Auswahl der wissenschaftlichen Literatur zum Thema „CNTNAP2 gene“

Central glutamatergic synapses and the molecular pathways that control them are emerging as common substrates in the pathogenesis of mental disorders. Genetic variation in the contactin associated protein-like 2 (CNTNAP2) gene, including copy number variations, exon deletions, truncations, single nucleotide variants, and polymorphisms have been associated with intellectual disability, epilepsy, schizophrenia, language disorders, and autism. CNTNAP2, encoded by Cntnap2, is required for dendritic spine development and its absence causes disease-related phenotypes in mice. However, the mechanisms whereby CNTNAP2 regulates glutamatergic synapses are not known, and cellular phenotypes have not been investigated in Cntnap2 knockout neurons. Here we show that CNTNAP2 is present in dendritic spines, as well as axons and soma. Structured illumination superresolution microscopy reveals closer proximity to excitatory, rather than inhibitory synaptic markers. CNTNAP2 does not promote the formation of synapses and cultured neurons from Cntnap2 knockout mice do not show early defects in axon and dendrite outgrowth, suggesting that CNTNAP2 is not required at this stage. However, mature neurons from knockout mice show reduced spine density and levels of GluA1 subunits of AMPA receptors in spines. Unexpectedly, knockout neurons show large cytoplasmic aggregates of GluA1. Here we characterize, for the first time to our knowledge, synaptic phenotypes in Cntnap2 knockout neurons and reveal a novel role for CNTNAP2 in GluA1 trafficking. Taken together, our findings provide insight into the biological roles of CNTNAP2 and into the pathogenesis of CNTNAP2-associated neuropsychiatric disorders.

Mouse knockouts of Cntnap2 show altered neurodevelopmental behavior, deficits in striatal GABAergic signaling, and a genome-wide disruption of an environmentally sensitive DNA methylation modification (5-hydroxymethylcytosine [5hmC]) in the orthologs of a significant number of genes implicated in human neurodevelopmental disorders. We tested adult Cntnap2 heterozygous mice (Cntnap2+/−; lacking behavioral or neuropathological abnormalities) subjected to a prenatal stress and found that prenatally stressed Cntnap2+/− female mice show repetitive behaviors and altered sociability, similar to the homozygote phenotype. Genomic profiling revealed disruptions in hippocampal and striatal 5hmC levels that are correlated to altered transcript levels of genes linked to these phenotypes (e.g., Reln, Dst, Trio, and Epha5). Chromatin immunoprecipitation coupled with high-throughput sequencing and hippocampal nuclear lysate pull-down data indicated that 5hmC abundance alters the binding of the transcription factor CLOCK near the promoters of these genes (e.g., Palld, Gigyf1, and Fry), providing a mechanistic role for 5hmC in gene regulation. Together, these data support gene-by-environment hypotheses for the origins of mental illness and provide a means to identify the elusive factors contributing to complex human diseases.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by three core symptoms, specifically impaired social behavior, stereotypic/repetitive behaviors, and sensory/communication deficits. Although the exact pathophysiology of ASD is still unknown, host genetics, oxidative stress, and compromised blood brain barrier (BBB) have been implicated in predisposition to ASD. With regards to genetics, mutations in the genes such as CNTNAP2 have been associated with increased susceptibility of developing ASD. Although some studies observed conflicting results suggesting no association of CNTNAP2 with ASD, other investigations correlated this gene with autism. In addition, CNTNAP2 mediated signaling is generally considered to play a role in neurological disorders due to its critical role in neurodevelopment, neurotransmission, and synaptic plasticity. In this investigation, we studied BBB integrity and oxidative stress in Cntnap2−/− rats. We observed that the BBB permeability was significantly increased in Cntnap2−/− rats compared to littermate wild-type (WT) animals as determined by FITC-dextran and Evans blue assay. High levels of thiobarbituric acid reactive substances and lower amounts of reduced glutathione were observed in brain homogenates of Cntnap2−/− rats, suggesting oxidative stress. Brain sections from Cntnap2−/− rats showed intense inducible nitric oxide synthase immunostaining, which was undetectable in WT animals. Quantification of nitric oxide in brain homogenates revealed significantly high levels in Cntnap2−/− rats compared to the control group. As increased permeability of the BBB and oxidative stress have been observed in ASD individuals, our results suggest that Cntnap2−/− rats have a high construct and face validity and can be explored to develop effective therapeutic modalities.

Thecontactin-associated protein-like 2(CNTNAP2) gene is highly expressed in the frontal lobe circuits in the developing human brain. Mutations in this gene have been associated with several neurodevelopmental disorders such as autism and specific language impairment. Here we describe a 450 kb deletion within theCNTNAP2gene that is maternally inherited in two male siblings, but with a variable clinical phenotype. This variability is described in the context of a limited number of other cases reported in the literature. The in-frame intragenic deletion removes a critical domain of the CNTNAP2 protein, and this case also highlights the challenges of correlating genotype and phenotype.

Objective. Genetic factors play an important role in the development of autism spectrum disorder (ASD). This case-control study was to determine the association between childhood ASD and single nucleotide polymorphisms (SNPs) rs3746599 in the DUSP15 gene, rs7794745 in the CNTNAP2 gene, and rs251379 in the PCDHA gene in a Chinese Han population. Methods. Genotypes of SNPs were examined in DNA extracted from blood cells from 201 children with ASD and 200 healthy controls. The Children Autism Rating Scale (CARS) was applied to evaluate the severity of the disease and language impairment. The relationship between SNPs and the risk of ASD or the severity of the disease was determined by logistic regression and one-way ANOVA. Results. The genotype G/G of rs3746599 in the DUSP15 gene was significantly associated with a decreased risk of ASD (odds ratio OR = 0.65 , 95% confidence interval (CI): 0.42-0.99, P = 0.0449 ). The T allele of rs7794745 in the CNTNAP2 gene was associated with an increased risk of ASD ( OR = 1.34 , 95% CI: 1.01-1.77, P = 0.0435 ). The SNP rs251379 was not associated with ASD. Though none of the SNPs examined were associated with ASD severity, rs7794745 was associated with severity of language impairment. Conclusions. Our findings suggest that both rs3746599 in the DUSP15 gene and rs7794745 in the CNTNAP2 gene are associated with risk of childhood ASD, and rs7794745 is also related to the severity of language impairment in autistic children from a Chinese Han population.

Purpose Successful oral feeding and speech emergence are dependent upon the coordination of shared oral muscles and facial nerves. We aimed to determine if the speech-associated genes, forkhead box P2 (FOXP2) , contactin-associated protein-like 2 (CNTNAP2 ), glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A) , and neurexin 1, were detectable in neonatal saliva and could predict feeding outcomes in premature newborns. Method In this prospective, observational, preliminary study, saliva collected from 51 premature infants (gestational ages: 30–34 6/7 weeks) at different stages of oral feeding development underwent gene expression analysis. Binary (+/–) expression profiles were explored and examined in relation to days to achieve full oral feeds. Results GRIN2A and neurexin 1 rarely amplified in neonatal saliva and were not informative. Infants who amplified FOXP2 but not CNTNAP2 at the start of oral feeds achieved oral feeding success 3.20 (95% CI [−2.5, 8.9]) days sooner than other gene combinations. Conclusions FOXP2 and CNTNAP2 may be informative in predicting oral feeding outcomes in newborns. Salivary analysis at the start of oral feeding trials may inform feeding outcomes in this population and warrants further investigation.

Background and Objectives: The development and standardization of genome-wide technologies able to carry out high-resolution, genomic analyses in a cost- and time-affordable way is increasing our knowledge regarding the molecular bases of complex diseases like autism spectrum disorder (ASD). ASD is a group of heterogeneous diseases with multifactorial origins. Genetic factors seem to be involved, albeit they remain still largely unknown. Here, we report the case of a child with a clinical suspicion of ASD investigated by using such a genomic high-resolution approach. Materials and Methods: Both array comparative genomic hybridization (aCGH) and exome sequencing were carried out on the family trio. aCGH was performed using the 4 × 180 K SurePrint G3 Human CGH Microarray, while the Human All Exon V7 targeted SureSelect XT HS panel was used for exome sequencing. Results: aCGH identified a paternally inherited duplication of chromosome 7 involving the CNTNAP2 gene, while 5 potentially clinically-relevant variants were identified by exome sequencing. Conclusions: Within the identified genomic alterations, the CNTNAP2 gene duplication may be related to the patient’s phenotype. Indeed, this gene has already been associated with brain development and cognitive functions, including language. The paternal origin of the alteration cannot exclude an incomplete penetrance. Moreover, other genomic factors may act as phenotype modifiers combined with CNTNAP2 gene duplication. Thus, the case reported herein strongly reinforces the need to use extensive genomic analyses to shed light on the bases of complex diseases.

The first objective of this study was to compare the brain network engaged by preference classification and the standard grammaticality classification after implicit artificial syntax acquisition by re-analyzing previously reported event-related fMRI data. The results show that preference and grammaticality classification engage virtually identical brain networks, including Broca’s region, consistent with previous behavioral findings. Moreover, the results showed that the effects related to artificial syntax in Broca’s region were essentially the same when masked with variability related to natural syntax processing in the same participants. The second objective was to explore CNTNAP2-related effects in implicit artificial syntax learning by analyzing behavioral and event-related fMRI data from a subsample. The CNTNAP2 gene has been linked to specific language impairment and is con-trolled by the FOXP2 transcription factor. CNTNAP2 is expressed in language related brain networks in the developing human brain and the FOXP2–CNTNAP2 pathway provides a mechanistic link between clinically distinct syndromes involving disrupted language. Finally, we discuss the implication of taking natural language to be a neurobiological system in terms of bounded recursion and suggest that the left inferior frontal region is a generic on-line sequence processor that unifies information from various sources in an incremental and recursive manner.

Pitt Hopkins-like syndrome 1 (PTHLS1, OMIM # 610042) is an ultra-rare autosomal recessive condition with a prevalence of <1/1,000,000. Intragenic deletions of CNTNAP2 has been implicated in PTHLS1, however to our knowledge a compound heterozygous deletion of exon 4 and a c.1977_1989del13; p.V660Ffsx9 frameshift variant have not been published previously. In this case report, the proband is a seven year old female with PTHLS1, developmental delay, autism spectrum disorder, focal epilepsy, hypotonia, refractory errors, strabismus, and obstructive sleep apnea. Whole exome sequencing analysis revealed biallelic pathogenic variants of the CNTNAP2 gene. Proband has a three year old sister who has who has a similar phenotype including, developmental delay, epilepsy, gait abnormality, refractory errors, strabismus. Family variants were tested and she shared the same CNTNAP2 variants as her sister. The sisters described highlight two novel variants leading to PTHLS1. Genetic workup is essential in identification and management guidance in these populations.

Les troubles du spectre autistique (TSA) sont des troubles neurodéveloppementaux définis par des déficits d'interaction sociale et des comportements restreints ou répétitifs. Les TSA présentent une forte héritabilité, déterminée par de rares mutations monogéniques, ainsi que par des variations dans de nombreux gènes de susceptibilité. Le gène CNTNAP2, qui code pour la protéine Caspr2, est considéré comme l'un des principaux gènes de risque pour les TSA, un grand nombre de variants hétérozygotes faux-sens ayant été identifiés chez les patients. Les souris knock-out Cntnap2 présentent des déficits comportementaux de type TSA, ce qui supporte les données de génétique humaine. Cependant, la signification clinique des variants hétérozygotes n'a pas encore été démontrée et reste débattue. Le projet de thèse visait à élucider cette question en évaluant la pathogénicité in vivo d'un variant CNTNAP2 hétérozygote faux-sens identifié chez un patient français atteint de TSA, I236S, qui a été prédit comme pathogène et pourrait être représentatif d'une large classe de variants CNTNAP2. Nous avons généré un nouveau modèle de souris knockin, les souris KI-I236S, et mené une étude comparant les souris de type sauvage et les souris hétérozygotes (HET) KI-I236S. Caspr2 est une glycoprotéine transmembranaire d'adhésion cellulaire neuronale identifiée à l'origine dans les régions juxtaparanodales des nœuds de Ranvier dans les neurones myélinisés matures. Récemment, en étudiant des souris knock-out Cntnap2, le laboratoire a montré que Caspr2 agit également comme un régulateur majeur du développement de l'axone et de la myélinisation. Dans le cerveau, Caspr2 contrôle le diamètre des axones aux premiers stades du développement postnatal, l'excitabilité intrinsèque des neurones corticaux au début de la myélinisation, ainsi que le diamètre des axones et l'épaisseur de la myéline à l'âge adulte. Caspr2 module également le diamètre des axones, l'épaisseur de la myéline et la morphologie du nœud de Ranvier dans les nerfs périphériques. Nous avons donc évalué l'impact du variant I235S sur le développement des axones, la myélinisation et l'organisation des nœuds de Ranvier dans le système nerveux central et périphérique. Nous avons également caractérisé en détail le comportement des souris HET KI-I236S, en utilisant une batterie de tests qui peuvent indiquer des déficits cognitifs, moteurs et sensorimoteurs. De façon intéressante, les souris HET KI-I236S présentent des déficits cognitifs et somatosensoriels dépendants du sexe par rapport aux souris de type sauvage (interaction sociale légèrement réduite chez les femelles ; sensibilité à la chaleur et force musculaire légèrement réduites chez les mâles). Elles présentent également des altérations sexe-dépendantes des axones myélinisés et des fibres C sensorielles non myélinisées du système nerveux périphérique. Les analyses du cerveau ne montrent pas de défauts majeurs de myélinisation chez les souris mutantes adultes, mais suggèrent que le variant pourrait perturber les fonctions de Caspr2 au début de la myélinisation, conduisant probablement à une accélération des processus de myélinisation à des stades précoces. Ainsi, nos résultats indiquent que les variants faux-sens hétérozygotes de CNTNAP2 tels que I236S peuvent affecter la fonction de Caspr2 de manière dépendante du sexe in vivo, et suggèrent que les variants de CNTNAP2 de la même classe pourraient être pathogènes et contribuer au développement des TSA chez les patients, et/ou contribuer à la variabilité interindividuelle dans les conditions physiologiques
Autism spectrum disorders (ASD) are neurodevelopmental disorders, defined by deficits in social interaction and restricted or repetitive behavior. ASD show high heritability, shaped by rare monogenic mutations, as well as variations in numerous susceptibility genes. Intriguingly, CNTNAP2, encoding the protein Caspr2, is considered to be one of the major ASD-risk genes, with a large number of heterozygous missense variants identified in patients. Cntnap2 knockout mice display ASD-related behavioral deficits supporting human genetic data. However, the clinical significance of the heterozygous variants has not yet been demonstrated and is still debated. The PhD project aimed to unravel this question by evaluating the pathogenicity of an inherited heterozygous missense CNTNAP2 variant identified in a French ASD patient, I236S, which was predicted to be disease-causing and may be representative of a large class of CNTNAP2 variants. We generated a novel knockin mouse model, the KI-I236S mice, and conducted a study comparing wild-type and KI-I236S heterozygous (HET) mice. Caspr2 is a neuronal cell-adhesion transmembrane glycoprotein originally identified in the juxtaparanodal regions of the nodes of Ranvier in mature myelinated neurons. Recently, studying Cntnap2 knockout mice the lab showed that Caspr2 also acts as a major regulator of axon development and myelination. In the brain, Caspr2 controls axon diameter at early postnatal developmental stages, cortical neuron intrinsic excitability at the onset of myelination, and axon diameter and myelin thickness at adulthood. Caspr2 also modulates axon diameter, myelin thickness and node of Ranvier morphology in peripheral nerves. We thus assessed the impact of the variant I235S on axon development, myelination, and node of Ranvier organization in both the central and peripheral nervous system, as well as thoroughly characterizing the behavior of HET KI-I236S mice, using a battery of tests that may indicate cognitive, motor, and sensorimotor deficits. Interestingly, KI-I236S HET mice display sex-dependent cognitive and somatosensory behavioral deficits as compared to wild-type mice (social interaction slightly decreased in females; heat sensitivity and muscular strength slightly decreased in males). They also show sex-dependent alterations in myelinated axons and unmyelinated sensory C-fibers of the peripheral nervous system. Brain analyses do not show major myelination defects in adult mutant mice, but suggest that the variant could perturb the functions of Caspr2 at the onset of myelination, leading likely to an acceleration of the myelination processes at early stages. Thus, our results indicate that CNTNAP2 heterozygous missense variants such as I236S can affect Caspr2 function in a sex-dependent manner in vivo and suggest that the CNTNAP2 variants of the same class could indeed be pathogenic and contribute to the development of ASD patients, and/or contribute to inter-individual variability in physiological conditions

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Os Transtornos do Espectro do Autismo (TEA) são afecções neuropsiquiátricas graves que se caracterizam por dificuldades, de início precoce, no domínio da comunicação social, por comportamentos atípicos, repetitivos e interesses restritos. Em cerca de 10 a 25% dos casos a etiologia pode ser esclarecida, o que reflete a natureza complexa e heterogênea da doença. Embora diversos fatores ambientais estejam relacionados com a etiopatogenia, muitos estudos, inclusive com gêmeos, mostram que a participação dos fatores genéticos é inequívoca. A literatura tem revelado, de maneira progressiva, muitos genes e variantes genéticas relacionados com a predisposição a estas afecções. Polimorfismos de nucleotídeo único (SNPs) têm sido considerados marcadores genéticos de predisposição a várias doenças complexas, o que sugere que também podem estar relacionados aos TEA. Há referências da associação de variantes comuns do gene sináptico CNTNAP2 com diferentes fenótipos neuropsiquiátricos e alterações no desenvolvimento da linguagem. SNPs do gene ADA, envolvido em neurotransmissão e metabolismo das purinas, também já foram associados a uma diminuição de atividade enzimática e predisposição ao fenótipo autista. Este estudo objetivou avaliar SNPs destes dois genes em autistas e controles, para investigar uma possível associação com o fenótipo comportamental. Foram avaliados dois SNPs (rs7794745 e rs2710102) do gene CNTNAP2 e o SNP G22A do gene ADA, genotipados em 210 indivíduos com TEA idiopático e em 200 indivíduos controles. A análise molecular foi feita por reação em cadeia da polimerase – polimorfismo de fragmentos de restrição (PCR-RFLP). Para análise estatística foi adotado nível de significância de 5%. Os resultados revelaram associação entre o SNP rs7794745 (OR=1,802, IC95%=1,054-3,083, p=0,042) em homozigose (TT) com a predisposição aos TEA na população estudada. Os indivíduos do sexo ...
Autism Spectrum Disorders (ASD) are severe neuropsychiatric disorders characterized by difficulties with early onset, in the field of social communication, atypical behaviors, restricted and repetitive interests. In about 10-25% of cases the etiology can be clarified, which reflects the complex and heterogeneous nature of the disease. Although several environmental factors are related to the pathogenesis, many studies, including twins, have showed that the involvement of genetic factors is clear. The literature has revealed, progressively, many genes and genetic variants related to the predisposition to these disorders. Single nucleotide polymorphisms (SNPs) have been considered genetic markers of predisposition to various diseases complex, suggesting that can also be related to ASD. There are references of association the common variants of the CNTNAP2 synaptic gene with different neuropsychiatric phenotypes and changes in language development. SNPs of ADA gene, involved in neurotransmission and metabolism of purines, have also been associated with a decrease in enzyme activity and predisposition to autism phenotype. This study aimed to evaluate SNPs of these two genes in autistic patients to investigate a possible association with the behavioral phenotype. It was evaluated two SNPs (rs7794745 and rs2710102) of the CNTNAP2 gene and the SNP G22A of the ADA gene, genotyped in 210 individuals with idiopathic ASD and 200 control subjects. Molecular analysis was performed by polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP). A 5% alpha error was considered significant in statistical analysis. The results revealed association between the SNP rs7794745 (OR = 1.802; 95%CI = 1.054 - 3.083; p = 0.042) in homozygous (TT) with predisposition to ASD at our study population. Affected individuals males also showed a significantly higher frequency of this polymorphism (p = 0.021) compared to men in the control group. For ...

Orientador: Agnes Cristina Fett-Conte
Banca: Ana Elizabete Silva
Banca: Karina Griesi Oliveira
Resumo: Os Transtornos do Espectro do Autismo (TEA) são afecções neuropsiquiátricas graves que se caracterizam por dificuldades, de início precoce, no domínio da comunicação social, por comportamentos atípicos, repetitivos e interesses restritos. Em cerca de 10 a 25% dos casos a etiologia pode ser esclarecida, o que reflete a natureza complexa e heterogênea da doença. Embora diversos fatores ambientais estejam relacionados com a etiopatogenia, muitos estudos, inclusive com gêmeos, mostram que a participação dos fatores genéticos é inequívoca. A literatura tem revelado, de maneira progressiva, muitos genes e variantes genéticas relacionados com a predisposição a estas afecções. Polimorfismos de nucleotídeo único (SNPs) têm sido considerados marcadores genéticos de predisposição a várias doenças complexas, o que sugere que também podem estar relacionados aos TEA. Há referências da associação de variantes comuns do gene sináptico CNTNAP2 com diferentes fenótipos neuropsiquiátricos e alterações no desenvolvimento da linguagem. SNPs do gene ADA, envolvido em neurotransmissão e metabolismo das purinas, também já foram associados a uma diminuição de atividade enzimática e predisposição ao fenótipo autista. Este estudo objetivou avaliar SNPs destes dois genes em autistas e controles, para investigar uma possível associação com o fenótipo comportamental. Foram avaliados dois SNPs (rs7794745 e rs2710102) do gene CNTNAP2 e o SNP G22A do gene ADA, genotipados em 210 indivíduos com TEA idiopático e em 200 indivíduos controles. A análise molecular foi feita por reação em cadeia da polimerase - polimorfismo de fragmentos de restrição (PCR-RFLP). Para análise estatística foi adotado nível de significância de 5%. Os resultados revelaram associação entre o SNP rs7794745 (OR=1,802, IC95%=1,054-3,083, p=0,042) em homozigose (TT) com a predisposição aos TEA na população estudada. Os indivíduos do sexo ...
Abstract: Autism Spectrum Disorders (ASD) are severe neuropsychiatric disorders characterized by difficulties with early onset, in the field of social communication, atypical behaviors, restricted and repetitive interests. In about 10-25% of cases the etiology can be clarified, which reflects the complex and heterogeneous nature of the disease. Although several environmental factors are related to the pathogenesis, many studies, including twins, have showed that the involvement of genetic factors is clear. The literature has revealed, progressively, many genes and genetic variants related to the predisposition to these disorders. Single nucleotide polymorphisms (SNPs) have been considered genetic markers of predisposition to various diseases complex, suggesting that can also be related to ASD. There are references of association the common variants of the CNTNAP2 synaptic gene with different neuropsychiatric phenotypes and changes in language development. SNPs of ADA gene, involved in neurotransmission and metabolism of purines, have also been associated with a decrease in enzyme activity and predisposition to autism phenotype. This study aimed to evaluate SNPs of these two genes in autistic patients to investigate a possible association with the behavioral phenotype. It was evaluated two SNPs (rs7794745 and rs2710102) of the CNTNAP2 gene and the SNP G22A of the ADA gene, genotyped in 210 individuals with idiopathic ASD and 200 control subjects. Molecular analysis was performed by polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP). A 5% alpha error was considered significant in statistical analysis. The results revealed association between the SNP rs7794745 (OR = 1.802; 95%CI = 1.054 - 3.083; p = 0.042) in homozygous (TT) with predisposition to ASD at our study population. Affected individuals males also showed a significantly higher frequency of this polymorphism (p = 0.021) compared to men in the control group. For ...
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