1. Belagodu AP, Zendeli L, Slater BJ, Galvez R. {{Blocking elevated VEGF-A attenuates non-vasculature Fragile X Syndrome abnormalities}}. {Dev Neurobiol};2016 (Jun 6)
Fragile X syndrome (FXS) is the most common form of inherited mental retardation. In exploring abnormalities associated with the syndrome, we have recently demonstrated abnormal vascular density in a FXS mouse model (Galvan and Galvez, 2012). One of the most prominent regulators of vascular growth is VEGF-A (Vascular Endothelial Growth Factor A), suggesting that FXS is associated with abnormal VEGF-A expression. In addition to its role in vascular regulation, VEGF-A also induces cellular changes such as increasing cell proliferation, and axonal and neurite outgrowth independent of its effects on vasculature. These VEGF-A induced cellular changes are consistent with FXS abnormalities such as increased axonal material, dendritic spine density, and cell proliferation. In support of these findings, the following study demonstrated that FXS mice exhibit increased expression of VEGF-A in brain. These studies suggest that increased VEGF-A expression in FXS is contributing to non-vascular FXS abnormalities. To explore the role of VEGF-A in mediating non-vascular FXS abnormalities, the monoclonal antibody Bevacizumab was used to block free VEGF-A. Bevacizumab treatment was found to decrease FXS Synapsin-1 expression, a presynaptic marker for synapse density, and reduce FXS testicle weight to control levels. Blocking VEGF-A also alleviated FXS abnormalities on novel object recognition, a test of cognitive performance. These findings demonstrate that VEGF-A is elevated in FXS brain and suggest that its expression promotes non-vascular FXS abnormalities. This article is protected by copyright. All rights reserved.
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2. Broihier HT. {{BMP signaling turns up in fragile X syndrome: FMRP represses BMPR2}}. {Sci Signal};2016;9(431):fs12.
Fragile X syndrome is the most common inherited form of intellectual disability and results from a loss of function of the translational repressor FMRP. In this issue of Science Signaling, Kashima et al find that FMRP binds to and represses a specific isoform of BMPR2, a type II bone morphogenetic protein (BMP) receptor. Reducing signaling through this BMP pathway reverses neuroanatomical defects observed in fragile X models.
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3. Christianto A, Katayama S, Kameshita I, Inazu T. {{A Novel CDKL5 mutation in a Japanese patient with atypical Rett syndrome}}. {Clin Chim Acta};2016 (Jun 2)
Rett syndrome (RTT) is a severe X-linked dominant inheritance disorder with a wide spectrum of clinical manifestations. Mutations in Methyl CpG binding protein 2 (MECP2), Cyclin dependent kinase-like 5 (CDKL5) and Forkhead box G1 (FOXG1) have been associated with classic and/or variant RTT. This study was conducted to identify the responsible gene(s) in atypical RTT patient, and to examine the effect of the mutation on protein function. DNA sequence analysis showed a novel heterozygous mutation in CDKL5 identified as c.530A>G which resulted in an amino acid substitution at position 177, from tyrosine to cysteine. Genotyping analysis indicated that the mutation was not merely a single nucleotide polymorphism (SNP). We also revealed that patient’s blood lymphocytes had random X-chromosome inactivation (XCI) pattern. Further examination by bioinformatics analysis demonstrated the mutation caused damage or deleterious in its protein. In addition, we demonstrated in vitro kinase assay of mutant protein showed impairment of its activity. Taken together, the results suggested the mutant CDKL5 was responsible for the disease.
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4. Kashima R, Roy S, Ascano M, Martinez-Cerdeno V, Ariza-Torres J, Kim S, Louie J, Lu Y, Leyton P, Bloch KD, Kornberg TB, Hagerman PJ, Hagerman R, Lagna G, Hata A. {{Augmented noncanonical BMP type II receptor signaling mediates the synaptic abnormality of fragile X syndrome}}. {Sci Signal};2016;9(431):ra58.
Epigenetic silencing of fragile X mental retardation 1 (FMR1) causes fragile X syndrome (FXS), a common inherited form of intellectual disability and autism. FXS correlates with abnormal synapse and dendritic spine development, but the molecular link between the absence of the FMR1 product FMRP, an RNA binding protein, and the neuropathology is unclear. We found that the messenger RNA encoding bone morphogenetic protein type II receptor (BMPR2) is a target of FMRP. Depletion of FMRP increased BMPR2 abundance, especially that of the full-length isoform that bound and activated LIM domain kinase 1 (LIMK1), a component of the noncanonical BMP signal transduction pathway that stimulates actin reorganization to promote neurite outgrowth and synapse formation. Heterozygosity for BMPR2 rescued the morphological abnormalities in neurons both in Drosophila and in mouse models of FXS, as did the postnatal pharmacological inhibition of LIMK1 activity. Compared with postmortem prefrontal cortex tissue from healthy subjects, the amount of full-length BMPR2 and of a marker of LIMK1 activity was increased in this brain region from FXS patients. These findings suggest that increased BMPR2 signal transduction is linked to FXS and that the BMPR2-LIMK1 pathway is a putative therapeutic target in patients with FXS and possibly other forms of autism.
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5. Malyar NL, Maximova EV, Talis VL. {{[Kinematics of Stair Ascent in Children and Adolescents with Autism Spectrum Disorder]}}. {Zh Vyssh Nerv Deiat Im I P Pavlova};2016 (Jan-Feb);66(1):62-73.
We analyzed kinematics of stair ascent and descent in autistic children and adolescents in comparison with age-matched healthy children and adolescents. Eight healthy adolescents, 6 autistic adolescents, 7 healthy children and 6 autistic children participated in the study. We found that autistic subjects of both groups showed significantly more fluctuations of hip joint angular velocity than age-matched control subjects while preparing for stair ascent. During preparation for stair descent these velocity fluctuations appeared mainly in autistic adolescents, moreover, autistic children exhibited less velocity fluctuations than children in control group while preparing for stair descent. The kinematics of the movement itself demonstrated significantly less hip abduction in both autistic children and adolescents than in age-matched controls during stair ascent, and less ankle joint plantar extension in autistic adolescents than in healthy adolescents during stair descent. We suppose that age-related changes in kinematics of leg motion during stair ascent and descent in autistic patients indicate aggravated motor coordination in autistic adolescents as compared with both healthy adolescents and autistic children.
6. Newbutt N, Sung C, Kuo HJ, Leahy MJ, Lin CC, Tong B. {{Brief Report: A Pilot Study of the Use of a Virtual Reality Headset in Autism Populations}}. {J Autism Dev Disord};2016 (Jun 7)
The application of virtual reality technologies (VRTs) for users with autism spectrum disorder (ASD) has been studied for decades. However, a gap remains in our understanding surrounding VRT head-mounted displays (HMDs). As newly designed HMDs have become commercially available (in this study the Oculus Rift) the need to investigate newer devices is immediate. This study explored willingness, acceptance, sense of presence and immersion of ASD participants. Results revealed that all 29 participants (mean age = 32; 33 % with IQ < 70) were willing to wear the HMD. The majority of the participants reported an enjoyable experience, high levels of 'presence', and were likely to use HMDs again. IQ was found to be independent of the willingness to use HMDs and related VRT immersion experience. Lien vers le texte intégral (Open Access ou abonnement)
7. Willyard C. {{New efforts to design better tools to track autism therapy response}}. {Nat Med};2016 (Jun 7);22(6):570-571.
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8. Xing J, Kimura H, Wang C, Ishizuka K, Kushima I, Arioka Y, Yoshimi A, Nakamura Y, Shiino T, Oya-Ito T, Takasaki Y, Uno Y, Okada T, Iidaka T, Aleksic B, Mori D, Ozaki N. {{Resequencing and Association Analysis of Six PSD-95-Related Genes as Possible Susceptibility Genes for Schizophrenia and Autism Spectrum Disorders}}. {Sci Rep};2016;6:27491.
PSD-95 associated PSD proteins play a critical role in regulating the density and activity of glutamate receptors. Numerous previous studies have shown an association between the genes that encode these proteins and schizophrenia (SZ) and autism spectrum disorders (ASD), which share a substantial portion of genetic risks. We sequenced the protein-encoding regions of DLG1, DLG2, DLG4, DLGAP1, DLGAP2, and SynGAP in 562 cases (370 SZ and 192 ASD patients) on the Ion PGM platform. We detected 26 rare (minor allele frequency <1%), non-synonymous mutations, and conducted silico functional analysis and pedigree analysis when possible. Three variants, G344R in DLG1, G241S in DLG4, and R604C in DLGAP2, were selected for association analysis in an independent sample set of 1315 SZ patients, 382 ASD patients, and 1793 healthy controls. Neither DLG4-G241S nor DLGAP2-R604C was detected in any samples in case or control sets, whereas one additional SZ patient was found that carried DLG1-G344R. Our results suggest that rare missense mutations in the candidate PSD genes may increase susceptibility to SZ and/or ASD. These findings may strengthen the theory that rare, non-synonymous variants confer substantial genetic risks for these disorders. Lien vers le texte intégral (Open Access ou abonnement)
