1. Constantino JN, Todorov A, Hilton C, Law P, Zhang Y, Molloy E, Fitzgerald R, Geschwind D. {{Autism recurrence in half siblings: strong support for genetic mechanisms of transmission in ASD}}. {Mol Psychiatry};2012 (Feb 28)
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2. Fatemi SH, Aldinger KA, Ashwood P, Bauman ML, Blaha CD, Blatt GJ, Chauhan A, Chauhan V, Dager SR, Dickson PE, Estes AM, Goldowitz D, Heck DH, Kemper TL, King BH, Martin LA, Millen KJ, Mittleman G, Mosconi MW, Persico AM, Sweeney JA, Webb SJ, Welsh JP. {{Consensus Paper: Pathological Role of the Cerebellum in Autism}}. {Cerebellum};2012 (Feb 28)
There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin-related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene-environment interactions, therapeutics in autism, and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia, and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation.
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3. Itoh M, Tahimic CG, Ide S, Otsuki A, Sasaoka T, Noguchi S, Oshimura M, Goto YI, Kurimasa A. {{Methyl CpG-binding Protein Isoform MeCP2_e2 Is Dispensable for Rett Syndrome Phenotypes but Essential for Embryo Viability and Placenta Development}}. {J Biol Chem};2012 (Feb 28)
Methyl CpG-binding protein 2 (MeCP2) mutations are implicated in Rett syndrome (RTT), one of the common causes of female mental retardation. Two MeCP2 isoforms have been reported: MeCP2_e2, splicing of all four exons and MeCP2_e1, alternative splicing of exons 1, 3 and 4. Their relative expression levels vary among tissues, with MeCP2_e1 being more dominant in adult brain while MeCP2_e2 is expressed more abundantly in placenta, liver, and skeletal muscle. In this study, we performed specific disruption of the MeCP2_e2-defining exon 2 using Cre-LoxP system and examined the consequences of selective loss of MeCP2_e2 function in vivo. We performed behavior evaluation, gene-expression analysis, using RT-PCR and real time quantitative PCR, and histological analysis. We demonstrate that selective deletion of MeCP2_e2 does not result in RTT-associated neurological phenotypes but confers a survival disadvantage to embryos carrying MeCP2_e2 null allele of maternal origin. In addition, we reveal a specific requirement for MeCP2_e2 function in extraembryonic tissue where selective loss of MeCP2_e2 results in placenta defects and upregulation of peg-1 as determined by the parental origin of the mutant allele. Taken together, our findings suggest a novel role for MeCP2 in normal placenta development and illustrate how paternal X chromosome inactivation in extraembryonic tissues confers a survival disadvantage for carriers of a mutant maternal MeCP2_e2 allele. Moreover, our findings provide an explanation for the absence of reports on MeCP2_e2-specific exon 2 mutations in RTT. MeCP2_e2 mutations in humans may result in a phenotype that evades a diagnosis of RTT.
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4. James WH. {{A potential explanation of some established major risk factors for autism}}. {Dev Med Child Neurol};2012 (Feb 28)
Baron-Cohen hypothesized that a cause of autism in infants is exposure to high concentrations of intrauterine testosterone concentrations. Some of the subsequent research on this hypothesis has focused on the possibility that the source of this testosterone is the fetus; however, this review shows that if the source is taken to be the mother, then many of the established risk factors for autism could be explained. If that were correct, it would follow that high maternally derived intrauterine androgen concentrations may be a major environmental cause of autism.
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5. Santoro MR, Bray SM, Warren ST. {{Molecular mechanisms of fragile x syndrome: a twenty-year perspective}}. {Annu Rev Pathol};2012 (Feb 28);7:219-245.
Fragile X syndrome (FXS) is a common form of inherited intellectual disability and is one of the leading known causes of autism. The mutation responsible for FXS is a large expansion of the trinucleotide CGG repeat in the 5′ untranslated region of the X-linked gene FMR1. This expansion leads to DNA methylation of FMR1 and to transcriptional silencing, which results in the absence of the gene product, FMRP, a selective messenger RNA (mRNA)-binding protein that regulates the translation of a subset of dendritic mRNAs. FMRP is critical for mGluR (metabotropic glutamate receptor)-dependent long-term depression, as well as for other forms of synaptic plasticity; its absence causes excessive and persistent protein synthesis in postsynaptic dendrites and dysregulated synaptic function. Studies continue to refine our understanding of FMRP’s role in synaptic plasticity and to uncover new functions of this protein, which have illuminated therapeutic approaches for FXS.
