Asunto(s)
Trastorno del Espectro Autista , Síndrome del Cromosoma X Frágil , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/genética , Niño , Pruebas Diagnósticas de Rutina , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/diagnóstico , Síndrome del Cromosoma X Frágil/genética , HumanosRESUMEN
Here, we describe a female patient with autism spectrum disorder and dysmorphic features that harbors a complex genetic alteration, involving a de novo balanced translocation t(2;X)(q11;q24), a 5q11 segmental trisomy and a maternally inherited isodisomy on chromosome 5. All the possibly damaging genetic effects of such alterations are discussed. In light of recent findings on ASD genetic causes, the hypothesis that all these alterations might be acting in orchestration and contributing to the phenotype is also considered.
Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/genética , Aberraciones Cromosómicas , Cromosomas Humanos/genética , Reordenamiento Génico/genética , Adulto , Niño , Cromosomas Humanos Par 2/genética , Cromosomas Humanos Par 5/genética , Cromosomas Humanos X/genética , Femenino , Estudios de Asociación Genética , Humanos , Recién Nacido , Masculino , Embarazo , Translocación Genética , Trisomía , Disomía Uniparental/genéticaRESUMEN
Several lines of indirect evidence, such as mutations or dysregulated expression of genes related to cytoskeleton, have suggested that cytoskeletal dynamics, a process essential for axons and dendrites development, is compromised in autism spectrum disorders (ASD). However, no study has yet examined whether cytoskeleton dynamics is functionally altered in cells from ASD patients. Here we investigated the regulation of actin cytoskeleton dynamics in stem cells from human exfoliated deciduous teeth (SHEDs) of 13 ASD patients and 8 control individuals by inducing actin filament depolymerization and then measuing their reconstruction upon activation of the RhoGTPases Rac, Cdc42 or RhoA. We observed that stem cells from seven ASD individuals (53%) presented altered dymanics of filament reconstruction, including a patient recently studied by our group whose iPSC-derived neuronal cells show shorten and less arborized neurites. We also report potentially pathogenic genetic variants that might be related to the alterations in actin repolymerization dynamics observed in some patient-derived cells. Our results suggest that, at least for a subgroup of ASD patients, the dynamics of actin polymerization is impaired, which might be ultimately leading to neuronal abnormalities.
Asunto(s)
Citoesqueleto de Actina/química , Actinas/química , Trastorno del Espectro Autista/genética , Neuronas/química , Citoesqueleto de Actina/genética , Actinas/genética , Animales , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/patología , Regulación de la Expresión Génica/genética , Humanos , Células Madre Pluripotentes Inducidas/química , Células Madre Pluripotentes Inducidas/metabolismo , Neuronas/metabolismo , Neuronas/patología , Exfoliación Dental , Proteína de Unión al GTP cdc42/genética , Proteínas de Unión al GTP rac/genética , Proteína de Unión al GTP rhoA/genéticaRESUMEN
Copy number variations (CNVs) are an important cause of ASD and those located at 15q11-q13, 16p11.2 and 22q13 have been reported as the most frequent. These CNVs exhibit variable clinical expressivity and those at 15q11-q13 and 16p11.2 also show incomplete penetrance. In the present work, through multiplex ligation-dependent probe amplification (MLPA) analysis of 531 ethnically admixed ASD-affected Brazilian individuals, we found that the combined prevalence of the 15q11-q13, 16p11.2 and 22q13 CNVs is 2.1% (11/531). Parental origin could be determined in 8 of the affected individuals, and revealed that 4 of the CNVs represent de novo events. Based on CNV prediction analysis from genome-wide SNP arrays, the size of those CNVs ranged from 206 kb to 2.27 Mb and those at 15q11-q13 were limited to the 15q13.3 region. In addition, this analysis also revealed 6 additional CNVs in 5 out of 11 affected individuals. Finally, we observed that the combined prevalence of CNVs at 15q13.3 and 22q13 in ASD-affected individuals with epilepsy (6.4%) was higher than that in ASD-affected individuals without epilepsy (1.3%; p<0.014). Therefore, our data show that the prevalence of CNVs at 15q13.3, 16p11.2 and 22q13 in Brazilian ASD-affected individuals is comparable to that estimated for ASD-affected individuals of pure or predominant European ancestry. Also, it suggests that the likelihood of a greater number of positive MLPA results might be found for the 15q13.3 and 22q13 regions by prioritizing ASD-affected individuals with epilepsy.
Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/complicaciones , Trastornos Generalizados del Desarrollo Infantil/genética , Cromosomas Humanos/genética , Variaciones en el Número de Copia de ADN , Epilepsia/complicaciones , Adolescente , Secuencia de Bases , Brasil , Niño , Cromosomas Humanos Par 15/genética , Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 22/genética , Femenino , Genómica , Humanos , Masculino , Linaje , Polimorfismo de Nucleótido SimpleRESUMEN
Identification of the causes of autism spectrum disorders (ASDs) is hampered by their genetic heterogeneity; however, the different genetic alterations leading to ASD seem to be implicated in the disturbance of common molecular pathways or biological processes. In this scenario, the search for differentially expressed genes (DEGs) between ASD patients and controls is a good alternative to identify the molecular etiology of such disorders. Here, we employed genome-wide expression analysis to compare the transcriptome of stem cells of human exfoliated deciduous teeth (SHEDs) of idiopathic autistic patients (n = 7) and control samples (n = 6). Nearly half of the 683 identified DEGs are expressed in the brain (P = 0.003), and a significant number of them are involved in mechanisms previously associated with ASD such as protein synthesis, cytoskeleton regulation, cellular adhesion and alternative splicing, which validate the use of SHEDs to disentangle the causes of autism. Autistic patients also presented overexpression of genes regulated by androgen receptor (AR), and AR itself, which in turn interacts with CHD8 (chromodomain helicase DNA binding protein 8), a gene recently shown to be associated with the cause of autism and found to be upregulated in some patients tested here. These data provide a rationale for the mechanisms through which CHD8 leads to these diseases. In summary, our results suggest that ASD share deregulated pathways and revealed that SHEDs represent an alternative cell source to be used in the understanding of the biological mechanisms involved in the etiology of ASD.
Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/genética , Pulpa Dental/citología , Perfilación de la Expresión Génica , Estudios de Asociación Genética , Estudio de Asociación del Genoma Completo , Células Madre/fisiología , Transcriptoma/genética , Empalme Alternativo/genética , Adhesión Celular/genética , Niño , Citoesqueleto/genética , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad/genética , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Biosíntesis de Proteínas/genética , Factores de Transcripción/genéticaRESUMEN
UNLABELLED: The aim of this study was to verify the efficacy of a programme for dental plaque control in autistics. Patients were evaluated on five occasions over a period of 180 days using the following instruments: OHI-S, DMF-T, the Fonnes brushing technique and diet questionnaire. Participants were divided into two groups according to level of co-operation on the programme: Group A (co-operative) and Group B (non-cooperative). A statistically significant improvement (p < 0.001) in Oral Hygiene was attained, with 84.2% showing regular or satisfactory hygiene at study end-point. CONCLUSION: Groups A and B both showed improvement in hygiene (p < 0.001 and p = 0.004), but improvement was significantly higher among co-operative patients (p < 0.001 at 180 days), who also had a higher mean age (p = 0.02).