Pleiotropic effects of candidate genes on autism spectrum disorder and comorbidities: genetics, funcional studies and animal models

[eng] Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social communication and interaction, as well as repetitive and restricted patterns of behaviour. Although growing evidence supports a main contribution of genetic factors to its neurobiology and hu...

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Detalhes bibliográficos
Autor: Antón Galindo, Ester
Formato: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2021
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/184168
Acesso em linha:https://hdl.handle.net/2445/184168
http://hdl.handle.net/10803/673823
Access Level:acceso abierto
Palavra-chave:Autisme
Genètica mèdica
Neurociències
Anomalies cromosòmiques
Models animals en la investigació
Autism
Medical genetics
Neurosciences
Chromosome abnormalities
Animal models in research
id ES_09c7b99d3dec3d28b27d176ea4ac18f4
oai_identifier_str oai:diposit.ub.edu:2445/184168
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Pleiotropic effects of candidate genes on autism spectrum disorder and comorbidities: genetics, funcional studies and animal models
title Pleiotropic effects of candidate genes on autism spectrum disorder and comorbidities: genetics, funcional studies and animal models
spellingShingle Pleiotropic effects of candidate genes on autism spectrum disorder and comorbidities: genetics, funcional studies and animal models
Antón Galindo, Ester
Autisme
Genètica mèdica
Neurociències
Anomalies cromosòmiques
Models animals en la investigació
Autism
Medical genetics
Neurosciences
Chromosome abnormalities
Animal models in research
title_short Pleiotropic effects of candidate genes on autism spectrum disorder and comorbidities: genetics, funcional studies and animal models
title_full Pleiotropic effects of candidate genes on autism spectrum disorder and comorbidities: genetics, funcional studies and animal models
title_fullStr Pleiotropic effects of candidate genes on autism spectrum disorder and comorbidities: genetics, funcional studies and animal models
title_full_unstemmed Pleiotropic effects of candidate genes on autism spectrum disorder and comorbidities: genetics, funcional studies and animal models
title_sort Pleiotropic effects of candidate genes on autism spectrum disorder and comorbidities: genetics, funcional studies and animal models
dc.creator.none.fl_str_mv Antón Galindo, Ester
author Antón Galindo, Ester
author_facet Antón Galindo, Ester
author_role author
dc.contributor.none.fl_str_mv Cormand Rifà, Bru
Fernàndez Castillo, Noèlia
Universitat de Barcelona. Departament de Genètica, Microbiologia i Estadística
dc.subject.none.fl_str_mv Autisme
Genètica mèdica
Neurociències
Anomalies cromosòmiques
Models animals en la investigació
Autism
Medical genetics
Neurosciences
Chromosome abnormalities
Animal models in research
topic Autisme
Genètica mèdica
Neurociències
Anomalies cromosòmiques
Models animals en la investigació
Autism
Medical genetics
Neurosciences
Chromosome abnormalities
Animal models in research
description [eng] Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social communication and interaction, as well as repetitive and restricted patterns of behaviour. Although growing evidence supports a main contribution of genetic factors to its neurobiology and hundreds of candidate genes have been identified in recent years, the genetic architecture of the disorder is still not fully understood. Moreover, ASD frequently co-occurs with other developmental and psychiatric disorders, and shared genetic mechanisms are hypothesized to underlie these comorbidities. In this doctoral thesis, we aimed to study the contribution of several candidate genes to ASD and comorbidities. We have focused on the 14-3-3 gene family, RBFOX1 and the BEX/TCEAL gene family, performed genetic and functional studies and further characterized the neurobiological effects of their deficiency using animal models. First, our results suggest a role for the 14-3-3 genes in ASD and schizophrenia (SCZ). Ultra-rare variants in the 14-3-3 genes are enriched in ASD and common and rare variants in the YWHAE and YWHAZ genes, respectively, are associated with SCZ. We have also reported alterations in the expression of these genes in postmortem brains of ASD or SCZ patients. Furthermore, we have demonstrated a loss-of-function effect of a damaging variant in the YWHAZ gene present in two siblings with ASD and attention deficit/hyperactivity disorder (ADHD). In addition, we have characterized ywhaz expression in zebrafish across development and in adulthood and demonstrated that ywhaz depletion causes alterations in behaviour, in neuronal activity and connectivity and in monoamine signalling. The behavioural changes included freezing and were rescued with drug treatments that target monoamine neurotransmission. Second, we have demonstrated a relevant contribution of common variants in RBFOX1 to psychiatric disorders and traits. Also, we have shown that a high number of copy number variants (CNVs) spanning RBFOX1 are reported in patients with psychiatric conditions, the vast majority in patients with ASD or SCZ, and patients with these disorders also show a decreased expression of RBFOX1 in cortex. Finally, we have used knockout animal models to understand its role in psychiatric disorders, and demonstrated that both mice and zebrafish RBFOX1- deficient models present behavioural alterations that can be related to neurodevelopmental disorders such as ASD, ADHD and SCZ. Third, we found that all BEX/TCEAL genes are downregulated in postmortem brain regions of ASD and SCZ patients and that rare CNVs spanning several BEX/TCEAL genes have been reported in patients with severe neurodevelopmental problems. Furthermore, Bex3-deficient mice show anatomical and molecular alterations in brain, an excitatory/inhibitory imbalance and behavioural alterations that can be assimilated to ASD- and SCZ-like symptoms.
publishDate 2021
dc.date.none.fl_str_mv 2021
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/184168
http://hdl.handle.net/10803/673823
url https://hdl.handle.net/2445/184168
http://hdl.handle.net/10803/673823
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv cc by-nc-sa (c) Antón Galindo, Ester, 2022
http://creativecommons.org/licenses/by-nc-sa/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by-nc-sa (c) Antón Galindo, Ester, 2022
http://creativecommons.org/licenses/by-nc-sa/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv Tesis Doctorals - Departament - Genètica, Microbiologia i Estadística
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869403125808365568
spelling Pleiotropic effects of candidate genes on autism spectrum disorder and comorbidities: genetics, funcional studies and animal modelsAntón Galindo, EsterAutismeGenètica mèdicaNeurociènciesAnomalies cromosòmiquesModels animals en la investigacióAutismMedical geneticsNeurosciencesChromosome abnormalitiesAnimal models in research[eng] Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social communication and interaction, as well as repetitive and restricted patterns of behaviour. Although growing evidence supports a main contribution of genetic factors to its neurobiology and hundreds of candidate genes have been identified in recent years, the genetic architecture of the disorder is still not fully understood. Moreover, ASD frequently co-occurs with other developmental and psychiatric disorders, and shared genetic mechanisms are hypothesized to underlie these comorbidities. In this doctoral thesis, we aimed to study the contribution of several candidate genes to ASD and comorbidities. We have focused on the 14-3-3 gene family, RBFOX1 and the BEX/TCEAL gene family, performed genetic and functional studies and further characterized the neurobiological effects of their deficiency using animal models. First, our results suggest a role for the 14-3-3 genes in ASD and schizophrenia (SCZ). Ultra-rare variants in the 14-3-3 genes are enriched in ASD and common and rare variants in the YWHAE and YWHAZ genes, respectively, are associated with SCZ. We have also reported alterations in the expression of these genes in postmortem brains of ASD or SCZ patients. Furthermore, we have demonstrated a loss-of-function effect of a damaging variant in the YWHAZ gene present in two siblings with ASD and attention deficit/hyperactivity disorder (ADHD). In addition, we have characterized ywhaz expression in zebrafish across development and in adulthood and demonstrated that ywhaz depletion causes alterations in behaviour, in neuronal activity and connectivity and in monoamine signalling. The behavioural changes included freezing and were rescued with drug treatments that target monoamine neurotransmission. Second, we have demonstrated a relevant contribution of common variants in RBFOX1 to psychiatric disorders and traits. Also, we have shown that a high number of copy number variants (CNVs) spanning RBFOX1 are reported in patients with psychiatric conditions, the vast majority in patients with ASD or SCZ, and patients with these disorders also show a decreased expression of RBFOX1 in cortex. Finally, we have used knockout animal models to understand its role in psychiatric disorders, and demonstrated that both mice and zebrafish RBFOX1- deficient models present behavioural alterations that can be related to neurodevelopmental disorders such as ASD, ADHD and SCZ. Third, we found that all BEX/TCEAL genes are downregulated in postmortem brain regions of ASD and SCZ patients and that rare CNVs spanning several BEX/TCEAL genes have been reported in patients with severe neurodevelopmental problems. Furthermore, Bex3-deficient mice show anatomical and molecular alterations in brain, an excitatory/inhibitory imbalance and behavioural alterations that can be assimilated to ASD- and SCZ-like symptoms.[spa] El trastorno del espectro autista (TEA) es un trastorno del neurodesarrollo caracterizado por problemas en la comunicación e interacción social, así como patrones restrictivos y repetitivos de comportamiento. El peso de la genética en su etiología es cada vez más evidente, aunque la compleja arquitectura genética del trastorno sigue siendo una incógnita. Además, el diagnóstico de otros trastornos comórbidos es frecuente en pacientes con TEA, por lo que se hipotetiza una base genética común. El objetivo de esta tesis doctoral es elucidar la contribución de varios genes candidatos, concretamente la familia de genes 14-3-3, el gen RBFOX1 y la familia BEX/TCEAL, al TEA y otros trastornos comórbidos, realizando estudios genéticos y funcionales, así como caracterizando los efectos neurobiológicos de su deficiencia en modelos animales. En primer lugar, nuestros resultados sugieren que variantes ultra-raras en los genes 14-3-3 contribuyen al TEA y que variantes comunes y raras en los genes YWHAE y YWHAZ, respectivamente, están asociadas a esquizofrenia (SCZ). Además, la expresión de los genes 14- 3-3 está alterada en pacientes con TEA o SCZ. Hemos demostrado que una variante patogénica en el gen YWHAZ presente en dos hermanos con TEA y trastorno de déficit de atención e hiperactividad (TDAH) provoca una pérdida de función de la proteína. Asimismo, hemos demostrado que la deleción de ywhaz produce alteraciones en la actividad y conectividad neuronal, la señalización monoaminérgica y el comportamiento, pudiéndose este último recuperar mediante fármacos. En segundo lugar, hemos demostrado que variantes comunes en RBFOX1 están asociadas a diferentes trastornos psiquiátricos y que un número elevado de variantes del número de copias (CNV) afectan a RBFOX1 en pacientes con trastornos psiquiátricos, siendo especialmente frecuentes en pacientes con TEA o SCZ que, además, presentan una disminución en la expresión de RBFOX1 en corteza cerebral. Asimismo, hemos usado modelos animales genoanulados para estudiar la implicación de RBFOX1 en trastornos psiquiátricos, demostrando que tanto el modelo murino como los de pez cebra presentan alteraciones de comportamiento relacionadas con trastornos del neurodesarrollo, como ASD, TDAH y SCZ. Por último, la expresión de los genes BEX/TCEAL está disminuida en regiones cerebrales de pacientes con TEA o SCZ y, además, se han descrito CNVs que abarcan varios genes BEX/TCEAL en pacientes con trastornos severos del neurodesarrollo. Los ratones genoanulados para Bex3 muestran alteraciones anatómicas y moleculares en cerebro, un desequilibro excitación/inhibición y alteraciones de comportamiento asimilables a síntomas de TEA y SCZ.Universitat de BarcelonaCormand Rifà, BruFernàndez Castillo, NoèliaUniversitat de Barcelona. Departament de Genètica, Microbiologia i Estadística2021info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/184168http://hdl.handle.net/10803/673823Tesis Doctorals - Departament - Genètica, Microbiologia i Estadísticareponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaIngléscc by-nc-sa (c) Antón Galindo, Ester, 2022http://creativecommons.org/licenses/by-nc-sa/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1841682026-05-27T06:46:51Z
score 15.301629

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