Pubmed du 07/07/15

Pubmed du jour

2015-07-07 12:03:50

1. Ander BP, Barger N, Stamova B, Sharp FR, Schumann CM. {{Atypical miRNA expression in temporal cortex associated with dysregulation of immune, cell cycle, and other pathways in autism spectrum disorders}}. {Mol Autism};2015;6:37.

BACKGROUND: Autism spectrum disorders (ASDs) likely involve dysregulation of multiple genes related to brain function and development. Abnormalities in individual regulatory small non-coding RNA (sncRNA), including microRNA (miRNA), could have profound effects upon multiple functional pathways. We assessed whether a brain region associated with core social impairments in ASD, the superior temporal sulcus (STS), would evidence greater transcriptional dysregulation of sncRNA than adjacent, yet functionally distinct, primary auditory cortex (PAC). METHODS: We measured sncRNA expression levels in 34 samples of postmortem brain from STS and PAC to find differentially expressed sncRNA in ASD compared with control cases. For differentially expressed miRNA, we further analyzed their predicted mRNA targets and carried out functional over-representation analysis of KEGG pathways to examine their functional significance and to compare our findings to reported alterations in ASD gene expression. RESULTS: Two mature miRNAs (miR-4753-5p and miR-1) were differentially expressed in ASD relative to control in STS and four (miR-664-3p, miR-4709-3p, miR-4742-3p, and miR-297) in PAC. In both regions, miRNA were functionally related to various nervous system, cell cycle, and canonical signaling pathways, including PI3K-Akt signaling, previously implicated in ASD. Immune pathways were only disrupted in STS. snoRNA and pre-miRNA were also differentially expressed in ASD brain. CONCLUSIONS: Alterations in sncRNA may underlie dysregulation of molecular pathways implicated in autism. sncRNA transcriptional abnormalities in ASD were apparent in STS and in PAC, a brain region not directly associated with core behavioral impairments. Disruption of miRNA in immune pathways, frequently implicated in ASD, was unique to STS.

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2. Demopoulos C, Brandes-Aitken AN, Desai SS, Hill SS, Antovich AD, Harris J, Marco EJ. {{Shared and Divergent Auditory and Tactile Processing in Children with Autism and Children with Sensory Processing Dysfunction Relative to Typically Developing Peers}}. {J Int Neuropsychol Soc};2015 (Jul 6):1-11.

The aim of this study was to compare sensory processing in typically developing children (TDC), children with Autism Spectrum Disorder (ASD), and those with sensory processing dysfunction (SPD) in the absence of an ASD. Performance-based measures of auditory and tactile processing were compared between male children ages 8-12 years assigned to an ASD (N=20), SPD (N=15), or TDC group (N=19). Both the SPD and ASD groups were impaired relative to the TDC group on a performance-based measure of tactile processing (right-handed graphesthesia). In contrast, only the ASD group showed significant impairment on an auditory processing index assessing dichotic listening, temporal patterning, and auditory discrimination. Furthermore, this impaired auditory processing was associated with parent-rated communication skills for both the ASD group and the combined study sample. No significant group differences were detected on measures of left-handed graphesthesia, tactile sensitivity, or form discrimination; however, more participants in the SPD group demonstrated a higher tactile detection threshold (60%) compared to the TDC (26.7%) and ASD groups (35%). This study provides support for use of performance-based measures in the assessment of children with ASD and SPD and highlights the need to better understand how sensory processing affects the higher order cognitive abilities associated with ASD, such as verbal and non-verbal communication, regardless of diagnostic classification. (JINS, 2015, 21, 1-11).

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3. Heffler KF, Oestreicher LM. {{Causation model of autism: Audiovisual brain specialization in infancy competes with social brain networks}}. {Med Hypotheses};2015 (Jun 27)
Earliest identifiable findings in autism indicate that the autistic brain develops differently from the typical brain in the first year of life, after a period of typical development. Twin studies suggest that autism has an environmental component contributing to causation. Increased availability of audiovisual (AV) materials and viewing practices of infants parallel the time frame of the rise in prevalence of autism spectrum disorder (ASD). Studies have shown an association between ASD and increased TV/cable screen exposure in infancy, suggesting AV exposure in infancy as a possible contributing cause of ASD. Infants are attracted to the saliency of AV materials, yet do not have the experience to recognize these stimuli as socially relevant. The authors present a developmental model of autism in which exposure to screen-based AV input in genetically susceptible infants stimulates specialization of non-social sensory processing in the brain. Through a process of neuroplasticity, the autistic infant develops the skills that are driven by the AV viewing. The AV developed neuronal pathways compete with preference for social processing, negatively affecting development of social brain pathways and causing global developmental delay. This model explains atypical face and speech processing, as well as preference for AV synchrony over biological motion in ASD. Neural hyper-connectivity, enlarged brain size and special abilities in visual, auditory and motion processing in ASD are also explained by the model. Positive effects of early intervention are predicted by the model. Researchers studying causation of autism have largely overlooked AV exposure in infancy as a potential contributing factor. The authors call for increased public awareness of the association between early screen viewing and ASD, and a concerted research effort to determine the extent of causal relationship.

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4. Hranilovic D, Blazevic S, Stefulj J, Zill P. {{DNA Methylation Analysis of HTR2A Regulatory Region in Leukocytes of Autistic Subjects}}. {Autism Res};2015 (Jul 7)
Disturbed brain and peripheral serotonin homeostasis is often found in subjects with autism spectrum disorder (ASD). The role of the serotonin receptor 2A (HTR2A) in the regulation of central and peripheral serotonin homeostasis, as well as its altered expression in autistic subjects, have implicated the HTR2A gene as a major candidate for the serotonin disturbance seen in autism. Several studies, yielding so far inconclusive results, have attempted to associate autism with a functional SNP -1438 G/A (rs6311) in the HTR2A promoter region, while possible contribution of epigenetic mechanisms, such as DNA methylation, to HTR2A dysregulation in autism has not yet been investigated. In this study, we compared the mean DNA methylation within the regulatory region of the HTR2A gene between autistic and control subjects. DNA methylation was analysed in peripheral blood leukocytes using bisulfite conversion and sequencing of the HTR2A region containing rs6311 polymorphism. Autistic subjects of rs6311 AG genotype displayed higher mean methylation levels within the analysed region than the corresponding controls (P < 0.05), while there was no statistically significant difference for AA and GG carriers. Our study provides preliminary evidence for increased HTR2A promoter methylation in leukocytes of a portion of adult autistic subjects, indicating that epigenetic mechanisms might contribute to HTR2A dysregulation observed in individuals with ASD. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.

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5. Kuijper SJ, Hartman CA, Hendriks P. {{Who Is He? Children with ASD and ADHD Take the Listener into Account in Their Production of Ambiguous Pronouns}}. {PLoS One};2015;10(7):e0132408.

During conversation, speakers constantly make choices about how specific they wish to be in their use of referring expressions. In the present study we investigate whether speakers take the listener into account or whether they base their referential choices solely on their own representation of the discourse. We do this by examining the cognitive mechanisms that underlie the choice of referring expression at different discourse moments. Furthermore, we provide insights into how children with Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD) use referring expressions and whether their use differs from that of typically developing (TD) children. Children between 6 and 12 years old (ASD: n=46; ADHD: n=37; TD: n=38) were tested on their production of referring expressions and on Theory of Mind, response inhibition and working memory. We found support for the view that speakers take the listener into account when choosing a referring expression: Theory of Mind was related to referential choice only at those moments when speakers could not solely base their choice on their own discourse representation to be understood. Working memory appeared to be involved in keeping track of the different referents in the discourse. Furthermore, we found that TD children as well as children with ASD and children with ADHD took the listener into account in their choice of referring expression. In addition, children with ADHD were less specific than TD children in contexts with more than one referent. The previously observed problems with referential choice in children with ASD may lie in difficulties in keeping track of longer and more complex discourses, rather than in problems with taking into account the listener.

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6. Lalanne L, Weiner L, Trojak B, Berna F, Bertschy G. {{Substance-use disorder in high-functioning autism: clinical and neurocognitive insights from two case reports}}. {BMC Psychiatry};2015;15:149.

BACKGROUND: Low prevalence of substance-use disorder has been reported in adults with autism. However, on a superficial level, adults with high-functioning autism (HFA) display a ‘normal’ facade when they drink alcohol, which may explain why their alcohol dependency is not better diagnosed. CASE PRESENTATION: Here, we report two cases of HFA adults who use alcohol and psychostimulants to cope with their anxiety and improve their cognitive abilities and social skills. We analyze how neurocognitive traits associated with HFA may be potential triggers for substance-use disorder. CONCLUSION: Better identification of autism and its cognitive impairments, which may be vulnerability traits for developing substance-use disorders, could help improve the diagnosis and treatment of substance-use disorders among this population.

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7. Luckhardt C, Jarczok TA, Bender S. {{Erratum to: Elucidating the neurophysiological underpinnings of autism spectrum disorder: new developments}}. {J Neural Transm};2015 (Jul 7)

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8. Peiker I, Schneider TR, Milne E, Schottle D, Vogeley K, Munchau A, Schunke O, Siegel M, Engel AK, David N. {{Stronger Neural Modulation by Visual Motion Intensity in Autism Spectrum Disorders}}. {PLoS One};2015;10(7):e0132531.

Theories of autism spectrum disorders (ASD) have focused on altered perceptual integration of sensory features as a possible core deficit. Yet, there is little understanding of the neuronal processing of elementary sensory features in ASD. For typically developed individuals, we previously established a direct link between frequency-specific neural activity and the intensity of a specific sensory feature: Gamma-band activity in the visual cortex increased approximately linearly with the strength of visual motion. Using magnetoencephalography (MEG), we investigated whether in individuals with ASD neural activity reflect the coherence, and thus intensity, of visual motion in a similar fashion. Thirteen adult participants with ASD and 14 control participants performed a motion direction discrimination task with increasing levels of motion coherence. A polynomial regression analysis revealed that gamma-band power increased significantly stronger with motion coherence in ASD compared to controls, suggesting excessive visual activation with increasing stimulus intensity originating from motion-responsive visual areas V3, V6 and hMT/V5. Enhanced neural responses with increasing stimulus intensity suggest an enhanced response gain in ASD. Response gain is controlled by excitatory-inhibitory interactions, which also drive high-frequency oscillations in the gamma-band. Thus, our data suggest that a disturbed excitatory-inhibitory balance underlies enhanced neural responses to coherent motion in ASD.

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9. Pusponegoro HD, Ismael S, Firmansyah A, Sastroasmoro S, Vandenplas Y. {{Gluten and casein supplementation does not increase symptoms in children with autism spectrum disorder}}. {Acta Paediatr};2015 (Jul 4)
AIM: A gluten and casein-free diet is often given to children with autism spectrum disorders (ASD). We aimed to determine the effect of gluten and casein supplementation on maladaptive behaviour, gastrointestinal symptom severity and intestinal fatty acids binding protein (I-FABP) excretion in children with ASD. METHODS: A randomised, controlled, double-blind trial was performed on 74 children with ASD with severe maladaptive behaviour and increased urinary I-FABP. Subjects were randomised to receive gluten-casein or a placebo for seven days. We evaluated maladaptive behaviour before and after supplementation, using I-FABP excretion, the approach withdrawal problem composite subtest of the Pervasive Developmental Disorder Behavior Inventory and the Gastrointestinal Symptom Severity Index. RESULTS: The mean approach withdrawal problem composite score was significantly higher before supplementation than after, both in the placebo and in the gluten-casein group. However, the mean difference was not significant and may have been caused by additional therapy. There was no significant difference in gastrointestinal symptoms and urinary I-FABP excretion. CONCLUSION: Administrating gluten-casein to children with ASD for one week did not increase maladaptive behaviour, gastrointestinal symptom severity or urinary I-FABP excretion. The effect of prolonged administration or other mechanisms of enterocyte damage in ASD should be explored. This article is protected by copyright. All rights reserved.

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10. Rane P, Cochran D, Hodge SM, Haselgrove C, Kennedy DN, Frazier JA. {{Connectivity in Autism: A Review of MRI Connectivity Studies}}. {Harv Rev Psychiatry};2015 (Jul-Aug);23(4):223-244.

LEARNING OBJECTIVE: After participating in this activity, learners should be better able to:Assess the resting state and diffusion tensor imaging connectivity literature regarding subjects with autism spectrum disorder. ABSTRACT: Autism spectrum disorder (ASD) affects 1 in 50 children between the ages of 6 and 17 years. The etiology of ASD is not precisely known. ASD is an umbrella term, which includes both low- (IQ < 70) and high-functioning (IQ > 70) individuals. A better understanding of the disorder and how it manifests in individual subjects can lead to more effective intervention plans to fulfill the individual’s treatment needs.Magnetic resonance imaging (MRI) is a non-invasive investigational tool that can be used to study the ways in which the brain develops or deviates from the typical developmental trajectory. MRI offers insights into the structure, function, and metabolism of the brain. In this article, we review published studies on brain connectivity changes in ASD using either resting state functional MRI or diffusion tensor imaging.The general findings of decreases in white matter integrity and in long-range neural coherence are well known in the ASD literature. Nevertheless, the detailed localization of these findings remains uncertain, and few studies link these changes in connectivity with the behavioral phenotype of the disorder. With the help of data sharing and large-scale analytic efforts, however, the field is advancing toward several convergent themes, including the reduced functional coherence of long-range intra-hemispheric cortico-cortical default mode circuitry, impaired inter-hemispheric regulation, and an associated, perhaps compensatory, increase in local and short-range cortico-subcortical coherence.

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11. Rosenbloom R, Mason RA, Wills HP, Mason BA. {{Technology Delivered Self-Monitoring Application to Promote Successful Inclusion of an Elementary Student with Autism}}. {Assist Technol};2015 (Jul 7)
The ever-increasing prevalence of children diagnosed with autism spectrum disorder (ASD) is paralleled in public educational settings including general education classrooms. Challenges with social/behavioral functioning, including limited self-management and behavior inhibition, can lead to off-task and disruptive behaviors that interfere with acquisition of academic and social skills. Without effective and efficient interventions, opportunities to participate in inclusive settings will likely be reduced. Self-monitoring (SM) is an intervention with strong evidence for increasing prosocial behaviors and decreasing challenging behaviors for students with ASD in educational settings, although the cuing mechanisms (e.g. timers, stopwatch) and tracking materials (e.g. paper, pencil) can be cumbersome and obtrusive. I-Connect is an SM application that allows for customizable prompts, recording, and data monitoring. The purpose of this study was to evaluate, utilizing an ABAB design, the functional relationship between implementation of I-Connect SM intervention and increases in on-task behavior with concurrent decreases in disruptive behavior for an elementary student with ASD in a general education classroom. Results indicate an immediate increase in on-task behavior as well as a decrease in disruptive behaviors with each introduction of I-Connect. Implications for practice and future research are discussed.

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12. Rozenkrantz L, Zachor D, Heller I, Plotkin A, Weissbrod A, Snitz K, Secundo L, Sobel N. {{A Mechanistic Link between Olfaction and Autism Spectrum Disorder}}. {Curr Biol};2015 (Jul 1)
Internal action models (IAMs) are brain templates for sensory-motor coordination underlying diverse behaviors [1]. An emerging theory suggests that impaired IAMs are a common theme in autism spectrum disorder (ASD) [2-4]. However, whether impaired IAMs occur across sensory systems and how they relate to the major phenotype of ASD, namely impaired social communication [5], remains unclear. Olfaction relies on an IAM known as the sniff response, where sniff magnitude is automatically modulated to account for odor valence [6-12]. To test the failed IAM theory in olfaction, we precisely measured the non-verbal non-task-dependent sniff response concurrent with pleasant and unpleasant odors in 36 children-18 with ASD and 18 matched typically developing (TD) controls. We found that whereas TD children generated a typical adult-like sniff response within 305 ms of odor onset, ASD children had a profoundly altered sniff response, sniffing equally regardless of odor valance. This difference persisted despite equal reported odor perception and allowed for 81% correct ASD classification based on the sniff response alone (binomial, p < 0.001). Moreover, increasingly aberrant sniffing was associated with increasingly severe ASD (r = -0.75, p < 0.001), specifically with social (r = -0.72, p < 0.001), but not motor (r < -0.38, p > 0.18), impairment. These results uncover a novel ASD marker implying a mechanistic link between the underpinnings of olfaction and ASD and directly linking an impaired IAM with impaired social abilities.

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13. Rubenstein E, Wiggins LD, Lee LC. {{A Review of the Differences in Developmental, Psychiatric, and Medical Endophenotypes Between Males and Females with Autism Spectrum Disorder}}. {J Dev Phys Disabil};2015 (Feb);27(1):119-139.

Autism spectrum disorder (ASD) is over four times more prevalent in males compared to females. Increased understanding of sex differences in ASD endophenotypes could add insight into possible etiologies and the assessment and management of the disorder. Consequently, the purpose of this review is to describe current literature regarding sex differences in the developmental, psychiatric, and medical endophenotypes of ASD in order to illustrate current knowledge and areas in need of further research. Our review found that repetitive behaviors and restricted interests are more common in males than females with ASD. Intellectual disability is more common in females than males with ASD. Attention to detail may be more common in males than females with ASD and epilepsy may be more common in females than males with ASD, although limited research in these areas prevent definitive conclusions from being drawn. There does not appear to be a sex difference in other developmental, psychiatric, and medical symptoms associated with ASD, or the research was contradictory or too sparse to establish a sex difference. Our review is unique in that it offers detailed discussion of sex differences in three major endophenotypes of ASD. Further research is needed to better understand why sex differences exist in certain ASD traits and to evaluate whether phenotypic sex differences are related to different pathways of development, assessment, and treatment of the disorder.

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14. Schaer M, Kochalka J, Padmanabhan A, Supekar K, Menon V. {{Sex differences in cortical volume and gyrification in autism}}. {Mol Autism};2015;6:42.

BACKGROUND: Male predominance is a prominent feature of autism spectrum disorders (ASD), with a reported male to female ratio of 4:1. Because of the overwhelming focus on males, little is known about the neuroanatomical basis of sex differences in ASD. Investigations of sex differences with adequate sample sizes are critical for improving our understanding of the biological mechanisms underlying ASD in females. METHODS: We leveraged the open-access autism brain imaging data exchange (ABIDE) dataset to obtain structural brain imaging data from 53 females with ASD, who were matched with equivalent samples of males with ASD, and their typically developing (TD) male and female peers. Brain images were processed with FreeSurfer to assess three key features of local cortical morphometry: volume, thickness, and gyrification. A whole-brain approach was used to identify significant effects of sex, diagnosis, and sex-by-diagnosis interaction, using a stringent threshold of p < 0.01 to control for false positives. Stability and power analyses were conducted to guide future research on sex differences in ASD. RESULTS: We detected a main effect of sex in the bilateral superior temporal cortex, driven by greater cortical volume in females compared to males in both the ASD and TD groups. Sex-by-diagnosis interaction was detected in the gyrification of the ventromedial/orbitofrontal prefrontal cortex (vmPFC/OFC). Post-hoc analyses revealed that sex-by-diagnosis interaction was driven by reduced vmPFC/OFC gyrification in males with ASD, compared to females with ASD as well as TD males and females. Finally, stability analyses demonstrated a dramatic drop in the likelihood of observing significant clusters as the sample size decreased, suggesting that previous studies have been largely underpowered. For instance, with a sample of 30 females with ASD (total n = 120), a significant sex-by-diagnosis interaction was only detected in 50 % of the simulated subsamples. CONCLUSIONS: Our results demonstrate that some features of typical sex differences are preserved in the brain of individuals with ASD, while others are not. Sex differences in ASD are associated with cortical regions involved in language and social function, two domains of deficits in the disorder. Stability analyses provide novel quantitative insights into why smaller samples may have previously failed to detect sex differences.

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15. Unwin LM, Maybery MT, Murphy A, Lilje W, Bellesini M, Hunt AM, Granich J, Jacoby P, Dissanayake C, Pennell CE, Hickey M, Whitehouse AJ. {{A Prospective Ultrasound Study of Prenatal Growth in Infant Siblings of Children With Autism}}. {Autism Res};2015 (Jul 7)
Numerous studies have observed that a proportion of infants later diagnosed with autism spectrum disorder (ASD) experience accelerated head growth during the first years of life. An emerging methodology for examining the developmental trajectory prior to a diagnosis of ASD is to investigate siblings of affected individuals. The current study is the first prospective investigation of fetal growth in siblings of children with ASD. Two groups of pregnant women were recruited as part of the PRegnancy Investigation of Siblings and Mothers of children with autism cohort in Perth, Western Australia. The « high risk » group (n = 23) comprised pregnant women who have an existing child with a diagnosis of ASD and the « low risk » group (n = 36) comprised pregnant mothers who have an existing child who has developed typically. Prenatal ultrasounds were procured at multiple time-points throughout the second- and third-trimesters, enabling an examination of growth trajectories. Growth measurements were then compared for the high- and low-risk fetuses. Mixed linear regression models identified no significant differences between the high- and low-risk fetuses in the rate of prenatal head and body growth throughout the second- and third-trimester (all P-values >0.05). Similarly, there were no significant differences observed when comparing high and low risk groups on a ratio of head circumference relative to body size (beta = -0.019, P = 0.75). Future studies may consider looking beyond the macro architecture of the prenatal brain and examine the growth of brain subregions that have been implicated in the presentation of ASD symptoms. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.

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16. Viana MC, Menezes AN, Moreira MA, Pissinatti A, Seuanez HN. {{MECP2, a gene associated with Rett syndrome in humans, shows conserved coding regions, independent Alu insertions, and a novel transcript across primate evolution}}. {BMC Genet};2015;16(1):77.

BACKGROUND: The methyl-CpG Binding Protein two gene (MECP2) encodes a multifunctional protein comprising two isoforms involved in nuclear organization and regulation of splicing and mRNA template activity. This gene is normally expressed in all tissues, with a higher expression level in the brain during neuronal maturation. Loss of MECP2 function is the primary cause of Rett syndrome (RTT) in humans, a dominant, X-linked disorder dramatically affecting neural and motor development. RESULTS: We investigated the molecular evolution of MECP2 in several primate taxa including 36 species in 16 genera of neotropical (platyrrhine) primates. The coding region of the MECP2_e2 isoform showed a high level of evolutionary conservation among humans and other primates, with amino acid substitutions in 14 codons and one in-frame insertion of a single serine codon, between codons 357 and 358, in Ateles paniscus. Most substitutions occurred in noncritical regions of MECP2 and the majority of the algorithms used for analyzing selection did not provide evidence of positive selection. Conversely, we found 48 sites under negative selection in different regions, 23 of which were consistently found by three different algorithms. Similar to an inverted Alu insert found previously in a lesser ape at a parallel location, one Alu insertion of approximately 300 bp in Cebus and Sapajus was found in intron 3. Phylogenetic reconstruction of the intron 3 data provided a topology that was coincident with the consensus arrangement of the primate taxa. RNAseq data in the neotropical primate Callimico goeldii revealed a novel transcript consisting of a noncontinuous region of the human-homologous intron 2 in this species; this transcript accounted for two putative polypeptides. CONCLUSIONS: Despite the remarkable evolutionary conservation of MECP2, one in-frame codon insertion was observed in A. paniscus, and one region of intron 3 was affected by a trans-specific Alu retrotransposition in two neotropical primate genera. Moreover, identification of novel MECP2 transcripts in Callimico suggests that part of a homologous human intronic region might be expressed, and that the potential open reading frame in this region might be a subject of interest in RTT patients who carry an apparently normal MECP2 sequence.

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