wang, K. , Cai, G. , Korvatska, O. , Kim, C. E. , Wood, S. , ... Hakonarson, H. (2009). Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature, 459, 569–573. First citation in articleCrossref Medline, Google Scholar

  • Hu-Lince, D. , Craig, D. W. , Huentelman, M. J. , Stephan, D. A. (2005). The autism genome project: Goals and strategies. American Journal of Pharmacogenomics, 5, 233–246. First citation in articleCrossref Medline, Google Scholar

  • Huppke, P. , Held, M. , Hanefeld, F. , Engel, W. , Laccone, F. (2002). Influence of mutation type and location on phenotype in 123 patients with Rett Syndrome. Neuropediatrics, 33, 63–68. First citation in articleCrossref Medline, Google Scholar

  • IMGSAC . (1998). A full genome screen for autism with evidence for linkage to a region on chromosome 7q. Human Molecular Genetics, 7, 571–578. First citation in articleCrossref Medline, Google Scholar

  • IMGSAC . (2001a). Further characterization of the autism susceptibility locus auts1 on chromosome 7q. Human Molecular Genetics, 10, 973–982. First citation in articleCrossref Medline, Google Scholar

  • IMGSAC . (2001b). A genomewide screen for autism: Strong evidence for linkage to chromosomes 2q, 7q, and 16p. American Journal of Human Genetics, 69, 570–581. First citation in articleCrossref Medline, Google Scholar

  • Jamain, S. , Quach, H. , Betancur, C. , Rastam, M. , Colineaux, C. , Gillberg, I. C. , ... Bourgeron, T. (2003). Mutations of the x-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nature Genetics, 34, 27–29. First citation in articleCrossref Medline, Google Scholar

  • Jin, P. , Zarnescu, D. C. , Ceman, S. , Nakamoto, M. , Mowrey, J. , Jongens, T. A. , ... Warren, S. T. (2004). Biochemical and genetic interaction between the Fragile X Mental Retardation protein and the microRNA pathway. Nature Neuroscience, 7, 113–117. First citation in articleCrossref Medline, Google Scholar

  • Kanner, L. (1943). Autistic disturbances of affective contact. The Nervous Child, 2, 270–250. First citation in articleGoogle Scholar

  • Karl, T. , Onder, K. , Kodzius, R. , Pichova, A. , Wimmer, H. , Thür, A. , ... Koller, L. (1999). Grc5 and nmd3 function in translational control of gene expression and interact genetically. Current Genetics, 34, 419–429. First citation in articleCrossref Medline, Google Scholar

  • Kelleher, R. J., 3rd , Bear, M. F. (2008). The autistic neuron: Troubled translation? Cell, 135, 401–406. First citation in articleCrossref Medline, Google Scholar

  • Kelleher, R. J., 3rd , Govindarajan, A. , Jung, H. Y. , Kang, H. , Tonegawa, S. (2004). Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell, 116, 467–479. First citation in articleCrossref Medline, Google Scholar

  • Kilpinen, H. , Ylisaukko-Oja, T. , Hennah, W. , Palo, O. M. , Varilo, T. , Vanhala, R. , ... Peltonen, L. (2008). Association of DISC1 with autism and Asperger syndrome. Molecular Psychiatry, 13, 187–196. First citation in articleCrossref Medline, Google Scholar

  • Kirov, G. , Gumus, D. , Chen, W. , Norton, N. , Georgieva, L. , Sari, M. , ... Ullmann, R. (2008). Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Human Molecular Genetics, 17, 458–465. First citation in articleCrossref Medline, Google Scholar

  • Klauck, S. M. (2006). Genetics of autism spectrum disorder. European Journal of Human Genetics, 14, 714–720. First citation in articleCrossref Medline, Google Scholar

  • Klauck, S. M. , Felder, B. , Kolb-Kokocinski, A. , Schuster, C. , Chiocchetti, A. , Schupp, I. , ... Poustka, A. (2006). Mutations in the ribosomal protein gene RPL10 suggest a novel modulating disease mechanism for autism. Molecular Psychiatry, 11, 1073–1084. First citation in articleCrossref Medline, Google Scholar

  • Kolb-Kokocinski, A. , Mehrle, A. , Bechtel, S. , Simpson, J. C. , Kioschis, P. , Wiemann, S. , ... Poustka, A. (2006). The systematic functional characterisation of Xq28 genes prioritises candidate disease genes. BMC Genomics, 7, 29. First citation in articleCrossref Medline, Google Scholar

  • Koller, H. T. , Klade, T. , Ellinger, A. , Breitenbach, M. (1996). The yeast growth control gene GRC5 is highly homologous to the mammalian putative tumor suppressor gene QM. Yeast, 12, 53–65. First citation in articleCrossref Medline, Google Scholar

  • Konishi, H. , Karakas, B. , Abukhdeir, A. M. , Lauring, J. , Gustin, J. P. , Garay, J. P. , ... Park, B. H. (2007). Knock-in of mutant k-ras in nontumorigenic human epithelial cells as a new model for studying k-ras mediated transformation. Cancer Research, 67, 8460–8467. First citation in articleCrossref Medline, Google Scholar

  • Kumar, R. A. , Marshall, C. R. , Badner, J. A. , Babatz, T. D. , Mukamel, Z. , Aldinger, K. A. , ... Christian, S. L. (2009). Association and mutation analyses of 16p11.2 autism candidate genes. PLoS One, 4, e4582. First citation in articleGoogle Scholar

  • Lauritsen, M. B. , Pedersen, C. B. , Mortensen, P. B. (2005). Effects of familial risk factors and place of birth on the risk of autism: A nationwide register-based study. The Journal of Child Psychology and Psychiatry, 46, 963–971. First citation in articleCrossref Medline, Google Scholar

  • Liu, X. Q. , Paterson, A. D. , Szatmari, P. , Autism Genome Project Consortium . (2008). Genome-wide linkage analyses of quantitative and categorical autism subphenotypes. Biological Psychiatry, 64, 561–570. First citation in articleCrossref Medline, Google Scholar

  • McCarthy, M. I. , Abecasis, G. R. , Cardon, L. R. , Goldstein, D. B. , Little, J. , Ioannidis, J. P. , Hirschhorn, J. N. (2008). Genome-wide association studies for complex traits: Consensus, uncertainty and challenges. Nature Reviews in Genetics, 9, 356–369. First citation in articleCrossref Medline, Google Scholar

  • Moessner, R. , Marshall, C. R. , Sutcliffe, J. S. , Skaug, J. , Pinto, D. , Vincent, J. , ... Scherer, S. W. (2007). Contribution of SHANK3 mutations to autism spectrum disorder. American Journal of Human Genetics, 81, 1289–1297. First citation in articleCrossref Medline, Google Scholar

  • Morrow, E. M. , Yoo, S. Y. , Flavell, S. W. , Kim, T. K. , Lin, Y. , Hill, R. S. , ... Walsh, C. A. (2008). Identifying autism loci and genes by tracing recent shared ancestry. Science, 321, 218–223. First citation in articleCrossref Medline, Google Scholar

  • Moy, S. S. , Nadler, J. J. , Magnuson, T. R. , Crawley, J. N. (2006). Mouse models of autism spectrum disorders: The challenge for behavioral genetics. American Journal of Medical Genetics, Part C(142C), 40–51. First citation in articleCrossref, Google Scholar

  • Oender, K. , Loeffler, M. , Doppler, E. , Eder, M. , Lach, S. , Heinrich, F. , ... Koller, L. (2003). Translational regulator RPL10p/GRC5p interacts physically and functionally with SED1p, a dynamic component of the yeast cell surface. Yeast, 20, 281–294. First citation in articleCrossref Medline, Google Scholar

  • Ovcharenko, I. , Loots, G. G. , Nobrega, M. A. , Hardison, R. C. , Miller, W. , Stubbs, L. (2005). Evolution and functional classification of vertebrate gene deserts. Genome Research, 15, 137–145. First citation in articleCrossref Medline, Google Scholar

  • Pachler, K. , Karl, T. , Kolmann, K. , Mehlmer, N. , Eder, M. , Loeffler, M. , ... Koller, L. (2004). Functional interaction in establishment of ribosomal integrity between small subunit protein RPS6 and translational regulator RPL10/GRC5p. FEMS Yeast Research, 5, 271–280. First citation in articleCrossref Medline, Google Scholar

  • Persico, A. M. , Bourgeron, T. (2006). Searching for ways out of the autism maze: Genetic, epigenetic and environmental clues. Trends in Neuroscience, 29, 349–358. First citation in articleCrossref Medline, Google Scholar

  • Pinto, D. , Pagnamenta, A. T. , Klei, L. , Anney, R. , Merico, D. , Regan, R. , ... Betancur, C. (2009). Functional impact of global rare copy number variation in autism spectrum disorders. Nature, 466, 368–872. First citation in articleCrossref, Google Scholar

  • Samaco, R. C. , Hogart, A. , Lasalle, J. M. (2005). Epigenetic overlap in autism-spectrum neurodevelopmental disorders: Mecp2 deficiency causes reduced expression of UBE3A and GABRB3. Human Molecular Genetics, 14, 483–492. First citation in articleCrossref Medline, Google Scholar

  • Schanen, C. , Houwink, E. J. , Dorrani, N. , Lane, J. , Everett, R. , Feng, A. , ... Percy, A. (2004). Phenotypic manifestations of MECP2 mutations in classical and atypical Rett syndrome. American Journal of Medical Genetics, Part A(126A), 129–140. First citation in articleCrossref, Google Scholar

  • Sebat, J. , Lakshmi, B. , Malhotra, D. , Troge, J. , Lese-Martin, C. , Walsh, T. , ... Wigler, M. (2007). Strong association of de novo copy number mutations with autism. Science, 316, 445–449. First citation in articleCrossref Medline, Google Scholar

  • Shibayama, A. , Cook, Jr., E. H. , Feng, J. , Glanzmann, C. , Yan, J. , Craddock, N. , ... Sommer, S. S. (2004). MECP2 structural and 3’-UTR variants in schizophrenia, autism and other psychiatric diseases: A possible association with autism. American Journal of Medical Genetics, Part B(128B), 50–53. First citation in articleCrossref, Google Scholar

  • Siepel, A. , Bejerano, G. , Pedersen, J. S. , Hinrichs, A. S. , Hou, M. , Rosenbloom, K. , ... Haussler, D. (2005). Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Research, 15, 1034–1050. First citation in articleCrossref Medline, Google Scholar

  • Szatmari, P. , Paterson, A. D. , Zwaigenbaum, L. , Roberts, W. , Brian, J. , Liu, X. Q. , ... Meyer, K. J. (2007). Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nature Genetics, 39, 319–328. First citation in articleCrossref Medline, Google Scholar

  • The Dutch-Belgian Fragile X Consortium . (1994). Fmr1 knockout mice: A model to study fragile × mental retardation. Cell, 78, 23–33. First citation in articleMedline, Google Scholar

  • Varoqueaux, F. , Aramuni, G. , Rawson, R. L. , Mohrmann, R. , Missler, M. , Gottmann, K. , ... Brose, N. (2006). Neuroligins determine synapse maturation and function. Neuron, 51, 741–754. First citation in articleCrossref Medline, Google Scholar

  • Vincent, J. B. , Melmer, G. , Bolton, P. F. , Hodgkinson, S. , Holmes, D. , Curtis, D. , Gurling, H. M. (2005). Genetic linkage analysis of the X chromosome in autism, with emphasis on the Fragile X region. Psychiatric Genetics, 15, 83–90. First citation in articleCrossref Medline, Google Scholar

  • Wang, K. , Zhang, H. , Ma, D. , Bucan, M. , Glessner, J. T. , Abrahams, B. S. , ... Hakonarson, H. (2009). Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature, 459, 528–533. First citation in articleCrossref Medline, Google Scholar

  • Weiss, L. A. , Arking, D. E. , The Gene Discovery Project of Johns Hopkins & the Autism Consortium, Daly, M. J. , Chakravarti, A. (2009). A genome-wide linkage and association scan reveals novel loci for autism. Nature, 461, 802–808. First citation in articleCrossref Medline, Google Scholar

  • Weiss, L. A. , Shen, Y. , Korn, J. M. , Arking, D. E. , Miller, D. T. , Fossdal, R. , ... Daly, M. J. (2008). Association between microdeletion and microduplication at 16p11.2 and autism. New England Journal of Medicine, 358, 667–675. First citation in articleCrossref Medline, Google Scholar

  • Wilson, H. L. , Wong, A. C. , Shaw, S. R. , Tse, W. Y. , Stapleton, G. A. , Phelan, M. C. , ... McDermid, H. E. (2003). Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms. Journal of Medical Genetics, 40, 575–584. First citation in articleCrossref Medline, Google Scholar