Non-specific
associations of a range of genetic conditions
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The polymerase chain reaction, in which selected DNA
fragment numbers are doubled in cycles.
Using this technique it is possible to look for exact DNA genetics.
However, it is also possible to look for non-specifics that then can be shown
to be similar or different to those from another source. Complex, but it allows genes in different
autistic to be looked for that are different from those in normal
individuals. |
Many attempts at findings the genetics of autism lead up many different paths It is quite clear that there is some genetic involvement in autism and that the environmental and developmental factors in some way interact with this. It is also clear that probably this genetic factor is probably present in a large proportion of the population and that it is only when the other factors are also present is it that we see the autism showing through.
Samples of DNA from a clinically autistic child can easily be obtained, and that using the polymerase chain reaction, we can work out exactly the bases that make up even a small gene, and that wide ranges of DNA from throughout the whole DNA of a cell from an autistic child…all mean that we can get a good idea as to any differences (or similarities) there are between autistic and control children. Attempts have been made to assess the entire DNA of autistic children. Some changes have been found to be found to be of significance and to be common in the children see: genetic change.
The amazing problem is that when experiments are tried many times in different laboratories, they find an association of the condition with different genetic oddities. However, we must
not ignore these findings in that commonly we don’t yet know their
significance. Although most of the findings are
apparently separate, some are in groups:
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Currently genetic changes reported in autism of unknown significance
You must realise that there are far more claims than just the ones below. These are generally the latter ones but many more have been suggested.
Warren RP, Singh VK, Cole P, Odell JD, Pingree CB, Warren WL, DeWitt CW, McCullough M. Possible association of the extended MHC haplotype B44-SC30-DR4 with autism. Immunogenetics. 1992;36(4):203-7.
Warren RP, Yonk J, Burger RW, Odell D, Warren WL. DR-positive T cells in autism: association with decreased plasma levels of the complement C4B protein Neuropsychobiology. 1995;31(2):53-7.
Nishimura Y, Martin CL, Vazquez-Lopez A, Spence SJ, Alvarez-Retuerto AI, Sigman M, Steindler C, Pellegrini S, Schanen NC, Warren ST, Geschwind DH. Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways. Hum Mol Genet. 2007 Jul 15;16(14):1682-98. Epub 2007 May 21
Nishimura K, Nakamura K, Anitha A, et al. Genetic analyses of the brain-derived neurotrophic factor (BDNF) gene in autism. Biochem Biophys Res Commun. 2007 Apr 27;356(1):200-6. (A protein that is associated with the serotonergic system. They found that alterations in haplotypes were associated with autism)
Nakamine A, Ouchanov L, Jiménez P, Manghi ER, Esquivel M, Monge S, Fallas M, Burton BK, Szomju B, Elsea SH, Marshall CR, Scherer SW, McInnes LA. Duplication of 17(p11.2p11.2) in a male child with autism and severe language delay. Am J Med Genet A. 2007
Hu VW, Frank BC, Heine S, Lee NH, Quackenbush J. Gene expression profiling of lymphoblastoid cell lines from monozygotic twins discordant in severity of autism reveals differential regulation of neurologically relevant genes. BMC Genomics. 2006 May 18;7:118. (suggesting how the environmental factor is involved)
Junaid MA, Kowal D, Barua M, Pullarkat PS, Sklower Brooks S, Pullarkat RK. Proteomic studies identified a single nucleotide polymorphism in glyoxalase I as autism susceptibility factor. Am J Med Genet A. 2004 Nov 15;131(1):11-7
James SJ, Melnyk S, Jernigan S, Cleves MA, Halsted CH, Wong DH, Cutler P, Bock K, Boris M, Bradstreet JJ, Baker SM, Gaylor DW. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B Neuropsychiatr Genet. 2006 Dec 5;141(8):947-56. (the interesting thing about this one is that they are suggesting that the oxidative stress problem comes first and, as a result the autism is seen…as opposed to the damage coming first and the oxidative stress appearing later)
Sahoo
T, Shaw CA, Young AS, Whitehouse NL, Schroer RJ, Stevenson RE, Beaudet AL.
Array-based comparative genomic mutation in analysis of recurrent chromosome
15q rearrangements. Am J Med Genet A. 2005 Dec 1;139(2):106-13. (15q is associated with
GABA receptors. New (non-published) data is coming out from the
Molloy CA, Keddache M, Martin LJ. Evidence for linkage on 21q and 7q in a subset of autism characterized by developmental regression. Mol Psychiatry. 2005 Aug;10(8):741-6.
Nishimura K, Nakamura K, Anitha A, Yamada K, Tsujii M, Iwayama Y, Hattori E, Toyota T, Takei N, Miyachi T, Iwata Y, Suzuki K, Matsuzaki H, Kawai M, Sekine Y, Tsuchiya K, Sugihara G, Suda S, Ouchi Y, Sugiyama T, Yoshikawa T, Mori N. Genetic analyses of the brain-derived neurotrophic factor (BDNF) gene in autism. Biochem Biophys Res Commun. 2007 Apr 27;356(1):200-6. Epub 2007
Toyoda T, Nakamura K, Yamada K, Thanseem I, Anitha A, Suda S, Tsujii M, Iwayama Y, Hattori E, Toyota T, Miyachi T, Iwata Y, Suzuki K, Matsuzaki H, Kawai M, Sekine Y, Tsuchiya K, Sugihara G, Ouchi Y, Sugiyama T, Takei N, Yoshikawa T, Mori N. SNP analyses of growth factor genes EGF, TGFbeta-1, and HGF reveal haplotypic association of EGF with autism. Biochem Biophys Res Commun. 2007 Sep 7;360(4):715-20. Epub 2007 Jun 18. (Epidermal growth factor (EGF) is detected in several regions of the developing and adult brain, where, it enhances the differentiation, maturation, and survival of a variety of neurons. Transforming growth factor-beta (TGFbeta) isoforms play an important role in neuronal survival, and the hepatocyte growth factor (HGF) has been shown to exhibit neurotrophic activity. They could find no oddities for TGF or HGF genetically but they suggest EGF changes may be involved)
Anitha A, Nakamura K, Yamada K, Suda S, Thanseem I, Tsujii M, Iwayama Y, Hattori E, Toyota T, Miyachi T, Iwata Y, Suzuki K, Matsuzaki H, Kawai M, Sekine Y, Tsuchiya K, Sugihara GI, Ouchi Y, Sugiyama T, Koizumi K, Higashida H, Takei N, Yoshikawa T, Mori N. Genetic analyses of Roundabout (ROBO) axon guidance receptors in autism. Am J Med Genet B Neuropsychiatr Genet. 2008 Feb 12. (Abnormalities of ROBO may lead to autism either by interfering with serotonergic system, or by disrupting neurodevelopment. To the best of our knowledge, this is the first report relating ROBO with autism. This is more of a suggestion than a finding of an answer)
Marui T, Koishi S, Funatogawa I, Yamamoto K, Matsumoto H, Hashimoto O, Ishijima M, Nanba E, Nishida H, Sugiyama T, Kasai K, Watanabe K, Kano Y, Kato N, Sasaki T. No association between the neuronal pentraxin II gene polymorphism and autism. Prog Neuropsychopharmacol Biol Psychiatry. 2007 May 9;31(4):940-3.
Ramoz N, Cai G, Reichert JG, Silverman JM, Buxbaum JD. An analysis of candidate autism loci on chromosome 2q24-q33: Evidence for association to the STK39 gene. Am J Med Genet B Neuropsychiatr Genet. 2008 Mar 17. (a quite wide statistical association )
Autism Genome Project Consortium, Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, Liu XQ, Vincent JB, Skaug JL, Thompson AP, Senman L, Feuk L, Qian C, Bryson SE, Jones MB, Marshall CR, Scherer SW, Vieland VJ, Bartlett C, Mangin LV, Goedken R, Segre A, Pericak-Vance MA, Cuccaro ML, Gilbert JR, Wright HH, Abramson RK, Betancur C, Bourgeron T, Gillberg C, Leboyer M, Buxbaum JD, Davis KL, Hollander E, Silverman JM, Hallmayer J, Lotspeich L, Sutcliffe JS, Haines JL, Folstein SE, Piven J, Wassink TH, Sheffield V, Geschwind DH, Bucan M, Brown WT, Cantor RM, Constantino JN, Gilliam TC, Herbert M, Lajonchere C, Ledbetter DH, Lese-Martin C, Miller J, Nelson S, Samango-Sprouse CA, Spence S, State M, Tanzi RE, Coon H, Dawson G, Devlin B, Estes A, Flodman P, Klei L, McMahon WM, Minshew N, Munson J, Korvatska E, Rodier PM, Schellenberg GD, Smith M, Spence MA, Stodgell C, Tepper PG, Wijsman EM, Yu CE, Rogé B, Mantoulan C, Wittemeyer K, Poustka A, Felder B, Klauck SM, Schuster C, Poustka F, Bölte S, Feineis-Matthews S, Herbrecht E, Schmötzer G, Tsiantis J, Papanikolaou K, Maestrini E, Bacchelli E, Blasi F, Carone S, Toma C, Van Engeland H, de Jonge M, Kemner C, Koop F, Langemeijer M, Hijmans C, Staal WG, Baird G, Bolton PF, Rutter ML, Weisblatt E, Green J, Aldred C, Wilkinson JA, Pickles A, Le Couteur A, Berney T, McConachie H, Bailey AJ, Francis K, Honeyman G, Hutchinson A, Parr JR, Wallace S, Monaco AP, Barnby G, Kobayashi K, Lamb JA, Sousa I, Sykes N, Cook EH, Guter SJ, Leventhal BL, Salt J, Lord C, Corsello C, Hus V, Weeks DE, Volkmar F, Tauber M, Fombonne E, Shih A, Meyer KJ. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet. 2007 Mar;39(3):319-28. Epub 2007 Feb 18. (they attempt to show an increase in certain gene loci (or decrease) being associated with autism. A very difficult process as few other elements of data are used to assess the patients)
Buxbaum JD, Cai G, Nygren G, Chaste P, Delorme R, Goldsmith J, Råstam M, Silverman JM, Hollander E, Gillberg C, Leboyer M, Betancur C. Mutation analysis of the NSD1 gene in patients with autism spectrum disorders and macrocephaly. BMC Med Genet. 2007 Nov 14;8:68.
Buxbaum JD, Cai G, Chaste P, Nygren G, Goldsmith J, Reichert J, Anckarsäter H, Rastam M, Smith CJ, Silverman JM, Hollander E, Leboyer M, Gillberg C, Verloes A, Betancur C. Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly.
Am J Med Genet B Neuropsychiatr Genet. 2007 Jun 5;144B(4):484-91
Sakurai T, Ramoz N, Reichert JG, Corwin TE, Kryzak L, Smith CJ, Silverman JM, Hollander E, Buxbaum JD. Association analysis of the NrCAM gene in autism and in subsets of families with severe obsessive-compulsive or self-stimulatory behaviors.
Psychiatr Genet. 2006 Dec;16(6):251-7.
Ramoz N, Cai G, Reichert JG, Corwin TE, Kryzak LA, Smith CJ, Silverman JM, Hollander E, Buxbaum JD. Family-based association study of TPH1 and TPH2 polymorphisms in autism. Am J Med Genet B Neuropsychiatr Genet. 2006 Dec 5;141B(8):861-7.
Ramoz N, Reichert JG, Corwin TE, Smith CJ, Silverman JM, Hollander E, Buxbaum JD. Lack of evidence for association of the serotonin transporter gene SLC6A4 with autism. Biol Psychiatry. 2006 Jul 15;60(2):186-91. Epub 2006 Apr 17. see other site on serotonin site
Richler E, Reichert JG, Buxbaum JD, McInnes LA. Autism and ultraconserved non-coding sequence on chromosome 7q. Psychiatr Genet. 2006 Feb;16(1):19-23. (results show that these sequences are unlikely to harbour major autism susceptibility alleles)
Faham M, Zheng J, Moorhead M, Fakhrai-Rad H, Namsaraev E, Wong K, Wang Z, Chow SG, Lee L, Suyenaga K, Reichert J, Boudreau A, Eberle J, Bruckner C, Jain M, Karlin-Neumann G, Jones HB, Willis TD, Buxbaum JD, Davis RW. Multiplexed variation scanning for 1,000 amplicons in hundreds of patients using mismatch repair detection (MRD) on tag arrays. Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14717-22. Epub 2005 Oct 3. (this was showing how the method that they were using would show a difference between specific different amplicons in an autistic patient compared with a control).
Buxbaum JD, Silverman J, Keddache M, Smith CJ, Hollander E, Ramoz N, Reichert JG. Linkage analysis for autism in a subset families with obsessive-compulsive behaviors: evidence for an autism susceptibility gene on chromosome 1 and further support for susceptibility genes on chromosome 6 and 19. Mol Psychiatry. 2004 Feb;9(2):144-50. (suggest that there is an autism susceptibility gene on chromosome 1 and provide further support for the presence of autism susceptibility genes on chromosomes 6 and 19)
Buxbaum JD, Silverman JM, Smith CJ, Kilifarski M, Reichert J, Hollander E, Lawlor BA, Fitzgerald M, Greenberg DA, Davis KL. Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity. Am J Hum Genet. 2001 Jun;68(6):1514-20. Epub 2001 May 14. Erratum in: Am J Hum Genet 2001 Aug;69(2):470.
Bolton PF, Veltman MW, Weisblatt E, Holmes JR, Thomas NS, Youings SA, Thompson RJ, Roberts SE, Dennis NR, Browne CE, Goodson S, Moore V, Brown J. Chromosome 15q11-13 abnormalities and other medical conditions in individuals with autism spectrum disorders.
Psychiatr Genet. 2004 Sep;14(3):131-7.#
Bacchelli E, Blasi F, Biondolillo M, Lamb JA, Bonora E, Barnby G, Parr J, Beyer KS, Klauck SM, Poustka A, Bailey AJ, Monaco AP, Maestrini E; International Molecular Genetic Study of Autism Consortium (IMGSAC). Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene. Mol Psychiatry. 2003 Nov;8(11):916-24.
Newbury DF, Bonora E, Lamb JA, Fisher SE, Lai CS, Baird G, Jannoun L, Slonims V, Stott CM, Merricks MJ, Bolton PF, Bailey AJ, Monaco AP; International Molecular Genetic Study of Autism Consortium. FOXP2 is not a major susceptibility gene for autism or specific language impairment. Am J Hum Genet. 2002 May;70(5):1318-27. Epub 2002 Mar 13.
International Molecular Genetic Study of Autism Consortium (IMGSAC). A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am J Hum Genet. 2001 Sep;69(3):570-81. Epub 2001 Jul 30. (they have got the money, the time, the laboratory, the methods but it is exceptionally difficult to nail down a specific gene that is the cause. These were some of the first attempts that they had)
International Molecular Genetic Study of Autism Consortium (IMGSAC). Further characterization of the autism susceptibility locus AUTS1 on chromosome 7q. Hum Mol Genet. 2001 Apr 15;10(9):973-82.
Sweeten TL, Odell DW, Odell JD, Torres AR. C4B null alleles are not associated with genetic polymorphisms in the adjacent gene CYP21A2 in autism. BMC Med Genet. 2008 Jan 7;9:1.
Chaste P, Nygren G, Anckarsäter H, Råstam M, Coleman M, Leboyer M, Gillberg C, Betancur C. Mutation screening of the ARX gene in patients with autism. Am J Med Genet B Neuropsychiatr Genet. 2007 Mar 5;144B(2):228-30. Mutations in the Aristaless related homeobox (ARX) gene are associated with a broad spectrum of disorders….but they found them to be very uncommon in autism.)
Nabi R, Serajee FJ, Chugani DC, Zhong H, Huq AH. Association of tryptophan 2,3 dioxygenase gene polymorphism with autism. Am J Med Genet B Neuropsychiatr Genet. 2004 Feb 15;125B(1):63-8. (Haplotype analysis also demonstrated significant difference in the transmission of TDO2 haplotypes to autistic subjects (P = 0.0027). Our results suggest the presence of a susceptibility mutation in the TDO2 or a nearby gene, but may also represent a chance finding.)
Asano
E, Kuivaniemi H, Huq AH, Tromp G, Behen M, Rothermel R, Herron J, Chugani DC.
A study of novel polymorphisms in the upstream region of vasoactive intestinal
peptide receptor type 2 gene in autism. J Child Neurol. 2001 May;16(5):357-63 (These
preliminary results suggest that VIPR2 may have a role in gastrointestinal
symptoms and stereotypical behaviors in autism, although they admit that a much
larger study would help)
Preliminary evidence for involvement of the folate gene
polymorphism 19bp deletion-DHFR in occurrence of autism. Adams M,
Lucock M, Stuart J, Fardell S, Baker K, Ng X.
Neurosci Lett. 2007 Jul 5;422(1):24-9.
Allan AM, Liang X, Luo Y, Pak C, Li X, Szulwach KE, Chen D, Jin P, Zhao X. The loss of methyl-CpG binding protein 1 leads to autism-like behavioral deficits. Hum Mol Genet. 2008 Jul 1;17(13):2047-57. Epub 2008 Apr 1.
Jill James S, Melnyk S, Jernigan S, Hubanks A, Rose S, Gaylor DW. Abnormal Transmethylation/transsulfuration Metabolism and DNA Hypomethylation Among Parents of Children with Autism. J Autism Dev Disord. 2008 May 30.
Vincent JB, Choufani S, Horike S, Stachowiak B, Li M, Dill FJ, Marshall C, Hrynchak M, Pewsey E, Ukadike KC, Friedman JM, Srivastava AK, Scherer SW. A translocation t(6;7)(p11-p12;q22) associated with autism and mental retardation: localization and identification of candidate genes at the breakpoints. Psychiatr Genet. 2008 Jun;18(3):101-9.
Maussion G, Carayol J, Lepagnol-Bestel AM, Tores F, Loe-Mie Y, Milbreta U, Rousseau F, Fontaine K, Renaud J, Moalic JM, Philippi A, Chedotal A, Gorwood P, Ramoz N, Hager J, Simonneau M. Convergent evidence identifying MAP/microtubule affinity-regulating kinase 1 (MARK1) as a susceptibility gene for autism. Hum Mol Genet. 2008 May 20.
Bayou N, M'rad R, Belhaj A, Daoud H, Ben Jemaa L, Zemni R, Briault S, Helayem MB, Chaabouni H. De novo balanced translocation t (7;16) (p22.1; p11.2) associated with autistic disorder. J Biomed Biotechnol. 2008;2008:231904.
Kent L, Emerton J, Bhadravathi V, Weisblatt E, Pasco G, Willatt LR, McMahon R, Yates JR. X linked ichthyosis (steroid sulphatase deficiency) is associated with increased risk of attention deficit hyperactivity disorder, autism and social communication deficits. J Med Genet. 2008 Apr 15.
Gamerdinger U, Eggermann T, Schubert R, Schwanitz G, Kreiss-Nachtsheim M. Rare interstitial deletion 9q31.2 to q33.1 de novo: longitudinal study in a patient over a period of more than 20 years. Am J Med Genet A. 2008 May 1;146A(9):1180-4.
Wassink TH, Vieland VJ, Sheffield VC, Bartlett CW, Goedken R, Childress D, Piven J. Posterior probability of linkage analysis of autism dataset identifies linkage to chromosome 16. Psychiatr Genet. 2008 Apr;18(2):85-91.
Ramoz N, Cai G, Reichert JG, Silverman JM, Buxbaum JD. An analysis of candidate autism loci on chromosome 2q24-q33: Evidence for association to the STK39 gene. Am J Med Genet B Neuropsychiatr Genet. 2008 Mar 17.
Grigorenko EL, Han SS, Yrigollen CM, Leng L, Mizue Y, Anderson GM, Mulder EJ, de Bildt A, Minderaa RB, Volkmar FR, Chang JT, Bucala R. Macrophage migration inhibitory factor and autism spectrum disorders. Pediatrics. 2008 Aug;122(2):e438-45. (they showed that MIF gene may be involved but required further investigation)
Rossi E, Verri AP, Patricelli MG, Destefani V, Ricca I, Vetro A, Ciccone R, Giorda R, Toniolo D, Maraschio P, Zuffardi O. A 12Mb deletion at 7q33-q35 associated with autism spectrum disorders and primary amenorrhea. Eur J Med Genet. 2008 Jul 16. (ahead of print)
Rojas DC, Maharajh K, Teale P, Rogers SJ. Reduced neural synchronization of gamma-band MEG oscillations in first-degree relatives of children with autism. BMC Psychiatry. 2008 Aug 1;8(1):66. (ahead of print)
Loat CS, Haworth CM, Plomin R, Craig IW. A Model Incorporating Potential Skewed X-Inactivation in MZ Girls Suggests that X-Linked QTLs Exist for Several Social Behaviours Including Autism Spectrum Disorder. Ann Hum Genet. 2008 Jul 29.
Marui T, Funatogawa I, Koishi S, Yamamoto K, Matsumoto H, Hashimoto O, Nanba E, Nishida H, Sugiyama T, Kasai K, Watanabe K, Kano Y, Kato N. Association of the neuronal cell adhesion molecule (NRCAM) gene variants with autism. Int J Neuropsychopharmacol. 2008 Jul 30:1-10.
Galasso C, Lo-Castro A, Lalli C, Nardone AM, Gullotta F, Curatolo P. Deletion 2q37: an identifiable clinical syndrome with mental retardation and autism. J Child Neurol. 2008 Jul;23(7):802-6.
Israel S, Lerer E, Shalev I, Uzefovsky F, Reibold M, Bachner-Melman R, Granot R, Bornstein G, Knafo A, Yirmiya N, Ebstein RP. Molecular genetic studies of the arginine vasopressin 1a receptor (AVPR1a) and the oxytocin receptor (OXTR) in human behaviour: from autism to altruism with some notes in between. Prog Brain Res. 2008;170:435-49.
Yan J, Feng J, Schroer R, Li W, Skinner C, Schwartz CE, Cook EH Jr, Sommer SS. Analysis of the neuroligin 4Y gene in patients with autism. Psychiatr Genet. 2008 Aug;18(4):204-7. (The absence of p.I679V in 2986 control Y chromosomes and the high similarity of NLGN4 and NLGN4Y are consistent with the hypothesis that p.I679V contributes to the etiology of autism. The presence of only one structural variant in our population of 335 males with autism/mental retardation, the unavailability of significant family cosegregation and an absence of functional assays are, however, important limitations of this study. As a result the significance must be questioned)
Gauthier J, Spiegelman D, Piton A, Lafrenière RG, Laurent S, St-Onge J, Lapointe L, Hamdan FF, Cossette P, Mottron L, Fombonne E, Joober R, Marineau C, Drapeau P, Rouleau GA. Novel de novo SHANK3 mutation in autistic patients. Am J Med Genet B Neuropsychiatr Genet. 2008 Jul 9.
Dutta S, Sinha S, Ghosh S, Chatterjee A, Ahmed S, Usha R. Genetic analysis of reelin gene (RELN) SNPs: No association with autism spectrum disorder in the Indian population. Neurosci Lett. 2008 Aug 15;441(1):56-60. Epub 2008 Jun 13. (Reelin gene (RELN) is located on chromosome 7q22; an important autism critical region identified through several genome-wide scans. But, we failed to detect either preferential parental transmission of any alleles of the markers to affected offspring or any biased allelic or genotypic distribution between the cases and controls.)
Chronic psychotropic drug treatment causes differential expression of Reelin signaling system in frontal cortex of rats. Fatemi SH, Reutiman TJ, Folsom TD. Schizophr Res. 2009 Jun;111(1-3):138-52. Psychotropic medications (clozapine, fluoxetine, haloperidol, lithium, olanzapine, and valproic acid) used in the treatment of psychiatric disorders alters levels of Reelin, its receptor Vldlr, downstream molecules Gsk3 beta, Dab-1, and Gad65/67 in rat prefrontal cortex as measured by qRT-PCR and SDS-PAGE and western blotting. qRT-PCR revealed that mRNAs for Reelin, Vldlr, Dab-1, Gsk3 beta, and Gad65 were each significantly altered by at least one of the drugs tested, and in the case of Reelin, Dab-1, and Gsk3 beta, by multiple drugs. Whether these effects might have significance in the pregnant woman is unclear.
Yoo HJ, Cho IH, Park M, Cho E, Cho SC, Kim BN, Kim JW, Kim SA. Association between PTGS2 polymorphism and autism spectrum disorders in Korean trios. Neurosci Res. 2008 Sep;62(1):66-9. Epub 2008 Jun 5.
Williams JM, Beck TF, Pearson DM, Proud MB, Cheung SW, Scott DA. A 1q42 deletion involving DISC1, DISC2, and TSNAX in an autism spectrum disorder. Am J Med Genet A. 2009 Jul 15;149A(8):1758-1762. A single case in which they looked for specific gene malformations that were known to be associated with neuropsychiatric conditions in older people. In this case they were present but no statistics in other children were shown.
Chakrabarti B, Dudbridge F, Kent L, Wheelwright S, Hill-Cawthorne G, Allison C, Banerjee-Basu S, Baron-Cohen S Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome. Autism Res. 2009 Jun;2(3):157-77. All they could really say was that certain cases where autism type syndromes had been seen are also found to have genetic changes associated with hormonal formation. This is simply not the whole story in that there are very good data in which many people have been found to be clinically completely normal but with these genetic changes, and quite severe changes both in the formation of the hormone and the receptor. They looked at 14 different genes that were known to be associated with the different conditions, and found some to be associated with them. They admit that a lot more work must be carried out.
Ma DQ, Rabionet R, Konidari I, Jaworski J, Cukier HN, Wright HH, Abramson RK, Gilbert JR, Cuccaro ML, Pericak-Vance MA, Martin ER. Association and gene-gene interaction of SLC6A4 and ITGB3 in autism. Am J Med Genet B Neuropsychiatr Genet. 2009 Jul 8. Gene-gene interactions were tested using extended multifactor dimensionality reduction (EMDR) and MDR-phenomics (MDR-P) using sex of affecteds and FH as covariates. While not significant in the overall dataset, nominally significant association was identified at RS2066713 (P = 0.006) within SLC6A4 in family-history negative (FH-) families, at RS2066713 (P = 0.038) in family-history positive (FH+) families but with the opposite risk allele as in the FH- families. Even what they found to be significant was in a small group and would need to be reviewed by further research.
Gadow KD, Roohi J, Devincent CJ, Kirsch S, Hatchwell E. J Autism Dev Disord. 2009 Jul 7. Association of COMT (Val158Met) and BDNF (Val66Met) Gene Polymorphisms with Anxiety, ADHD and Tics in Children with Autism Spectrum Disorder. The aim of the study is to examine rs4680 (COMT) and rs6265 (BDNF) as genetic markers of anxiety, ADHD, and tics. Parents and teachers completed a DSM-IV-referenced rating scale for a total sample of 67 children with autism spectrum disorder (ASD). Both COMT (p = 0.06) and BDNF (p = 0.07) genotypes were marginally significant for teacher ratings of social phobia (etap (2) = 0.06). Analyses also indicated associations of BDNF genotype with parent-rated ADHD (p = 0.01, etap (2) = 0.10) and teacher-rated tics (p = 0.04; etap (2) = 0.07). There was also evidence of a possible interaction (p = 0.02, etap (2) = 0.09) of BDNF genotype with DAT1 3' VNTR with tic severity. BDNF and COMT may be biomarkers for phenotypic variation in ASD, but these preliminary findings remain tentative pending replication with larger, independent samples. All very tentative but an interesting finding.
A genome-wide association study of autism reveals a common novel risk locus at 5p14.1. Ma D, Salyakina D, Jaworski JM, Konidari I, Whitehead PL, Andersen AN, Hoffman JD, Slifer SH, Hedges DJ, Cukier HN, Griswold AJ, McCauley JL, Beecham GW, Wright HH, Abramson RK, Martin ER, Hussman JP, Gilbert JR, Cuccaro ML, Haines JL, Pericak-Vance MA. Ann Hum Genet. 2009 May;73(Pt 3):263-73. All that they could show was an association rather than a cause at this point.
The MTHFR 677C-->T polymorphism and behaviors in children with autism: exploratory genotype-phenotype correlations. Goin-Kochel RP, Porter AE, Peters SU, Shinawi M, Sahoo T, Beaudet AL. Autism Res. 2009 Apr;2(2):98-108. New evidence suggests that autism may be associated with (a) varied behavioral responses to folate therapy and (b) metabolic anomalies, including those in folate metabolism, that contribute to hypomethylation of DNA. Their attempt was to look for methylation of DNA genes. They tried to look for specific clinical differences in cases with genetic methylation differences. They might have found some but it was difficult to be sure and they call for further research.
High-density SNP association study of the 17q21 chromosomal region linked to autism identifies CACNA1G as a novel candidate gene. Strom SP, Stone JL, Ten Bosch JR, Merriman B, Cantor RM, Geschwind DH, Nelson SF. Mol Psychiatry. 2009 May 19. 17q11-q21 is a region of the genome likely to harbour susceptibility to autism (MIM(209850)) based on earlier evidence of linkage to the disorder. However it was difficult to work out in the group of children that they tested any specific changes that were present and suggested that higher frequency changes at different sites may be of more value.
Genome-wide linkage in Utah autism pedigrees. Allen-Brady K, Robison R, Cannon D, Varvil T, Villalobos M, Pingree C, Leppert MF, Miller J, McMahon WM, Coon H. Mol Psychiatry. 2009 May 19 This genome-wide screen of 70 families includes 20 large extended pedigrees of 6-9 generations, 6 moderate-sized families of 4-5 generations and 44 smaller families of 2-3 generations. The Center for Inherited Disease Research (CIDR) provided genotyping using the Illumina Linkage Panel 12, a 6K single-nucleotide polymorphism (SNP) platform. Results from 192 subjects with an autism spectrum disorder (ASD) and 461 of their relatives revealed genome-wide significance on chromosome 15q, with three possibly distinct peaks: 15q13.1-q14 (heterogeneity LOD (HLOD)=4.09 at 29 459 872 bp); 15q14-q21.1 (HLOD=3.59 at 36 837 208 bp); and 15q21.1-q22.2 (HLOD=5.31 at 55 629 733 bp). Two of these peaks replicate earlier findings. Additional suggestive results on chromosomes 2p25.3-p24.1 (HLOD=1.87), 7q31.31-q32.3 (HLOD=1.97) and 13q12.11-q12.3 (HLOD=1.93). Affected subjects in families supporting the linkage peaks found in this study did not reveal strong evidence for distinct phenotypic subgroups.
Linkage and linkage disequilibrium scan for autism loci in an extended pedigree from Finland. Kilpinen H, Ylisaukko-oja T, Rehnström K, Gaál E, Turunen JA, Kempas E, von Wendt L, Varilo T, Peltonen L. Hum Mol Genet. 2009 Aug 1;18(15):2912-21. We have here used this special opportunity to identify rare alleles in autism by genealogically tracing 20 autism families into one extended pedigree with verified genealogical links reaching back to the 17th century. In this unique pedigree, we performed a dense microsatellite marker genome-wide scan of linkage and LD and followed initial findings with extensive fine-mapping. We identified a putative autism susceptibility locus at 19p13.3 and obtained further evidence for previously identified loci at 1q23 and 15q11-q13. Most promising candidate genes were TLE2 and TLE6 clustered at 19p13 and ATP1A2 at 1q23.
Aberrations in folate metabolic pathway and altered susceptibility to autism. Mohammad NS, Jain JM, Chintakindi KP, Singh RP, Naik U, Akella RR. Psychiatr Genet. 2009 Aug;19(4):171-6. This was done as a genetic assessment by taking the sample from the child (and control) and looking for abnormalities in specific genes. Methylene tetrahydrofolate reductase 677T-allele frequency was found to be higher in autistic children compared with nonautistic children (16.3 vs. 6.5%) with 2.79-fold increased risk for autism [95% confidence interval (CI): 1.58-4.93]. They also looked for other changes in the folate chain and found no association with autism.
Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, Zhang H, Estes A, Brune CW, Bradfield JP, Imielinski M, Frackelton EC, Reichert J, Crawford EL, Munson J, Sleiman PM, Chiavacci R, Annaiah K, Thomas K, Hou C, Glaberson W, Flory J, Otieno F, Garris M, Soorya L, Klei L, Piven J, Meyer KJ, Anagnostou E, Sakurai T, Game RM, Rudd DS, Zurawiecki D, McDougle CJ, Davis LK, Miller J, Posey DJ, Michaels S, Kolevzon A, Silverman JM, Bernier R, Levy SE, Schultz RT, Dawson G, Owley T, McMahon WM, Wassink TH, Sweeney JA, Nurnberger JI, Coon H, Sutcliffe JS, Minshew NJ, Grant SF, Bucan M, Cook EH, Buxbaum JD, Devlin B, Schellenberg GD, Hakonarson H. Nature. 2009 May 28;459(7246):569-73. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 x 10(-3)). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 x 10(-3)). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 x 10(-6)). The researchers suggested that this was an important finding in that they had looked in such a large cohort, and although each individual gene modification or duplication might be rare, many of them were in association with neuronal or ubiquitin pathways.
Common genetic variants on 5p14.1 associate with autism spectrum disorders. Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS, Salyakina D, Imielinski M, Bradfield JP, Sleiman PM, Kim CE, Hou C, Frackelton E, Chiavacci R, Takahashi N, Sakurai T, Rappaport E, Lajonchere CM, Munson J, Estes A, Korvatska O, Piven J, Sonnenblick LI, Alvarez Retuerto AI, Herman EI, Dong H, Hutman T, Sigman M, Ozonoff S, Klin A, Owley T, Sweeney JA, Brune CW, Cantor RM, Bernier R, Gilbert JR, Cuccaro ML, McMahon WM, Miller J, State MW, Wassink TH, Coon H, Levy SE, Schultz RT, Nurnberger JI, Haines JL, Sutcliffe JS, Cook EH, Minshew NJ, Buxbaum JD, Dawson G, Grant SF, Geschwind DH, Pericak-Vance MA, Schellenberg GD, Hakonarson H.Nature. 2009 May 28;459(7246):528-33.
High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility. Maestrini E, Pagnamenta AT, Lamb JA, Bacchelli E, Sykes NH, Sousa I, Toma C, Barnby G, Butler H, Winchester L, Scerri TS, Minopoli F, Reichert J, Cai G, Buxbaum JD, Korvatska O, Schellenberg GD, Dawson G, Bildt AD, Minderaa RB, Mulder EJ, Morris AP, Bailey AJ, Monaco AP. Mol Psychiatry. 2009 Apr 28.
Copy number variation and association analysis of SHANK3 as a candidate gene for autism in the IMGSAC collection. Sykes NH, Toma C, Wilson N, Volpi EV, Sousa I, Pagnamenta AT, Tancredi R, Battaglia A, Maestrini E, Bailey AJ, Monaco AP. Eur J Hum Genet. 2009 Apr 22.
A large-scale screen for coding variants in SERT/SLC6A4 in autism spectrum disorders. Sakurai T, Reichert J, Hoffman EJ, Cai G, Jones HB, Faham M, Buxbaum JD. Autism Res. 2008 Aug;1(4):251-7
Influence of the 5-HTTLPR polymorphism and environmental risk factors in a Brazilian sample of patients with autism spectrum disorders. Longo D, Schüler-Faccini L, Brandalize AP, dos Santos Riesgo R, Bau CH. Brain Res. 2009 Apr 24;1267:9-17
Screening for copy number alterations in loci associated with autism spectrum disorders by two-color multiplex ligation-dependent probe amplification. Bremer A, Giacobini M, Nordenskjöld M, Brøndum-Nielsen K, Mansouri M, Dahl N, Anderlid B, Schoumans J. Am J Med Genet B Neuropsychiatr Genet. 2009 Mar 24.
Mapping of partially overlapping de novo deletions across an autism susceptibility region (AUTS5) in two unrelated individuals affected by developmental delays with communication impairment. Newbury DF, Warburton PC, Wilson N, Bacchelli E, Carone S; International Molecular Genetic Study of Autism Consortium, Lamb JA, Maestrini E, Volpi EV, Mohammed S, Baird G, Monaco AP. Am J Med Genet A. 2009 Feb 15;149A(4):588-97. What they are trying to do is to take the change that they have found in an ASD patient and look to see if it is the same as that found in another patient, neither of which appear to have caught it from parents as familial form. They found that the changes were similar but not the same.
Association of the alpha4 integrin subunit gene (ITGA4) with autism. Correia C, Coutinho AM, Almeida J, Lontro R, Lobo C, Miguel TS, Martins M, Gallagher L, Conroy J, Gill M, Oliveira G, Vicente AM. Am J Med Genet B Neuropsychiatr Genet. 2009 Mar 3 further evidence for the involvement of the integrin alpha-4 precursor gene (ITGA4) in the etiology of autism, by replicating previous findings of a genetic association with autism in various independent populations. The ITGA4 gene maps to the autism linkage region on 2q31-33 and is therefore a plausible positional candidate. Evidence for association was found for the rs155100 marker (P = 0.019) and for a number of specific marker haplotypes containing this SNP (0.00053 < P < 0.022). In this study, an association was found between the ITGA4 rs1449263 marker and levels of a serum autoantibody directed to brain tissue, which was previously shown to be significantly more frequent in autistic patients than in age-matched controls in our population. Integrin is a compound associated with neuroinflammation.
Association and mutation analyses of 16p11.2 autism candidate genes. Kumar RA, Marshall CR, Badner JA, Babatz TD, Mukamel Z, Aldinger KA, Sudi J, Brune CW, Goh G, Karamohamed S, Sutcliffe JS, Cook EH, Geschwind DH, Dobyns WB, Scherer SW, Christian SL. PLoS One. 2009;4(2):e4582. they claim to have identified sequence variation in at least one candidate gene in 16p11.2 that may represent a novel genetic risk factor for autism. However, further studies are required to substantiate these preliminary findings.
Preliminary evidence of the in vitro effects of BDE-47 on innate immune responses in children with autism spectrum disorders. Ashwood P, Schauer J, Pessah IN, Van de Water J. J Neuroimmunol. 2009 Mar 31;208(1-2):130-5. A common environmental contaminant, 2,2',4,4'-tetrabrominated biphenyl (BDE-47), was tested for differential effects on the immune response of peripheral blood mononuclear cells (PBMC) isolated from children with ASD (n=19) and age-matched typically developing controls (TD, n=18). PBMC were exposed in vitro to either 100 nM or 500 nM BDE-47, before challenge with bacterial lipopolysaccharide (LPS), an innate immune activator, with resultant cytokine production measured using the Luminex multiplex platform. The cytokine responses of LPS stimulated PBMC from ASD and TD subjects diverged in the presence of 100 nM BDE. For example, cells cultured from the TD group demonstrated significantly decreased levels of the cytokines IL-12p40, GM-CSF, IL-6, TNFalpha, and the chemokines MIP-1alpha and MIP-1beta following LPS stimulation of PBMC pretreated with 100 nM BDE-47 compared with samples treated with vehicle control (p<0.05). In contrast, cells cultured from subjects with ASD demonstrated an increased IL-1beta response to LPS (p=0.033) when pretreated with 100 nM BDE-47 compared with vehicle control. Preincubation with 500 nM BDE-47 significantly increased the stimulated release of the inflammatory chemokine IL-8 (p<0.04) in cells cultured from subjects with ASD but not in cells from TD controls. These data suggest that in vitro exposure of PBMC to BDE-47 affects cell cytokine production in a pediatric population. Moreover, PBMC from the ASD subjects were differentially affected when compared with the TD controls suggesting a biological basis for altered sensitivity to BDE-47 in the ASD population. This is an interesting finding in that it suggests that simply available mononucleocytes from the blood of a ASD child may be used to identify some aspect of its illness. Clearly this work needs to be carried out at different points in the child’s development and a reason for it should be found. Whether this is a genetic effect or an environmental one is not currently clear.
Tabarés-Seisdedos R, Rubenstein JL. Mol
Psychiatry. 2009 Jun;14(6):563-89. In this review, they consider the
current state of evidence from cytogenetic, linkage, association, gene
expression and endophenotyping studies for the role of these 8p genes in
neuropsychiatric disease. What tends to come out of it is that ASD is
difficult to nail down as being involved.
Genetic variant of glutathione peroxidase 1 in autism.
Ming X, Johnson WG, Stenroos ES, Mars A, Lambert GH, Buyske S. Brain Dev. 2009
Feb 3
Family-based transmission analysis of HLA genetic markers
in Sardinian children with autistic spectrum disorders. Guerini FR,
Bolognesi E, Manca S, Sotgiu S, Zanzottera M, Agliardi C, Usai S, Clerici
M. Hum Immunol. 2009 Mar;70(3):184-90.
Genetic correlation between autistic traits and IQ in a
population-based sample of twins with autism spectrum disorders (ASDs).
Nishiyama T, Taniai H, Miyachi T, Ozaki K, Tomita M, Sumi S. J Hum Genet.
2009;54(1):56-61. This was impossible to carry out adequately and no
adequate agreement was found.
Association of ADHD, tics, and anxiety with dopamine transporter (DAT1) genotype in autism spectrum disorder. Gadow KD, Roohi J, DeVincent CJ, Hatchwell E. J Child Psychol Psychiatry. 2008 Dec;49(12):1331-8 Collectively, these results suggest that the extraordinary variability in ASD clinical phenotypes may be explained in part by the same genes that are implicated in a host of other psychiatric disorders in non-ASD populations. Nevertheless, replication with independent samples is necessary to confirm this preliminary finding
Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selection. Flavell SW, Kim TK, Gray JM, Harmin DA, Hemberg M, Hong EJ, Markenscoff-Papadimitriou E, Bear DM, Greenberg ME. Neuron. 2008 Dec 26;60(6):1022-38. characterized the genetic program that is activated by MEF2, a key regulator of activity-dependent synapse development. These MEF2 target genes have diverse functions at synapses, revealing a broad role for MEF2 in synapse development. Several of the MEF2 targets are mutated in human neurological disorders including epilepsy and autism spectrum disorders, suggesting that these disorders may be caused by disruption of an activity-dependent gene program that controls synapse development. This study just looks at the action of the gene rather than its association with ASD.
Replication study of candidate genes for cognitive abilities: the Lothian Birth Cohort 1936. Houlihan LM, Harris SE, Luciano M, Gow AJ, Starr JM, Visscher PM, Deary IJ. Genes Brain Behav. 2009 Mar;8(2):238-47. Previous studies on cognition and illnesses with cognitive impairments have identified single nucleotide polymorphisms (SNPs) within candidate genes that might influence cognition or age-related cognitive change. This study investigated 10 candidate genes in over 1000 Scots: the Lothian Birth Cohort 1936 (LBC1936). These participants were tested on general cognitive ability (Scottish Mental Survey 1947) at age 11. At mean age 70, they completed the same general cognitive ability test and a battery of diverse cognitive tests. Nineteen SNPs in 10 genes previously associated with cognition, Alzheimer's disease or autism were genotyped in 1063 individuals. The genes include BDNF, COMT, DISC1, KL, NCSTN, PPP1R1B, PRNP, SHANK3, SORL1 and WRN.
MOMO syndrome associated with autism: a case report.
Allelic variants in HTR3C show association with autism. Rehnström K, Ylisaukko-oja T, Nummela I, Ellonen P, Kempas E, Vanhala R, von Wendt L, Järvelä I, Peltonen L. Am J Med Genet B Neuropsychiatr Genet. 2009 Jul 5;150B(5):741-6.
Comparative analysis of neurological disorders focuses genome-wide search for autism genes. Wall DP, Esteban FJ, Deluca TF, Huyck M, Monaghan T, Velez de Mendizabal N, Goñí J, Kohane IS. Genomics. 2009 Feb;93(2):120-9. This really gets going in looking for genetics that are present in several patients. They conducted a large comparative analysis of the network of genes linked to autism with those of 432 other neurological diseases to circumscribe a multi-disorder subcomponent of autism. They identified 154 genes not previously linked to autism of which 42% were significantly differentially expressed in autistic individuals. Then, using prior knowledge from interaction networks of disorders related to autism, we uncovered 334 new genes that interact with published autism genes, of which 87% were significantly differentially regulated in autistic individuals.
Fine mapping and association studies in a candidate region for autism on chromosome 2q31-q32. Conroy J, Cochrane L, Anney RJ, Sutcliffe JS, Carthy P, Dunlop A, Mullarkey M, O'hici B, Green AJ, Ennis S, Gill M, Gallagher L. Am J Med Genet B Neuropsychiatr Genet. 2009 Jun 5;150B(4):535-44. It appears that they worked very hard through large numbers of genes. A non-significant trend towards overtransmission of the associated allele of rs12690517 in the Irish sample (OR = 1.2; P = 0.067) and haplotypes at the 3' end of ITGA4 was observed in the AGRE sample. The VT sample showed association with markers and haplotypes across the gene, but no association with the rs12690517 marker or its surrounding haplotypes. The combined sample showed evidence of association with rs12690517 (OR = 1.3; P = 0.008) and surrounding haplotypes. The findings indicate some evidence for the role of ITGA4 as candidate gene for autism.
The DLX1and DLX2 genes and susceptibility to autism spectrum disorders. Liu X, Novosedlik N, Wang A, Hudson ML, Cohen IL, Chudley AE, Forster-Gibson CJ, Lewis SM, Holden JJ. Eur J Hum Genet. 2009 Feb;17(2):228-35. The DLX genes encode homeodomain-containing transcription factors controlling the generation of GABAergic cortical interneurons. The DLX1 and DLX2 genes lie head-to-head in 2q32, a region associated with autism susceptibility. Further testing in 306 SPX families replicated the association at rs4519482 (P=0.033) and the over transmission of the haplotype GGGTG (P=0.012) although P-values were not significant after correction for multiple testing. The findings support the presence of two functional polymorphisms, one in or near each of the DLX genes that increase susceptibility to, or cause, autism in MPX families where there is a greater genetic component for these conditions.
A novel 6.14 Mb duplication of chromosome 8p21 in a patient with autism and self mutilation. Ozgen HM, Staal WG, Barber JC, de Jonge MV, Eleveld MJ, Beemer FA, Hochstenbach R, Poot M. J Autism Dev Disord. 2009 Feb;39(2):322-9.
Association of the neuronal cell adhesion molecule (NRCAM) gene variants with autism. Marui T, Funatogawa I, Koishi S, Yamamoto K, Matsumoto H, Hashimoto O, Nanba E, Nishida H, Sugiyama T, Kasai K, Watanabe K, Kano Y, Sasaki T, Kato N. Int J Neuropsychopharmacol. 2009 Feb;12(1):1-10. Epub 2008 Jul 30. Erratum in: Int J Neuropsychopharmacol. 2009 Apr;12(3):439. Sasaki, Tsukasa [added].
Family-based association study between NOS-I and -IIA polymorphisms and autism spectrum disorders in Korean trios. Kim HW, Cho SC, Kim JW, Cho IH, Kim SA, Park M, Cho EJ, Yoo HJ. Am J Med Genet B Neuropsychiatr Genet. 2009 Mar 5;150B(2):300-6.
Abnormal transmethylation/transsulfuration metabolism and DNA hypomethylation among parents of children with autism. James SJ, Melnyk S, Jernigan S, Hubanks A, Rose S, Gaylor DW. J Autism Dev Disord. 2008 Nov;38(10):1966-75. Epub 2008 May 30. Erratum in: J Autism Dev Disord. 2008 Nov;38(10):1976. Jill James, S. Recent evidence suggests that some autistic children may have reduced detoxification capacity and may be under chronic oxidative stress. Based on reports of abnormal methionine and glutathione metabolism in autistic children, it was of interest to examine the same metabolic profile in the parents. The results indicated that parents share similar metabolic deficits in methylation capacity and glutathione-dependent antioxidant/detoxification capacity observed in many autistic children. At this point they had not found whether it is due to a genetic change or not.
Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant. Hannes FD, Sharp AJ, Mefford HC, de Ravel T, Ruivenkamp CA, Breuning MH, Fryns JP, Devriendt K, Van Buggenhout G, Vogels A, Stewart H, Hennekam RC, Cooper GM, Regan R, Knight SJ, Eichler EE, Vermeesch JR. J Med Genet. 2009 Apr;46(4):223-32.
Association and mutation analyses of 16p11.2 autism candidate genes. Kumar RA, Marshall CR, Badner JA, Babatz TD, Mukamel Z, Aldinger KA, Sudi J, Brune CW, Goh G, Karamohamed S, Sutcliffe JS, Cook EH, Geschwind DH, Dobyns WB, Scherer SW, Christian SL. PLoS One. 2009;4(2):e4582.
Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression. Lintas C, Sacco R, Garbett K, Mirnics K, Militerni R, Bravaccio C, Curatolo P, Manzi B, Schneider C, Melmed R, Elia M, Pascucci T, Puglisi-Allegra S, Reichelt KL, Persico AM. Mol Psychiatry. 2009 Jul;14(7):705-18.
A high-density SNP genome-wide linkage scan in a large autism extended pedigree. Allen-Brady K, Miller J, Matsunami N, Stevens J, Block H, Farley M, Krasny L, Pingree C, Lainhart J, Leppert M, McMahon WM, Coon H. Mol Psychiatry. 2009 Jun;14(6):590-600. Analysis on the entire genome using a 10K SNP chip to identify potential regions of interest. Three regions met genome-wide significance criteria after controlling for LD: 3q13.2-q13.31 (nonparametric linkage (NPL), 5.58), 3q26.31-q27.3 (NPL, 4.85) and 20q11.21-q13.12 (NPL, 5.56). Two regions met suggestive criteria for significance 7p14.1-p11.22 (NPL, 3.18) and 9p24.3 (NPL, 3.44). All five chromosomal regions are consistent with other published findings. Although no common autism susceptibility genes were found for all seven autism cases, these results suggest that multiple genetic loci within these regions may contribute to the autism phenotype in this family
Mutations in SYNGAP1 in autosomal nonsyndromic mental
retardation. Hamdan FF, Gauthier J, Spiegelman D, Noreau A, Yang Y,
Pellerin S, Dobrzeniecka S, Côté M, Perreault-Linck E, Carmant L, D'Anjou G,
Fombonne E, Addington AM, Rapoport JL, Delisi LE, Krebs MO, Mouaffak F, Joober
R, Mottron L, Drapeau P, Marineau C, Lafrenière RG, Lacaille JC, Rouleau GA,
Michaud JL; Synapse to Disease Group. N Engl J Med.
2009 Feb 5;360(6):599-605. We sequenced the autosomal gene SYNGAP1, which
encodes a ras GTPase-activating protein that is critical for cognition and
synapse function, in 94 patients with nonsyndromic mental retardation. We
identified de novo truncating mutations (K138X, R579X, and L813RfsX22) in three
of these patients.
Functional analysis of a potassium-chloride
co-transporter 3 (SLC12A6) promoter polymorphism leading to an additional DNA
methylation site. Moser D, Ekawardhani S, Kumsta R, Palmason H, Bock
C, Athanassiadou Z, Lesch KP, Meyer J. Neuropsychopharmacology.
2009 Jan;34(2):458-67. (this may have nothing to do with it)
Regulation of cerebral cortical size and neuron number by
fibroblast growth factors: implications for autism. Vaccarino
FM, Grigorenko EL, Smith KM, Stevens HE. J Autism Dev
Disord. 2009 Mar;39(3):511-20. The idea being that if the gene is
modified then the size of the brain would alter.
Weiss
LA, Escayg A, Kearney JA, Trudeau M, MacDonald BT, Mori M, Reichert J, Buxbaum
JD, Meisler MH. Sodium channels SCN1A, SCN2A and SCN3A in familial
autism. Mol Psychiatry. 2003 Feb;8(2):186-94. (The variant R1902C in
SCN2A is located in the calmodulin binding site and was found to reduce binding
affinity for calcium-bound calmodulin. R542Q in SCN1A was observed in one
autism family…just a bit lacking in statistics for autism and further work needs
to be carried out)
Autism-associated familial microdeletion of Xp11.22.
Qiao Y, Liu X,
Harvard C, Hildebrand MJ, Rajcan-Separovic E, Holden JJ, Lewis ME. Clin Genet. 2008 Aug;74(2):134-44
Genetics alteration in calcium
regulation
The E646D-ATP13A4 Mutation Associated with Autism Reveals a Defect in Calcium Regulation. Vallipuram J, Grenville J, Crawford DA. Cell Mol Neurobiol. 2009 Sep 3. The intracellular calcium concentration was measured in COS-7 cells over-expressing mouse ATP13A4 using ratiometric calcium imaging with fura-2 AM as a calcium indicator. The results of this study show that ATP13A4 is localized to the endoplasmic reticulum (ER). Furthermore, we demonstrate that over-expression of ATP13A4 in COS-7 cells caused a significant increase in the intracellular calcium level. Interestingly, over-expression of the sequence variant containing a substitution of aspartic acid for a glutamic acid (E646D), previously found in patients with autism spectrum disorder (ASD), did not increase the free cellular calcium likely due to the mutation. They then showed the gene to be exposed at specific points in the development of the mouse. Overall, this study provides support for the hypothesis that ATP13A4 may play a vital role in the developing nervous system and its impairment can contribute to the symptoms seen in ASD
Genetic calcium signaling abnormalities in the central
nervous system: seizures, migraine, and autism. Gargus JJ. Ann N Y
Acad Sci. 2009 Jan;1151:133-56. Many of the calciumopathies are common complex
polygenic diseases, but leads to their understanding come most prominently from
rare monogenic channelopathy paradigms. Monogenic forms of common neuronal
disease phenotypes-such as seizures, ataxia, and migraine-produce a
constitutionally hyperexcitable tissue that is susceptible to periodic
decompensations. The gene families and genetic lesions underlying familial
hemiplegic migraine, FHM1/CACNA1A, FHM2/ATP1A2, and FHM3/SCN1A, and monogenic
mitochondrial migraine syndromes, provide a robust platform from which genes,
such as CACNA1C, which encodes the calcium channel mutated in Timothy syndrome,
can be evaluated for their role in autism and bipolar disease. A great
idea but the work had not at this point been done for ASD.
Mutations in the calcium-related gene IL1RAPL1 are
associated with autism.
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