1. Coffee RL, Jr., Williamson AJ, Adkins CM, Gray MC, Page TL, Broadie K. {{In vivo neuronal function of the fragile X mental retardation protein is regulated by phosphorylation}}. {Hum Mol Genet};2012 (Feb 15);21(4):900-915.
Fragile X syndrome (FXS), caused by loss of the Fragile X Mental Retardation 1 (FMR1) gene product (FMRP), is the most common heritable cause of intellectual disability and autism spectrum disorders. It has been long hypothesized that the phosphorylation of serine 500 (S500) in human FMRP controls its function as an RNA-binding translational repressor. To test this hypothesis in vivo, we employed neuronally targeted expression of three human FMR1 transgenes, including wild-type (hFMR1), dephosphomimetic (S500A-hFMR1) and phosphomimetic (S500D-hFMR1), in the Drosophila FXS disease model to investigate phosphorylation requirements. At the molecular level, dfmr1 null mutants exhibit elevated brain protein levels due to loss of translational repressor activity. This defect is rescued for an individual target protein and across the population of brain proteins by the phosphomimetic, whereas the dephosphomimetic phenocopies the null condition. At the cellular level, dfmr1 null synapse architecture exhibits increased area, branching and bouton number. The phosphomimetic fully rescues these synaptogenesis defects, whereas the dephosphomimetic provides no rescue. The presence of Futsch-positive (microtubule-associated protein 1B) supernumerary microtubule loops is elevated in dfmr1 null synapses. The human phosphomimetic restores normal Futsch loops, whereas the dephosphomimetic provides no activity. At the behavioral level, dfmr1 null mutants exhibit strongly impaired olfactory associative learning. The human phosphomimetic targeted only to the brain-learning center restores normal learning ability, whereas the dephosphomimetic provides absolutely no rescue. We conclude that human FMRP S500 phosphorylation is necessary for its in vivo function as a neuronal translational repressor and regulator of synaptic architecture, and for the manifestation of FMRP-dependent learning behavior.
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2. Motil KJ, Caeg E, Barrish JO, Geerts S, Lane JB, Percy AK, Annese F, McNair L, Skinner SA, Lee HS, Neul JL, Glaze DG. {{Gastrointestinal And Nutritional Problems Occur Frequently Throughout Life In Girls And Women With Rett Syndrome}}. {J Pediatr Gastroenterol Nutr};2012 (Feb 10)
OBJECTIVE:: We conducted a nationwide survey to determine the prevalence of common gastrointestinal and nutritional disorders in Rett syndrome (RTT) based on parental reporting and related the occurrence of these problems to age and methyl-CpG-binding protein 2 (MECP2) status. METHODS:: We designed a questionnaire that probed symptoms, diagnoses, diagnostic tests, and treatment interventions related to gastrointestinal and nutritional problems in RTT. The International Rett Syndrome Foundation distributed the questionnaire to 1666 family-based members and forwarded their responses for our review. We interrogated the Rare Disease Clinical Research Network database to supplement findings related to medications used to treat gastrointestinal problems in RTT. RESULTS:: Parents of 983 RTT females (59%) responded and identified symptoms and diagnoses associated with gastrointestinal dysmotility (92%); chewing and swallowing difficulties (81%); weight deficits or excess (47%); growth deficits (45%); low bone mineral content or fractures (37%); biliary tract disorders (3%). Height, weight, and BMI z-scores decreased significantly with age; height and weight, but not BMI, z-scores were significantly lower in females with MECP2 mutations than those without. Vomiting, nighttime awakening, gastroesophageal reflux, chewing difficulty, and choking with feeding were significantly less likely to occur with increasing age. Short stature, low bone mineral content, fractures, and gastrostomy placement were significantly more likely to occur with increasing age. Chewing difficulty, choking with feeding, and nighttime awakening were significantly less likely to occur, whereas short stature was significantly more likely to occur, in females with MECP2 mutations than those without. Diagnostic evaluations and therapeutic interventions were utilized less frequently than the occurrence of symptoms or diagnoses in the RTT cohort. CONCLUSION:: Gastrointestinal and nutritional problems perceived by parents are prevalent throughout life in girls and women with RTT and may pose a substantial medical burden for their caregivers. Physician awareness of these features of RTT may improve the health and quality of life of individuals affected with this disorder.
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3. Pooni J, Ninteman A, Bryant-Waugh R, Nicholls D, Mandy W. {{Investigating autism spectrum disorder and autistic traits in early onset eating disorder}}. {Int J Eat Disord};2012 (Feb 13)
OBJECTIVE: To investigate whether young people (8-16 years) with an eating disorder have a higher prevalence of autism spectrum disorder (ASDs) and elevated autistic traits compared to typically developing (TD) peers. METHOD: Twenty-two participants with early onset eating disorder (EOED) were assessed using standardized ASD measures and compared to IQ matched TD (n = 24) and ASD (n = 20) controls. RESULTS: An ASD diagnosis was no more common in EOED than in TD controls. However, repetitive and stereotyped behavior was more often observed in the EOED group and, compared to TD controls, there was a trend (p = .07) toward greater autistic social impairment in EOED. DISCUSSION: Whilst participants with EOED did not show increased ASD prevalence, they did have elevated autistic traits of clinical significance, particularly repetitive and stereotyped behavior. Further work is required to determine whether inflexibility and social difficulties in EOED have identical phenomenology and etiology to those seen in ASD. (c) 2012 by Wiley Periodicals, Inc.
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4. Putnam SK, Lopata C, Fox JD, Thomeer ML, Rodgers JD, Volker MA, Lee GK, Neilans EG, Werth J. {{Comparison of Saliva Collection Methods in Children with High-Functioning Autism Spectrum Disorders: Acceptability and Recovery of Cortisol}}. {Child Psychiatry Hum Dev};2012 (Feb 14)
This study compared cortisol concentrations yielded using three saliva collection methods (passive drool, salivette, and sorbette) in both in vitro and in vivo conditions, as well as method acceptability for a sample of children (n = 39) with High Functioning Autism Spectrum Disorders. No cortisol concentration differences were observed between passive and sorbette samples obtained in vitro or in vivo. The salivette derived concentration was lower than the other two methods for the in vitro derived comparisons but did not differ from the other methods when collected in vivo. Cross-day comparison for the salivettes was also found to differ significantly, whereas the cross-day comparisons did not differ for the passive method or the sorbette method. Overall, passive drool and sorbettes were found to produce similar and stable readings of cortisol, whereas the salivette yielded unstable and variable concentrations. Ratings suggested that the children generally perceived all methods as acceptable.
