Impairment of translation in neurons as a putative causative factor for autism

Biology Direct

Eugenia Poliakov²  Eugene V Koonin¹  Igor B Rogozin¹ 

[1] National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA

[2] Laboratory of Retinal Cell & Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA

关键词: Neurotoxin;    Transcription factor binding;    mRNA secondary structure;    Splicing silencer;    Splicing enhancer;    Codon usage;    Single nucleotide polymorphism;    Synonymous mutations;   

Others  :  1070622
DOI  :  10.1186/1745-6150-9-16

 received in 2014-04-01, accepted in 2014-07-01,  发布年份 2014

【 摘 要 】

Background

A dramatic increase in the prevalence of autism and Autistic Spectrum Disorders (ASD) has been observed over the last two decades in USA, Europe and Asia. Given the accumulating data on the possible role of translation in the etiology of ASD, we analyzed potential effects of rare synonymous substitutions associated with ASD on mRNA stability, splicing enhancers and silencers, and codon usage.

Presentation of the hypothesis

We hypothesize that subtle impairment of translation, resulting in dosage imbalance of neuron-specific proteins, contributes to the etiology of ASD synergistically with environmental neurotoxins.

Testing the hypothesis

A statistically significant shift from optimal to suboptimal codons caused by rare synonymous substitutions associated with ASD was detected whereas no effect on other analyzed characteristics of transcripts was identified. This result suggests that the impact of rare codons on the translation of genes involved in neuron development, even if slight in magnitude, could contribute to the pathogenesis of ASD in the presence of an aggressive chemical background. This hypothesis could be tested by further analysis of ASD-associated mutations, direct biochemical characterization of their effects, and assessment of in vivo effects on animal models.

Implications of the hypothesis

It seems likely that the synergistic action of environmental hazards with genetic variations that in themselves have limited or no deleterious effects but are potentiated by the environmental factors is a general principle that underlies the alarming increase in the ASD prevalence.

Reviewers

This article was reviewed by Andrey Rzhetsky, Neil R. Smalheiser, and Shamil R. Sunyaev.

【 授权许可】

   
2014 Poliakov et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Wingate M, Kirby RS, Pettygrove S, Cunniff C, Schulz E, Ghosh T, Robinson C, Lee LC, Landa R, Constantino J, Fitzgerald R, Zahorodny W, Daniels J, Nicholas J, Charles J, McMahon W, Bilder D, Durkin M, Baio J, Christensen D, Braun KV, Clayton H, Goodman A, Doernberg N, Yeargin-Allsopp M, Lott E, Mancilla KC, Hudson A, Kast K, Jolly K, et al.: Prevalence of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2010. MMWR Surveill Summ 2014, 63(2):1-21.
• [2]Wingate M, Mulvihill B, Kirby RS, Pettygrove S, Cunniff C, Meaney F, Schulz E, Miller L, Robinson C, Quintana G, Kaiser MY, Lee LC, Landa R, Newschaffer C, Constantino J, Fitzgerald R, Zahorodny W, Daniels J, Giarelli E, Pinto-Martin J, Levy SE, Nicholas J, Charles J, Zimmerman J, Maenner MJ, Durkin M, Rice C, Baio J, Van Naarden Braun K, Phillips K, et al.: Prevalence of autism spectrum disorders - autism and developmental disabilities monitoring network, 14 sites, United States, 2008. MMWR Surveill Summ 2012, 61(3):1-19.
• [3]Grandjean P, Landrigan PJ: Neurobehavioural effects of developmental toxicity. Lancet Neurol 2014, 13(3):330-338.
• [4]Neale BM, Kou Y, Liu L, Ma’ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, et al.: Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 2012, 485(7397):242-245.
• [5]O’Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ, Girirajan S, Karakoc E, Mackenzie AP, Ng SB, Baker C, Rieder MJ, Nickerson DA, Bernier R, Fisher SE, Shendure J, Eichler EE: Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet 2012, 43(6):585-589.
• [6]Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Gunel M, Roeder K, Geschwind DH, Devlin B, State MW: De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 2012, 485(7397):237-241.
• [7]Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, Yamrom B, Lee YH, Narzisi G, Leotta A, Kendall J, Grabowska E, Ma B, Marks S, Rodgers L, Stepansky A, Troge J, Andrews P, Bekritsky M, Pradhan K, Ghiban E, Kramer M, Parla J, Demeter R, Fulton LL, Fulton RS, Magrini VJ, Ye K, Darnell JC, Darnell RB, et al.: De novo gene disruptions in children on the autistic spectrum. Neuron 2012, 74(2):285-299.
• [8]Drake JW, Charlesworth B, Charlesworth D, Crow JF: Rates of spontaneous mutation. Genetics 1998, 148(4):1667-1686.
• [9]Kondrashov AS: Direct estimates of human per nucleotide mutation rates at 20 loci causing mendelian diseases. Hum Mutat 2003, 21(1):12-27.
• [10]Stenson PD, Mort M, Ball EV, Shaw K, Phillips AD, Cooper DN: The human gene mutation database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet 2014, 133(1):1-9.
• [11]Ramos-Arroyo MA, Moreno S, Valiente A: Incidence and mutation rates of Huntington’s disease in Spain: experience of 9 years of direct genetic testing. J Neurol Neurosurg Psychiatry 2005, 76(3):337-342.
• [12]Pringsheim T, Wiltshire K, Day L, Dykeman J, Steeves T, Jette N: The incidence and prevalence of Huntington’s disease: a systematic review and meta-analysis. Mov Disord 2012, 27(9):1083-1091.
• [13]Kirkbride JB, Errazuriz A, Croudace TJ, Morgan C, Jackson D, Boydell J, Murray RM, Jones PB: Incidence of schizophrenia and other psychoses in England, 1950–2009: a systematic review and meta-analyses. PLoS One 2011, 7(3):e31660.
• [14]Stonebraker JS, Bolton-Maggs PH, Soucie JM, Walker I, Brooker M: A study of variations in the reported haemophilia a prevalence around the world. Haemophilia 2010, 16(1):20-32.
• [15]Scotet V, Dugueperoux I, Saliou P, Rault G, Roussey M, Audrezet MP, Ferec C: Evidence for decline in the incidence of cystic fibrosis: a 35-year observational study in Brittany, France. Orphanet J Rare Dis 2012, 7:14.
• [16]Yau V, Lynch F, Madden J, Owen-Smith A, Coleman K, Bent S, Massolo M, Pearson K, Crawford P, Freiman H, Pomichowski M: PS1-13: variation in the incidence and prevalence of autism from multiple health systems: findings from the mental health research network autism registry study. Clin Med Res 2013, 11(3):166.
• [17]Bishop DV, Whitehouse AJ, Watt HJ, Line EA: Autism and diagnostic substitution: evidence from a study of adults with a history of developmental language disorder. Dev Med Child Neurol 2008, 50(5):341-345.
• [18]Hertz-Picciotto I, Delwiche L: The rise in autism and the role of age at diagnosis. Epidemiology 2009, 20(1):84-90.
• [19]King M, Bearman P: Diagnostic change and the increased prevalence of autism. Int J Epidemiol 2009, 38(5):1224-1234.
• [20]Grether JK, Rosen NJ, Smith KS, Croen LA: Investigation of shifts in autism reporting in the California department of developmental services. J Autism Dev Disord 2009, 39(10):1412-1419.
• [21]Deth R, Muratore C, Benzecry J, Power-Charnitsky VA, Waly M: How environmental and genetic factors combine to cause autism: a redox/methylation hypothesis. Neurotoxicology 2008, 29(1):190-201.
• [22]Herbert MR: Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders. Curr Opin Neurol 2010, 23(2):103-110.
• [23]Garrecht M, Austin DW: The plausibility of a role for mercury in the etiology of autism: a cellular perspective. Toxicol Environ Chem 2011, 93(5–6):1251-1273.
• [24]Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, Miller J, Fedele A, Collins J, Smith K, Lotspeich L, Croen LA, Ozonoff S, Lajonchere C, Grether JK, Risch N: Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry 2011, 68(11):1095-1102.
• [25]Ritvo ER, Spence MA, Freeman BJ, Mason-Brothers A, Mo A, Marazita ML: Evidence for autosomal recessive inheritance in 46 families with multiple incidences of autism. Am J Psychiatry 1985, 142(2):187-192.
• [26]Smalley SL, Asarnow RF, Spence MA: Autism and genetics. A decade of research. Arch Gen Psychiatry 1988, 45(10):953-961.
• [27]Steffenburg S, Gillberg C, Hellgren L, Andersson L, Gillberg IC, Jakobsson G, Bohman M: A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry 1989, 30(3):405-416.
• [28]Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, Rutter M: Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 1995, 25(1):63-77.
• [29]Greenberg DA, Hodge SE, Sowinski J, Nicoll D: Excess of twins among affected sibling pairs with autism: implications for the etiology of autism. Am J Hum Genet 2001, 69(5):1062-1067.
• [30]Roberts EM, English PB, Grether JK, Windham GC, Somberg L, Wolff C: Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California Central Valley. Environ Health Perspect 2007, 115(10):1482-1489.
• [31]Windham GC, Zhang L, Gunier R, Croen LA, Grether JK: Autism spectrum disorders in relation to distribution of hazardous air pollutants in the san francisco bay area. Environ Health Perspect 2006, 114(9):1438-1444.
• [32]Kalkbrenner AE, Daniels JL, Chen JC, Poole C, Emch M, Morrissey J: Perinatal exposure to hazardous air pollutants and autism spectrum disorders at age 8. Epidemiology 2010, 21(5):631-641.
• [33]Volk HE, Hertz-Picciotto I, Delwiche L, Lurmann F, McConnell R: Residential proximity to freeways and autism in the CHARGE study. Environ Health Perspect 2011, 119(6):873-877.
• [34]Croen LA, Grether JK, Yoshida CK, Odouli R, Hendrick V: Antidepressant use during pregnancy and childhood autism spectrum disorders. Arch Gen Psychiatry 2011, 68(11):1104-1112.
• [35]Landrigan PJ: What causes autism? Exploring the environmental contribution. Curr Opin Pediatr 2010, 22(2):219-225.
• [36]Rzhetsky A, Bagley SC, Wang K, Lyttle CS, Cook EH Jr, Altman RB, Gibbons RD: Environmental and state-level regulatory factors affect the incidence of autism and intellectual disability. PLoS Comput Biol 2014, 10(3):e1003518.
• [37]DeSoto MC: Ockham’s razor and autism: the case for developmental neurotoxins contributing to a disease of neurodevelopment. Neurotoxicology 2009, 30(3):331-337.
• [38]Kelleher RJ 3rd, Bear MF: The autistic neuron: troubled translation? Cell 2008, 135(3):401-406.
• [39]Darnell JC, Van Driesche SJ, Zhang C, Hung KY, Mele A, Fraser CE, Stone EF, Chen C, Fak JJ, Chi SW, Licatalosi DD, Richter JD, Darnell RB: FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 2011, 146(2):247-261.
• [40]Sauna ZE, Kimchi-Sarfaty C: Understanding the contribution of synonymous mutations to human disease. Nat Rev Genet 2011, 12(10):683-691.
• [41]Basu SN, Kollu R, Banerjee-Basu S: AutDB: a gene reference resource for autism research. Nucleic Acids Res 2009, 37(Database issue):D832-D836.
• [42]Kelleher RJ 3rd, Geigenmuller U, Hovhannisyan H, Trautman E, Pinard R, Rathmell B, Carpenter R, Margulies D: High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism. PLoS One 2012, 7(4):e35003.
• [43]Terekhanova NV, Bazykin GA, Neverov A, Kondrashov AS, Seplyarskiy VB: Prevalence of multinucleotide replacements in evolution of primates and drosophila. Mol Biol Evol 2013, 30(6):1315-1325.
• [44]Kimura M: The Neutral Theory of Molecular Evolution. Cambridge: Cambridge University Press; 1983.
• [45]Petrovski S, Wang Q, Heinzen EL, Allen AS, Goldstein DB: Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet 2013, 9(8):e1003709.
• [46]Khromov-Borisov NN, Rogozin IB, Pegas Henriques JA, de Serres FJ: Similarity pattern analysis in mutational distributions. Mutat Res 1999, 430(1):55-74.
• [47]Semon M, Lobry JR, Duret L: No evidence for tissue-specific adaptation of synonymous codon usage in humans. Mol Biol Evol 2006, 23(3):523-529.
• [48]Plotkin JB, Robins H, Levine AJ: Tissue-specific codon usage and the expression of human genes. Proc Natl Acad Sci U S A 2004, 101(34):12588-12591.
• [49]Warrington JA, Nair A, Mahadevappa M, Tsyganskaya M: Comparison of human adult and fetal expression and identification of 535 housekeeping/maintenance genes. Physiol Genomics 2000, 2(3):143-147.
• [50]Sharp PM, Li WH: The codon adaptation index–a measure of directional synonymous codon usage bias, and its potential applications. Nucleic Acids Res 1987, 15(3):1281-1295.
• [51]Chamary JV, Parmley JL, Hurst LD: Hearing silence: non-neutral evolution at synonymous sites in mammals. Nat Rev Genet 2006, 7(2):98-108.
• [52]Waldman YY, Tuller T, Shlomi T, Sharan R, Ruppin E: Translation efficiency in humans: tissue specificity, global optimization and differences between developmental stages. Nucleic Acids Res 2010, 38(9):2964-2974.
• [53]Waldman YY, Tuller T, Keinan A, Ruppin E: Selection for translation efficiency on synonymous polymorphisms in recent human evolution. Genome Biol Evol 2011, 3:749-761.
• [54]Plotkin JB, Kudla G: Synonymous but not the same: the causes and consequences of codon bias. Nat Rev Genet 2011, 12(1):32-42.
• [55]Zuker M: Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res 2003, 31(13):3406-3415.
• [56]Ogurtsov AY, Shabalina SA, Kondrashov AS, Roytberg MA: Analysis of internal loops within the RNA secondary structure in almost quadratic time. Bioinformatics 2006, 22(11):1317-1324.
• [57]Fairbrother WG, Yeh RF, Sharp PA, Burge CB: Predictive identification of exonic splicing enhancers in human genes. Science 2002, 297(5583):1007-1013.
• [58]Ke S, Zhang XH, Chasin LA: Positive selection acting on splicing motifs reflects compensatory evolution. Genome Res 2008, 18(4):533-543.
• [59]Blencowe BJ: Exonic splicing enhancers: mechanism of action, diversity and role in human genetic diseases. Trends Biochem Sci 2000, 25(3):106-110.
• [60]Hurst LD, Pal C: Evidence for purifying selection acting on silent sites in BRCA1. Trends Genet 2001, 17(2):62-65.
• [61]Willie E, Majewski J: Evidence for codon bias selection at the pre-mRNA level in eukaryotes. Trends Genet 2004, 20(11):534-538.
• [62]Fairbrother WG, Holste D, Burge CB, Sharp PA: Single nucleotide polymorphism-based validation of exonic splicing enhancers. PLoS Biol 2004, 2(9):E268.
• [63]Dewey CN, Rogozin IB, Koonin EV: Compensatory relationship between splice sites and exonic splicing signals depending on the length of vertebrate introns. BMC Genomics 2006, 7:311.
• [64]Parmley JL, Chamary JV, Hurst LD: Evidence for purifying selection against synonymous mutations in mammalian exonic splicing enhancers. Mol Biol Evol 2006, 23(2):301-309.
• [65]Schaal TD, Maniatis T: Selection and characterization of pre-mRNA splicing enhancers: identification of novel SR protein-specific enhancer sequences. Mol Cell Biol 1999, 19(3):1705-1719.
• [66]Shabalina SA, Ogurtsov AY, Spiridonov NA: A periodic pattern of mRNA secondary structure created by the genetic code. Nucleic Acids Res 2006, 34(8):2428-2437.
• [67]Resch AM, Carmel L, Marino-Ramirez L, Ogurtsov AY, Shabalina SA, Rogozin IB, Koonin EV: Widespread positive selection in synonymous sites of mammalian genes. Mol Biol Evol 2007, 24(8):1821-1831.
• [68]Stergachis AB, Haugen E, Shafer A, Fu W, Vernot B, Reynolds A, Raubitschek A, Ziegler S, LeProust EM, Akey JM, Stamatoyannopoulos JA: Exonic transcription factor binding directs codon choice and affects protein evolution. Science 2013, 342(6164):1367-1372.
• [69]Duret L: Evolution of synonymous codon usage in metazoans. Curr Opin Genet Dev 2002, 12(6):640-649.
• [70]Urrutia AO, Hurst LD: Codon usage bias covaries with expression breadth and the rate of synonymous evolution in humans, but this is not evidence for selection. Genetics 2001, 159(3):1191-1199.
• [71]Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV, Gottesman MM: A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science 2007, 315(5811):525-528.
• [72]Tsai CJ, Sauna ZE, Kimchi-Sarfaty C, Ambudkar SV, Gottesman MM, Nussinov R: Synonymous mutations and ribosome stalling can lead to altered folding pathways and distinct minima. J Mol Biol 2008, 383(2):281-291.
• [73]Brown V, Jin P, Ceman S, Darnell JC, O’Donnell WT, Tenenbaum SA, Jin X, Feng Y, Wilkinson KD, Keene JD, Darnell RB, Warren ST: Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome. Cell 2001, 107(4):477-487.
• [74]Graber TE, Hebert-Seropian S, Khoutorsky A, David A, Yewdell JW, Lacaille JC, Sossin WS: Reactivation of stalled polyribosomes in synaptic plasticity. Proc Natl Acad Sci U S A 2013, 110(40):16205-16210.
• [75]Stoner R, Chow ML, Boyle MP, Sunkin SM, Mouton PR, Roy S, Wynshaw-Boris A, Colamarino SA, Lein ES, Courchesne E: Patches of disorganization in the neocortex of children with autism. N Engl J Med 2014, 370(13):1209-1219.
• [76]Buchan JR, Stansfield I: Halting a cellular production line: responses to ribosomal pausing during translation. Biol Cell 2007, 99(9):475-487.
• [77]Harigaya Y, Parker R: No-go decay: a quality control mechanism for RNA in translation. Wiley Interdiscip Rev RNA 2010, 1(1):132-141.
• [78]Rachidi M, Lopes C: Mental retardation in down syndrome: from gene dosage imbalance to molecular and cellular mechanisms. Neurosci Res 2007, 59(4):349-369.
• [79]Veitia RA, Birchler JA: Dominance and gene dosage balance in health and disease: why levels matter! J Pathol 2010, 220(2):174-185.
• [80]Arguello PA, Gogos JA: Genetic and cognitive windows into circuit mechanisms of psychiatric disease. Trends Neurosci 2012, 35(1):3-13.
• [81]Frydman J: Folding of newly translated proteins in vivo: the role of molecular chaperones. Annu Rev Biochem 2001, 70:603-647.
• [82]Hartl FU, Hayer-Hartl M: Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 2002, 295(5561):1852-1858.
• [83]Willmund F, del Alamo M, Pechmann S, Chen T, Albanese V, Dammer EB, Peng J, Frydman J: The cotranslational function of ribosome-associated Hsp70 in eukaryotic protein homeostasis. Cell 2013, 152(1–2):196-209.
• [84]Hasday JD, Singh IS: Fever and the heat shock response: distinct, partially overlapping processes. Cell Stress Chaperones 2000, 5(5):471-480.
• [85]Atladottir HO, Henriksen TB, Schendel DE, Parner ET: Autism after infection, febrile episodes, and antibiotic use during pregnancy: an exploratory study. Pediatrics 2012, 130(6):e1447-e1454.
• [86]Zerbo O, Iosif AM, Walker C, Ozonoff S, Hansen RL, Hertz-Picciotto I: Is maternal influenza or fever during pregnancy associated with autism or developmental delays? Results from the CHARGE (CHildhood autism risks from genetics and environment) study. J Autism Dev Disord 2013, 43(1):25-33.
• [87]Rajdev S, Sharp FR: Stress proteins as molecular markers of neurotoxicity. Toxicol Pathol 2000, 28(1):105-112.
• [88]El-Ansary AK, Ben Bacha A, Kotb M: Etiology of autistic features: the persisting neurotoxic effects of propionic acid. J Neuroinflammation 2012, 9(1):74.
• [89]Thomas RH, Foley KA, Mepham JR, Tichenoff LJ, Possmayer F, MacFabe DF: Altered brain phospholipid and acylcarnitine profiles in propionic acid infused rodents: further development of a potential model of autism spectrum disorders. J Neurochem 2010, 113(2):515-529.
• [90]Barrett MJ, Alones V, Wang KX, Phan L, Swerdlow RH: Mitochondria-derived oxidative stress induces a heat shock protein response. J Neurosci Res 2004, 78(3):420-429.
• [91]Roullet FI, Lai JK, Foster JA: In utero exposure to valproic acid and autism–a current review of clinical and animal studies. Neurotoxicol Teratol 2013, 36:47-56.
• [92]Christensen J, Gronborg TK, Sorensen MJ, Schendel D, Parner ET, Pedersen LH, Vestergaard M: Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. Jama 2013, 309(16):1696-1703.
• [93]Marinova Z, Ren M, Wendland JR, Leng Y, Liang MH, Yasuda S, Leeds P, Chuang DM: Valproic acid induces functional heat-shock protein 70 via class I histone deacetylase inhibition in cortical neurons: a potential role of Sp1 acetylation. J Neurochem 2009, 111(4):976-987.
• [94]Rossignol DA, Genuis SJ, Frye RE: Environmental toxicants and autism spectrum disorders: a systematic review. Transl Psychiatry 2014, 4:e360.
• [95]Freitag CM: The genetics of autistic disorders and its clinical relevance: a review of the literature. Mol Psychiatry 2007, 12(1):2-22.
• [96]Buizer-Voskamp JE, Franke L, Staal WG, van Daalen E, Kemner C, Ophoff RA, Vorstman JA, van Engeland H, Wijmenga C: Systematic genotype-phenotype analysis of autism susceptibility loci implicates additional symptoms to co-occur with autism. Eur J Hum Genet 2010, 18(5):588-595.
• [97]El-Fishawy P, State MW: The genetics of autism: key issues, recent findings, and clinical implications. Psychiatr Clin North Am 2010, 33(1):83-105.
• [98]Hussman JP, Chung RH, Griswold AJ, Jaworski JM, Salyakina D, Ma D, Konidari I, Whitehead PL, Vance JM, Martin ER, Cuccaro ML, Gilbert JR, Haines JL, Pericak-Vance MA: A noise-reduction GWAS analysis implicates altered regulation of neurite outgrowth and guidance in autism. Mol Autism 2011, 2(1):1.
• [99]Rogozin IB, Pavlov YI: Theoretical analysis of mutation hotspots and their DNA sequence context specificity. Mutat Res 2003, 544(1):65-85.
• [100]McFarland CD, Korolev KS, Kryukov GV, Sunyaev SR, Mirny LA: Impact of deleterious passenger mutations on cancer progression. Proc Natl Acad Sci U S A 2013, 110(8):2910-2915.
• [101]Stamatoyannopoulos JA, Adzhubei I, Thurman RE, Kryukov GV, Mirkin SM, Sunyaev SR: Human mutation rate associated with DNA replication timing. Nat Genet 2009, 41(4):393-395.
• [102]Xu B, Roos JL, Dexheimer P, Boone B, Plummer B, Levy S, Gogos JA, Karayiorgou M: Exome sequencing supports a de novo mutational paradigm for schizophrenia. Nat Genet 2011, 43(9):864-868.
• [103]Xu B, Ionita-Laza I, Roos JL, Boone B, Woodrick S, Sun Y, Levy S, Gogos JA, Karayiorgou M: De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nat Genet 2012, 44(12):1365-1369.
• [104]Ayoub MA, Angelicheva D, Vile D, Chandler D, Morar B, Cavanaugh JA, Visscher PM, Jablensky A, Pfleger KD, Kalaydjieva L: Deleterious GRM1 mutations in schizophrenia. PLoS One 2012, 7(3):e32849.
• [105]Courchesne E, Mouton PR, Calhoun ME, Semendeferi K, Ahrens-Barbeau C, Hallet MJ, Barnes CC, Pierce K: Neuron number and size in prefrontal cortex of children with autism. Jama 2011, 306(18):2001-2010.
• [106]Chow ML, Pramparo T, Winn ME, Barnes CC, Li HR, Weiss L, Fan JB, Murray S, April C, Belinson H, Fu XD, Wynshaw-Boris A, Schork NJ, Courchesne E: Age-dependent brain gene expression and copy number anomalies in autism suggest distinct pathological processes at young versus mature ages. PLoS Genet 2012, 8(3):e1002592.
• [107]Ecker C, Suckling J, Deoni SC, Lombardo MV, Bullmore ET, Baron-Cohen S, Catani M, Jezzard P, Barnes A, Bailey AJ, Williams SC, Murphy DG: Brain anatomy and its relationship to behavior in adults with autism spectrum disorder: a multicenter magnetic resonance imaging study. Arch Gen Psychiatry 2012, 69(2):195-209.
• [108]Morgan JT, Chana G, Abramson I, Semendeferi K, Courchesne E, Everall IP: Abnormal microglial-neuronal spatial organization in the dorsolateral prefrontal cortex in autism. Brain Res 2012, 1456:72-81.
• [109]Duffy FH, Als H: A stable pattern of EEG spectral coherence distinguishes children with autism from neuro-typical controls - a large case control study. BMC Med 2012, 10:64.
• [110]Silverman JL, Tolu SS, Barkan CL, Crawley JN: Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP. Neuropsychopharmacology 2010, 35(4):976-989.
• [111]Silverman JL, Smith DG, Rizzo SJ, Karras MN, Turner SM, Tolu SS, Bryce DK, Smith DL, Fonseca K, Ring RH, Crawley JN: Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism. Sci Transl Med 2012, 4(131):131ra151.
• [112]Michalon A, Sidorov M, Ballard TM, Ozmen L, Spooren W, Wettstein JG, Jaeschke G, Bear MF, Lindemann L: Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron 2012, 74(1):49-56.
• [113]Harrison C: Neurodevelopmental disorders: glutamate blockers show benefit in models of autism spectrum disorders. Nat Rev Drug Discov 2012, 11(6):440-441.
• [114]Calvo PL, Brunati A, Spada M, Romagnoli R, Corso G, Parenti G, Rossi M, Baldi M, Carbonaro G, David E, Pucci A, Amoroso A, Salizzoni M: Liver transplantation in defects of cholesterol biosynthesis: the case of lathosterolosis. Am J Transplant 2014, 14(4):960-965.
• [115]Stannard JN, Horecker BL: The in vitro inhibition of cytochrome oxidase by azide and cyanide. J Biol Chem 1948, 172(2):599-608.
• [116]Leary SC, Hill BC, Lyons CN, Carlson CG, Michaud D, Kraft CS, Ko K, Glerum DM, Moyes CD: Chronic treatment with azide in situ leads to an irreversible loss of cytochrome c oxidase activity via holoenzyme dissociation. J Biol Chem 2002, 277(13):11321-11328.
• [117]Martin W, White DG, Henderson AH: Endothelium-derived relaxing factor and atriopeptin II elevate cyclic GMP levels in pig aortic endothelial cells. Br J Pharmacol 1988, 93(1):229-239.
• [118]Ceman S, O’Donnell WT, Reed M, Patton S, Pohl J, Warren ST: Phosphorylation influences the translation state of FMRP-associated polyribosomes. Hum Mol Genet 2003, 12(24):3295-3305.
• [119]Betterton EA: Environmental fate of sodium azide derived from automobile airbags. Crit Rev Environ Sci Technol 2003, 33:423-458.
• [120]Peca J, Feliciano C, Ting JT, Wang W, Wells MF, Venkatraman TN, Lascola CD, Fu Z, Feng G: Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 2011, 472(7344):437-442.
• [121]Spooren W, Lindemann L, Ghosh A, Santarelli L: Synapse dysfunction in autism: a molecular medicine approach to drug discovery in neurodevelopmental disorders. Trends Pharmacol Sci 2012, 33(12):669-684.
• [122]Ghosh A, Michalon A, Lindemann L, Fontoura P, Santarelli L: Drug discovery for autism spectrum disorder: challenges and opportunities. Nat Rev Drug Discov 2013, 12(10):777-790.
• [123]Leblond CS, Heinrich J, Delorme R, Proepper C, Betancur C, Huguet G, Konyukh M, Chaste P, Ey E, Rastam M, Anckarsater H, Nygren G, Gillberg IC, Melke J, Toro R, Regnault B, Fauchereau F, Mercati O, Lemiere N, Skuse D, Poot M, Holt R, Monaco AP, Jarvela I, Kantojarvi K, Vanhala R, Curran S, Collier DA, Bolton P, Chiocchetti A: Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. PLoS Genet 2012, 8(2):e1002521.
• [124]Lada AG, Stepchenkova EI, Waisertreiger IS, Noskov VN, Dhar A, Eudy JD, Boissy RJ, Hirano M, Rogozin IB, Pavlov YI: Genome-wide mutation avalanches induced in diploid yeast cells by a base analog or an APOBEC deaminase. PLoS Genet 2013, 9(9):e1003736.