Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 39
Filter
Add more filters










Publication year range
1.
Transl Psychiatry ; 13(1): 404, 2023 Dec 21.
Article in English | MEDLINE | ID: mdl-38129378

ABSTRACT

The landscape of autism spectrum disorder (ASD) in Lebanon is unique because of high rates of consanguinity, shared ancestry, and increased remote consanguinity. ASD prevalence in Lebanon is 1 in 68 with a male-to-female ratio of 2:1. This study aims to investigate the impact of an inherited deletion in UBLCP1 (Ubiquitin-Like Domain-Containing CTD Phosphatase 1) on the ubiquitin-proteasome system (UPS) and proteolysis. Whole exome sequencing in a Lebanese family with ASD without pathogenic copy number variations (CNVs) uncovered a deletion in UBLCP1. Functional evaluation of the identified variant is described in fibroblasts from the affected. The deletion in UBLCP1 exon 10 (g.158,710,261CAAAG > C) generates a premature stop codon interrupting the phosphatase domain and is predicted as pathogenic. It is absent from databases of normal variation worldwide and in Lebanon. Wild-type UBLCP1 is widely expressed in mouse brains. The mutation results in decreased UBLCP1 protein expression in patient-derived fibroblasts from the autistic patient compared to controls. The truncated UBLCP1 protein results in increased proteasome activity decreased ubiquitinated protein levels, and downregulation in expression of other proteasome subunits in samples from the affected compared to controls. Inhibition of the proteasome by using MG132 in proband cells reverses alterations in gene expression due to the restoration of protein levels of the common transcription factor, NRF1. Finally, treatment with gentamicin, which promotes premature termination codon read-through, restores UBLCP1 expression and function. Discovery of an ASD-linked mutation in UBLCP1 leading to overactivation of cell proteolysis is reported. This, in turn, leads to dysregulation of proteasome subunit transcript levels as a compensatory response.


Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Animals , Female , Humans , Male , Mice , Autism Spectrum Disorder/genetics , DNA Copy Number Variations , Mutation , Proteasome Endopeptidase Complex/genetics , Proteasome Endopeptidase Complex/metabolism , Ubiquitins/genetics
2.
Am J Hum Genet ; 110(12): 2103-2111, 2023 Dec 07.
Article in English | MEDLINE | ID: mdl-37924809

ABSTRACT

Hereditary spastic parapareses (HSPs) are clinically heterogeneous motor neuron diseases with variable age of onset and severity. Although variants in dozens of genes are implicated in HSPs, much of the genetic basis for pediatric-onset HSP remains unexplained. Here, we re-analyzed clinical exome-sequencing data from siblings with HSP of unknown genetic etiology and identified an inherited nonsense mutation (c.523C>T [p.Arg175Ter]) in the highly conserved RAB1A. The mutation is predicted to produce a truncated protein with an intact RAB GTPase domain but without two C-terminal cysteine residues required for proper subcellular protein localization. Additional RAB1A mutations, including two frameshift mutations and a mosaic missense mutation (c.83T>C [p.Leu28Pro]), were identified in three individuals with similar neurodevelopmental presentations. In rescue experiments, production of the full-length, but not the truncated, RAB1a rescued Golgi structure and cell proliferation in Rab1-depleted cells. In contrast, the missense-variant RAB1a disrupted Golgi structure despite intact Rab1 expression, suggesting a dominant-negative function of the mosaic missense mutation. Knock-down of RAB1A in cultured human embryonic stem cell-derived neurons resulted in impaired neuronal arborization. Finally, RAB1A is located within the 2p14-p15 microdeletion syndrome locus. The similar clinical presentations of individuals with RAB1A loss-of-function mutations and the 2p14-p15 microdeletion syndrome implicate loss of RAB1A in the pathogenesis of neurodevelopmental manifestations of this microdeletion syndrome. Our study identifies a RAB1A-related neurocognitive disorder with speech and motor delay, demonstrates an essential role for RAB1a in neuronal differentiation, and implicates RAB1A in the etiology of the neurodevelopmental sequelae associated with the 2p14-p15 microdeletion syndrome.


Subject(s)
Haploinsufficiency , Spastic Paraplegia, Hereditary , Child , Humans , Haploinsufficiency/genetics , Mutation , Mutation, Missense/genetics , rab GTP-Binding Proteins/genetics , rab GTP-Binding Proteins/metabolism , Golgi Apparatus/metabolism , Spastic Paraplegia, Hereditary/genetics
3.
Sci Adv ; 9(47): eadi0074, 2023 11 24.
Article in English | MEDLINE | ID: mdl-37992166

ABSTRACT

Chromatin regulation plays a pivotal role in establishing and maintaining cellular identity and is one of the top pathways disrupted in autism spectrum disorder (ASD). The hippocampus, composed of distinct cell types, is often affected in patients with ASD. However, the specific hippocampal cell types and their transcriptional programs that are dysregulated in ASD are unknown. Using single-nucleus RNA sequencing, we show that the ASD gene, lysine demethylase 5A (KDM5A), regulates the development of specific subtypes of excitatory and inhibitory neurons. We found that KDM5A is essential for establishing hippocampal cell identity by controlling a differentiation switch early in development. Our findings define a role for the chromatin regulator KDM5A in establishing hippocampal cell identity and contribute to the emerging convergent mechanisms across ASD.


Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Humans , Chromatin/genetics , Histones/genetics , Histones/metabolism , Autistic Disorder/genetics , Autism Spectrum Disorder/genetics , Cell Differentiation/genetics , Retinoblastoma-Binding Protein 2/genetics
4.
Cell Genom ; 3(7): 100322, 2023 Jul 12.
Article in English | MEDLINE | ID: mdl-37492102

ABSTRACT

Autism spectrum disorder (ASD) is a group of complex neurodevelopmental conditions affecting communication and social interaction in 2.3% of children. Studies that demonstrated its complex genetic architecture have been mainly performed in populations of European ancestry. We investigate the genetics of ASD in an East African cohort (129 individuals) from a population with higher prevalence (5%). Whole-genome sequencing identified 2.13 million private variants in the cohort and potentially pathogenic variants in known ASD genes (including CACNA1C, CHD7, FMR1, and TCF7L2). Admixture analysis demonstrated that the cohort comprises two ancestral populations, African and Eurasian. Admixture mapping discovered 10 regions that confer ASD risk on the African haplotypes, containing several known ASD genes. The increased ASD prevalence in this population suggests decreased heterogeneity in the underlying genetic etiology, enabling risk allele identification. Our approach emphasizes the power of African genetic variation and admixture analysis to inform the architecture of complex disorders.

5.
Autism Res ; 16(1): 31-39, 2023 01.
Article in English | MEDLINE | ID: mdl-36415077

ABSTRACT

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in communication, diminished social skills, and restrictive and repetitive behaviors and interests. ASD affects approximately 2.3% of the population and is highly heterogeneous, both phenotypically and genetically. As genomic technologies advance, our understanding of the genetic architecture of ASD is becoming clearer, encompassing spontaneous and inherited alterations throughout the genome, and delineating alterations that are either rare or common in the population. This commentary provides an overview of the genomic strategies and resulting major findings of genetic alterations associated with ASD.


Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Humans , Autistic Disorder/genetics , Autism Spectrum Disorder/genetics , Genomics , Causality , Mutation
6.
Med ; 3(6): 369-370, 2022 Jun 10.
Article in English | MEDLINE | ID: mdl-35690058
7.
NPJ Genom Med ; 7(1): 13, 2022 Feb 21.
Article in English | MEDLINE | ID: mdl-35190550

ABSTRACT

Autism spectrum disorder (ASD) is a collection of neurodevelopmental disorders characterized by deficits in social communication and restricted, repetitive patterns of behavior or interests. ASD is highly heritable, but genetically and phenotypically heterogeneous, reducing the power to identify causative genes. We performed whole genome sequencing (WGS) in an ASD cohort of 68 individuals from 22 families enriched for recent shared ancestry. We identified an average of 3.07 million variants per genome, of which an average of 112,512 were rare. We mapped runs of homozygosity (ROHs) in affected individuals and found an average genomic homozygosity of 9.65%, consistent with expectations for multiple generations of consanguineous unions. We identified potentially pathogenic rare exonic or splice site variants in 12 known (including KMT2C, SCN1A, SPTBN1, SYNE1, ZNF292) and 12 candidate (including CHD5, GRB10, PPP1R13B) ASD genes. Furthermore, we annotated noncoding variants in ROHs with brain-specific regulatory elements and identified putative disease-causing variants within brain-specific promoters and enhancers for 5 known ASD and neurodevelopmental disease genes (ACTG1, AUTS2, CTNND2, CNTNAP4, SPTBN4). We also identified copy number variants in two known ASD and neurodevelopmental disease loci in two affected individuals. In total we identified potentially etiological variants in known ASD or neurodevelopmental disease genes for ~61% (14/23) of affected individuals. We combined WGS with homozygosity mapping and regulatory element annotations to identify candidate ASD variants. Our analyses add to the growing number of ASD genes and variants and emphasize the importance of leveraging recent shared ancestry to map disease variants in complex neurodevelopmental disorders.

9.
Afr J Health Sci ; 34(3): 364-373, 2021 Aug 11.
Article in English | MEDLINE | ID: mdl-37920188

ABSTRACT

BACKGROUND: Autism spectrum disorder (ASD) continues to climb in prevalence worldwide. Developed nations have focused on aligning their medical and research communities in order to investigate the mechanisms of pathogenesis, diagnosis, and societal impact of this disorder. A simultaneous rise of ASD has impacted developing nations, such as Ethiopia, without a commensurate ability to research the knowledge, beliefs, resources, and training regarding this condition in the country. MATERIALS AND METHODS: We administered a brief survey during a medical conference in Bahir Dar, Ethiopia, to investigate some of the education, information, and experiences with ASD within a small sample of medical and mental health providers in Ethiopia. RESULTS: The data provided insight into the following areas pertaining to ASD in Ethiopia: perceived causes, knowledge, training, and areas of need. CONCLUSIONS: Understanding local beliefs for causes and cures, as well as gaining indigenous opinions regarding what is needed for ASD education and resources in their nation, is the first step towards understanding the impact of this disorder and the approach to its treatment in Ethiopia.

10.
Elife ; 92020 12 22.
Article in English | MEDLINE | ID: mdl-33350388

ABSTRACT

Autism spectrum disorder (ASD) is a constellation of neurodevelopmental disorders with high phenotypic and genetic heterogeneity, complicating the discovery of causative genes. Through a forward genetics approach selecting for defective vocalization in mice, we identified Kdm5a as a candidate ASD gene. To validate our discovery, we generated a Kdm5a knockout mouse model (Kdm5a-/-) and confirmed that inactivating Kdm5a disrupts vocalization. In addition, Kdm5a-/- mice displayed repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis. Loss of KDM5A also resulted in dysregulation of the hippocampal transcriptome. To determine if KDM5A mutations cause ASD in humans, we screened whole exome sequencing and microarray data from a clinical cohort. We identified pathogenic KDM5A variants in nine patients with ASD and lack of speech. Our findings illustrate the power and efficacy of forward genetics in identifying ASD genes and highlight the importance of KDM5A in normal brain development and function.


Subject(s)
Autism Spectrum Disorder/genetics , Retinoblastoma-Binding Protein 2/genetics , Adolescent , Animals , Child, Preschool , Female , Genetic Predisposition to Disease/genetics , Genetic Techniques , Humans , Male , Mice , Mice, Knockout , Mutation
11.
Sci Rep ; 10(1): 14045, 2020 08 20.
Article in English | MEDLINE | ID: mdl-32820185

ABSTRACT

More than 98% of the human genome is made up of non-coding DNA, but techniques to ascertain its contribution to human disease have lagged far behind our understanding of protein coding variations. Autism spectrum disorder (ASD) has been mostly associated with coding variations via de novo single nucleotide variants (SNVs), recessive/homozygous SNVs, or de novo copy number variants (CNVs); however, most ASD cases continue to lack a genetic diagnosis. We analyzed 187 consanguineous ASD families for biallelic CNVs. Recessive deletions were significantly enriched in affected individuals relative to their unaffected siblings (17% versus 4%, p < 0.001). Only a small subset of biallelic deletions were predicted to result in coding exon disruption. In contrast, biallelic deletions in individuals with ASD were enriched for overlap with regulatory regions, with 23/28 CNVs disrupting histone peaks in ENCODE (p < 0.009). Overlap with regulatory regions was further demonstrated by comparisons to the 127-epigenome dataset released by the Roadmap Epigenomics project, with enrichment for enhancers found in primary brain tissue and neuronal progenitor cells. Our results suggest a novel noncoding mechanism of ASD, describe a powerful method to identify important noncoding regions in the human genome, and emphasize the potential significance of gene activation and regulation in cognitive and social function.


Subject(s)
Autism Spectrum Disorder/genetics , Epigenesis, Genetic , Gene Deletion , Homozygote , DNA Copy Number Variations , Female , Genetic Predisposition to Disease , Humans , Male
12.
Proc Natl Acad Sci U S A ; 116(9): 3662-3667, 2019 02 26.
Article in English | MEDLINE | ID: mdl-30808755

ABSTRACT

Kaufman oculocerebrofacial syndrome (KOS) is a recessive neurodevelopmental disorder characterized by intellectual disability and lack of speech. KOS is caused by inactivating mutations in UBE3B, but the underlying biological mechanisms are completely unknown. We found that loss of Ube3b in mice resulted in growth retardation, decreased grip strength, and loss of vocalization. The brains of Ube3b-/- mice had hypoplasia of the corpus callosum, enlarged ventricles, and decreased thickness of the somatosensory cortex. Ube3b-/- cortical neurons had abnormal dendritic morphology and synapses. We identified 22 UBE3B interactors and found that branched-chain α-ketoacid dehydrogenase kinase (BCKDK) is an in vivo UBE3B substrate. Since BCKDK targets several metabolic pathways, we profiled plasma and cortical metabolomes from Ube3b-/- mice. Nucleotide metabolism and the tricarboxylic acid cycle were among the pathways perturbed. Substrate-induced mitochondrial respiration was reduced in skeletal muscle but not in liver of Ube3b-/- mice. To assess the relevance of these findings to humans, we identified three KOS patients who had compound heterozygous UBE3B mutations. We discovered changes in metabolites from similar pathways in plasma from these patients. Collectively, our results implicate a disease mechanism in KOS, suggest that it is a metabolic encephalomyopathy, and provide an entry to targeted therapies.


Subject(s)
Eye Abnormalities/genetics , Intellectual Disability/genetics , Language Development Disorders/genetics , Limb Deformities, Congenital/genetics , Microcephaly/genetics , Protein Kinases/genetics , Ubiquitin-Protein Ligases/genetics , Adolescent , Adult , Animals , Brain/physiopathology , Child , Eye Abnormalities/physiopathology , Facies , Humans , Intellectual Disability/physiopathology , Language Development Disorders/physiopathology , Limb Deformities, Congenital/physiopathology , Male , Metabolic Networks and Pathways , Mice , Mice, Knockout , Microcephaly/physiopathology , Mutation , Phenotype , Ubiquitin/genetics
13.
Neurobiol Learn Mem ; 165: 106791, 2019 11.
Article in English | MEDLINE | ID: mdl-29398581

ABSTRACT

The ubiquitin proteasome system (UPS) is a highly conserved pathway that tightly regulates protein turnover in cells. This process is integral to neuronal development, differentiation, and function. Several members of the UPS are disrupted in neuropsychiatric disorders, highlighting the importance of this pathway in brain development and function. In this review, we discuss some of these pathway members, the molecular processes they regulate, and the potential for targeting the UPS in an effort to develop therapeutic strategies in neuropsychiatric and neurodevelopmental disorders.


Subject(s)
Mental Disorders/metabolism , Proteasome Endopeptidase Complex/metabolism , Ubiquitin/metabolism , Attention Deficit Disorder with Hyperactivity/metabolism , Autism Spectrum Disorder/metabolism , Brain Diseases/metabolism , Humans , Intellectual Disability/metabolism , Metabolic Networks and Pathways/physiology , Proteasome Endopeptidase Complex/physiology , Schizophrenia/metabolism , Ubiquitin/physiology
14.
Am J Med Genet B Neuropsychiatr Genet ; 177(8): 736-745, 2018 12.
Article in English | MEDLINE | ID: mdl-30421579

ABSTRACT

Protein homeostasis is tightly regulated by the ubiquitin proteasome pathway. Disruption of this pathway gives rise to a host of neurological disorders. Through whole exome sequencing (WES) in families with neurodevelopmental disorders, we identified mutations in PSMD12, a core component of the proteasome, underlying a neurodevelopmental disorder with intellectual disability (ID) and features of autism spectrum disorder (ASD). We performed WES on six affected siblings from a multiplex family with ID and autistic features, the affected father, and two unaffected mothers, and a trio from a simplex family with one affected child with ID and periventricular nodular heterotopia. We identified an inherited heterozygous nonsense mutation in PSMD12 (NM_002816: c.367C>T: p.R123X) in the multiplex family and a de novo nonsense mutation in the same gene (NM_002816: c.601C>T: p.R201X) in the simplex family. PSMD12 encodes a non-ATPase regulatory subunit of the 26S proteasome. We confirm the association of PSMD12 with ID, present the first cases of inherited PSMD12 mutation, and demonstrate the heterogeneity of phenotypes associated with PSMD12 mutations.


Subject(s)
Intellectual Disability/genetics , Proteasome Endopeptidase Complex/genetics , Adolescent , Adult , Autism Spectrum Disorder/genetics , Autistic Disorder/genetics , Child , Child, Preschool , Family , Female , Genetic Predisposition to Disease , Haploinsufficiency/genetics , Humans , Male , Mutation , Neurodevelopmental Disorders/genetics , Pedigree , Proteasome Endopeptidase Complex/metabolism , Siblings , Exome Sequencing
15.
Elife ; 62017 07 11.
Article in English | MEDLINE | ID: mdl-28695822

ABSTRACT

Sequencing studies have implicated haploinsufficiency of ARID1B, a SWI/SNF chromatin-remodeling subunit, in short stature (Yu et al., 2015), autism spectrum disorder (O'Roak et al., 2012), intellectual disability (Deciphering Developmental Disorders Study, 2015), and corpus callosum agenesis (Halgren et al., 2012). In addition, ARID1B is the most common cause of Coffin-Siris syndrome, a developmental delay syndrome characterized by some of the above abnormalities (Santen et al., 2012; Tsurusaki et al., 2012; Wieczorek et al., 2013). We generated Arid1b heterozygous mice, which showed social behavior impairment, altered vocalization, anxiety-like behavior, neuroanatomical abnormalities, and growth impairment. In the brain, Arid1b haploinsufficiency resulted in changes in the expression of SWI/SNF-regulated genes implicated in neuropsychiatric disorders. A focus on reversible mechanisms identified Insulin-like growth factor (IGF1) deficiency with inadequate compensation by Growth hormone-releasing hormone (GHRH) and Growth hormone (GH), underappreciated findings in ARID1B patients. Therapeutically, GH supplementation was able to correct growth retardation and muscle weakness. This model functionally validates the involvement of ARID1B in human disorders, and allows mechanistic dissection of neurodevelopmental diseases linked to chromatin-remodeling.


Subject(s)
Developmental Disabilities/genetics , Haploinsufficiency , Mental Disorders/genetics , Transcription Factors/deficiency , Animals , Behavior, Animal , Brain/pathology , Developmental Disabilities/physiopathology , Disease Models, Animal , Gene Expression Regulation , Growth Hormone-Releasing Hormone/metabolism , Heterozygote , Insulin-Like Growth Factor I/metabolism , Mental Disorders/physiopathology , Mice , Protein Serine-Threonine Kinases/metabolism
16.
Sci Rep ; 7: 45336, 2017 03 30.
Article in English | MEDLINE | ID: mdl-28358038

ABSTRACT

Autism spectrum disorder (ASD) is characterized by ritualistic-repetitive behaviors and impaired verbal/non-verbal communication. Many ASD susceptibility genes implicated in neuronal pathways/brain development have been identified. The Lebanese population is ideal for uncovering recessive genes because of shared ancestry and a high rate of consanguineous marriages. Aims here are to analyze for published ASD genes and uncover novel inherited ASD susceptibility genes specific to the Lebanese. We recruited 36 ASD families (ASD: 37, unaffected parents: 36, unaffected siblings: 33) and 100 unaffected Lebanese controls. Cytogenetics 2.7 M Microarrays/CytoScan™ HD arrays allowed mapping of homozygous regions of the genome. The CNTNAP2 gene was screened by Sanger sequencing. Homozygosity mapping uncovered DPP4, TRHR, and MLF1 as novel candidate susceptibility genes for ASD in the Lebanese. Sequencing of hot spot exons in CNTNAP2 led to discovery of a 5 bp insertion in 23/37 ASD patients. This mutation was present in unaffected family members and unaffected Lebanese controls. Although a slight increase in number was observed in ASD patients and family members compared to controls, there were no significant differences in allele frequencies between affecteds and controls (C/TTCTG: γ2 value = 0.014; p = 0.904). The CNTNAP2 polymorphism identified in this population, hence, is not linked to the ASD phenotype.


Subject(s)
Autism Spectrum Disorder/genetics , Dipeptidyl Peptidase 4/genetics , Membrane Proteins/genetics , Nerve Tissue Proteins/genetics , Proteins/genetics , Receptors, Thyrotropin-Releasing Hormone/genetics , Adolescent , Cell Cycle Proteins , Child , Child, Preschool , Consanguinity , DNA-Binding Proteins , Female , Genetic Predisposition to Disease , Heredity , Homozygote , Humans , Lebanon , Male , Mutagenesis, Insertional , Oligonucleotide Array Sequence Analysis , Pedigree , Sequence Analysis, DNA , Young Adult
17.
Nat Genet ; 49(4): 527-536, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28288114

ABSTRACT

Gain-of-function mutations in some genes underlie neurodegenerative conditions, whereas loss-of-function mutations in the same genes have distinct phenotypes. This appears to be the case with the protein ataxin 1 (ATXN1), which forms a transcriptional repressor complex with capicua (CIC). Gain of function of the complex leads to neurodegeneration, but ATXN1-CIC is also essential for survival. We set out to understand the functions of the ATXN1-CIC complex in the developing forebrain and found that losing this complex results in hyperactivity, impaired learning and memory, and abnormal maturation and maintenance of upper-layer cortical neurons. We also found that CIC activity in the hypothalamus and medial amygdala modulates social interactions. Informed by these neurobehavioral features in mouse mutants, we identified five individuals with de novo heterozygous truncating mutations in CIC who share similar clinical features, including intellectual disability, attention deficit/hyperactivity disorder (ADHD), and autism spectrum disorder. Our study demonstrates that loss of ATXN1-CIC complexes causes a spectrum of neurobehavioral phenotypes.


Subject(s)
Ataxin-1/genetics , Autism Spectrum Disorder/genetics , Neurodegenerative Diseases/genetics , Nuclear Proteins/genetics , Repressor Proteins/genetics , Animals , Cerebellum/pathology , Female , Humans , Intellectual Disability/genetics , Interpersonal Relations , Male , Mice , Nerve Tissue Proteins/genetics , Phenotype
18.
Dialogues Clin Neurosci ; 19(4): 335-343, 2017 12.
Article in English | MEDLINE | ID: mdl-29398929

ABSTRACT

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by social deficits and repetitive/restrictive interests. ASD is associated with multiple comorbidities, including intellectual disability, anxiety, and epilepsy. Evidence that ASD is highly heritable has spurred major efforts to unravel its genetics, revealing possible contributions from hundreds of genes through rare and common variation and through copy-number changes. In this perspective, we provide an overview of the current state of ASD genetics and of how genetic research has spurred the development of in vivo and in vitro models using animals and patient cells to evaluate the impact of genetic mutations on cellular function leading to disease. Efforts to translate these findings into successful therapies have yet to bear fruit. We discuss how the valuable insight into the disorder provided by these new models can be used to better understand ASD and develop future clinical trials.


El trastorno del espectro autista (TEA) es un complejo trastorno del neurodesarrollo caracterizado por déficits sociales e intereses repetitivos/restrictivos. El TEA se asocia con múltiples comorbilidades, incluyendo discapacidad intelectual, ansiedad y epilepsia. La evidencia de la alta heredabilidad del TEA ha estimulado los mayores esfuerzos para descifrar su genética, revelando posibles contribuciones de cientos de genes a través de variaciones raras y comunes, y de la variabilidad en el número de copias. Desde esta perspectiva se entrega una panorámica del estado actual de la genética del TEA y de cómo la investigación genética ha estimulado el desarrollo de modelos in vivo e in vitro que emplean células de animales y de pacientes para evaluar el impacto de las mutaciones genéticas en la función celular que lleva a la enfermedad. Aún no han dado frutos los esfuerzos realizados en la traducción de estos hallazgos en terapias exitosas. Se discute cómo se puede emplear la valiosa información acerca del trastorno, proporcionada por estos nuevos modelos, para una mejor comprensión del TEA y para desarrollar futuros ensayos clínicos.


Le trouble du spectre de l'autisme (TSA) représente un trouble complexe neurodéveloppemental caractérisé par des déficits sociaux et des intérêts répétitifs et restreints. Les comorbidités associées au TSA sont multiples, comme la déficience intellectuelle, l'anxiété et l'épilepsie. La transmissibilité élevée démontrée du TSA a encouragé des efforts importants pour décoder sa génétique, des centaines de gènes étant potentiellement impliqués par des variations rares et courantes et par la variabilité du nombre de copies. Dans cette perspective, nous présentons un aperçu de l'état actuel de la génétique du TSA et de la façon dont la recherche génétique a stimulé le développement de modèles in vivo et in vitro utilisant des cellules humaines et animales pour évaluer l'incidence de mutations génétiques sur les fonctions cellulaires responsables de la maladie. Les efforts pour traduire ces résultats en traitements efficaces n'ont pas encore porté leurs fruits. Nous expliquons comment les informations précieuses apportées par ces nouveaux modèles peuvent être utilisées pour mieux comprendre le TSA et développer de futurs essais cliniques.


Subject(s)
Autistic Disorder/genetics , Autistic Disorder/therapy , Genetic Therapy/methods , Mutation , Translational Research, Biomedical , Animals , Disease Models, Animal , Humans
19.
J Child Neurol ; 32(3): 271-285, 2017 03.
Article in English | MEDLINE | ID: mdl-27920266

ABSTRACT

To describe pontine axonal anomalies across diverse brain malformations. Institutional review board-approved review of magnetic resonance imaging (MRI) and genetic testing of 31 children with brain malformations and abnormal pons by diffusion tensor imaging. Anomalous dorsal pontocerebellar tracts were seen in mid-hindbrain anomalies and in diffuse malformations of cortical development including lissencephaly, gyral disorganization with dysplastic basal ganglia, presumed congenital fibrosis of extraocular muscles type 3, and in callosal agenesis without malformations of cortical development. Heterotopic and hypoplastic corticospinal tracts were seen in callosal agenesis and in focal malformations of cortical development. There were no patterns by chromosomal microarray analysis in the non-lissencephalic brains. In lissencephaly, there was no relationship between severity, deletion size, or appearance of the pontocerebellar tract. Pontine axonal anomalies may relate to defects in precerebellar neuronal migration, chemotactic signaling of the pontine neurons, and/or corticospinal tract pathfinding and collateral branching not detectable with routine genetic testing.


Subject(s)
Cerebellum/diagnostic imaging , Nervous System Malformations/diagnostic imaging , Pons/diagnostic imaging , Child, Preschool , Diffusion Tensor Imaging , Female , Genetic Testing , Humans , Infant , Infant, Newborn , Magnetic Resonance Imaging , Male , Malformations of Cortical Development/diagnostic imaging , Malformations of Cortical Development/genetics , Nervous System Malformations/genetics , Neural Pathways/diagnostic imaging
20.
J Neurosci ; 36(45): 11402-11410, 2016 11 09.
Article in English | MEDLINE | ID: mdl-27911742

ABSTRACT

Autism spectrum disorder (ASD) is a constellation of neurodevelopmental presentations with high heritability and both phenotypic and genetic heterogeneity. To date, mutations in hundreds of genes have been associated to varying degrees with increased ASD risk. A better understanding of the functions of these genes and whether they fit together in functional groups or impact similar neuronal circuits is needed to develop rational treatment strategies. We will review current areas of emphasis in ASD research, starting from human genetics and exploring how mouse models of human mutations have helped identify specific molecular pathways (protein synthesis and degradation, chromatin remodeling, intracellular signaling), which are linked to alterations in circuit function and cognitive/social behavior. We will conclude by discussing how we can leverage the findings on molecular and cellular alterations found in ASD to develop therapies for neurodevelopmental disorders.


Subject(s)
Autism Spectrum Disorder/genetics , Autism Spectrum Disorder/therapy , Brain/metabolism , Genetic Therapy/methods , Nerve Tissue Proteins/genetics , Autism Spectrum Disorder/diagnosis , Evidence-Based Medicine , Genetic Markers/genetics , Genetic Predisposition to Disease/genetics , Genetic Testing/methods , Humans , Molecular Targeted Therapy/methods , Nerve Tissue Proteins/metabolism , Treatment Outcome
SELECTION OF CITATIONS
SEARCH DETAIL
...