scholarly journals Two Novel Compound Heterozygous Mutations in the TRAPPC9 Gene Reveal a Connection of Non-syndromic Intellectual Disability and Autism Spectrum Disorder

2021 ◽  
Vol 11 ◽  
Author(s):  
Johannes Krämer ◽  
Meinrad Beer ◽  
Harald Bode ◽  
Benedikt Winter
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
Structural Changes ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Speech Development ◽  
Spectrum Disorder ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Cerebral Mri

IntroductionAutism spectrum disorder (ASD) is characterized by deficits in communication, social interaction, and repetitive behavior. Up to 70% of ASD cases are linked with intellectual disability (ID). The major genetic causes for ASD and ID are largely unknown, however, a shared genetic etiology between ASD and ID must be assumed. The trafficking protein particle complex subunit 9 (TRAPPC9) is highly expressed in postmitotic neurons of the cerebral cortex, playing a key role in development. Among 43 reported cases with mutations in TRAPPC9, all (100%) showed ID and developmental delay. Among the cases including information about ASD, 26% were affected (19 cases with information, among them 5 with ASD). Nevertheless, in some cases not classified as ASD, descriptions of autistic features like hand-flapping movements were present.Clinical FindingsThe affected individual presented with delay of speech development. Physical development was normal. Besides lateral slope of the eye-lid axis no facial abnormalities were evident. The individual was diagnosed with ID and ASD by structured testing. Cerebral MRI revealed associated abnormalities.Genetical FindingsThe chromosome set was 46,XY without structural changes. Array-CGH showed a normal molecular karyotype (arr(1-22)x2,(X,Y)x1). PCR for the FMR1 gene showed 41 ± 1 CGG repeats, and therefore no evidence of fragile X syndrome. A panel diagnostic for syndromal ID (CASK, EP300, HIVEP2, KIF1A, TRAPPC9) revealed two structural changes in TRAPPC9 in the compound heterozygosity. The mutations c.1678C > T (p.Arg560Cys) and c.3370C > T (p.Pro1124Ser) are classified as missense mutations and are both not described in the literature.ConclusionWe report two new missense mutations in the TRAPPC9 gene in one individual with ID and ASD. The TRAPPC9 gene should be part of the diagnostic assessment in ID. ASD must be considered as a feature of TRAPPC9-associated ID. It might have been neglected in the literature and should result in specific testing for ASD in affected individuals.

scholarly journals Biallelic SYNE2 Missense Mutations Leading to Nesprin-2 Giant Hypo-Expression Are Associated with Intellectual Disability and Autism

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1294
Author(s):  
Natalie Young ◽  
Maria Asif ◽  
Matthew Jackson ◽  
Daniel Martín Fernández-Mayoralas ◽  
Mar Jimenez de la Peña ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
Quantitative Polymerase Chain Reaction ◽  
Transcript Level ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Spectrin Repeat ◽  
Protein Levels

Autism spectrum disorder (ASD) is a group of neurological and developmental disabilities characterised by clinical and genetic heterogeneity. The current study aimed to expand ASD genotyping by investigating potential associations with SYNE2 mutations. Specifically, the disease-causing variants of SYNE2 in 410 trios manifesting neurodevelopmental disorders using whole-exome sequencing were explored. The consequences of the identified variants were studied at the transcript level using quantitative polymerase chain reaction (qPCR). For validation, immunofluorescence and immunoblotting were performed to analyse mutational effects at the protein level. The compound heterozygous variants of SYNE2 (NM_182914.3:c.2483T>G; p.(Val828Gly) and NM_182914.3:c.2362G>A; p.(Glu788Lys)) were identified in a 4.5-year-old male, clinically diagnosed with autism spectrum disorder, developmental delay and intellectual disability. Both variants reside within the nesprin-2 giant spectrin repeat (SR5) domain and are predicted to be highly damaging using in silico tools. Specifically, a significant reduction of nesprin-2 giant protein levels is revealed in patient cells. SYNE2 transcription and the nuclear envelope localisation of the mutant proteins was however unaffected as compared to parental control cells. Collectively, these data provide novel insights into the cardinal role of the nesprin-2 giant in neurodevelopment and suggest that the biallelic hypomorphic SYNE2 mutations may be a new cause of intellectual disability and ASD.

scholarly journals The Potential Effect of Nav1.8 in Autism Spectrum Disorder: Evidence From a Congenital Case With Compound Heterozygous SCN10A Mutations

2021 ◽  
Vol 14 ◽  
Author(s):  
Björn Heinrichs ◽  
Baowen Liu ◽  
Jin Zhang ◽  
Jannis E. Meents ◽  
Kim Le ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Expression System ◽  
Repetitive Behavior ◽  
Potential Effect ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Behavioral Experiments ◽  
Sensory Reactivity

Apart from the most prominent symptoms in Autism spectrum disorder (ASD), namely deficits in social interaction, communication and repetitive behavior, patients often show abnormal sensory reactivity to environmental stimuli. Especially potentially painful stimuli are reported to be experienced in a different way compared to healthy persons. In our present study, we identified an ASD patient carrying compound heterozygous mutations in the voltage-gated sodium channel (VGSC) Nav1.8, which is preferentially expressed in sensory neurons. We expressed both mutations, p.I1511M and p.R512∗, in a heterologous expression system and investigated their biophysical properties using patch-clamp recordings. The results of these experiments reveal that the p.R512∗ mutation renders the channel non-functional, while the p.I1511M mutation showed only minor effects on the channel’s function. Behavioral experiments in a Nav1.8 loss-of-function mouse model additionally revealed that Nav1.8 may play a role in autism-like symptomatology. Our results present Nav1.8 as a protein potentially involved in ASD pathophysiology and may therefore offer new insights into the genetic basis of this disease.

scholarly journals The Potential Effect of Nav1.8 in Autism Spectrum Disorder: Evidence from a Congenital Case with Compound Heterozygous SCN10A Mutations

2020 ◽  
Author(s):  
Björn Heinrichs ◽  
Baowen Liu ◽  
Jin Zhang ◽  
Jannis E Meents ◽  
Kim Le ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Expression System ◽  
Repetitive Behavior ◽  
Potential Effect ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Behavioral Experiments ◽  
Sensory Reactivity

Abstract Apart from the most prominent symptoms in Autism spectrum disorder (ASD), namely deficits in social interaction and repetitive behavior, patients often show abnormal sensory reactivity to environmental stimuli. Especially potentially painful stimuli are reported to be experienced in a different way compared to healthy persons. In our present study, we present an ASD patient carrying compound heterozygous mutations in the voltage-gated sodium channel (VGSC) Nav1.8, which is preferentially expressed in sensory neurons. We expressed both identified mutations, p.I1511M and p.R512X, in a heterologous expression system and investigated their biophysical properties using patch-clamp recordings. The results of these experiments suggest that both mutations lead to different degrees of loss-of-function of Nav1.8. Behavioral experiments in a Nav1.8 loss-of-function mouse model additionally revealed Nav1.8 may play a role in autistic behavior. Our results present Nav1.8 as a protein potentially involved in ASD pathophysiology and may therefore offer new insights to the genetic basis of this disease.

scholarly journals The Potential Effect of Nav1.8 in Autism Spectrum Disorder: Evidence from A Congenital Case with Compound Heterozygous SCN10A Mutations

2020 ◽  
Author(s):  
Björn Heinrichs ◽  
Baowen Liu ◽  
Jin Zhang ◽  
Jannis Meents ◽  
Kim Le ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Expression System ◽  
Repetitive Behavior ◽  
Potential Effect ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Behavioral Experiments

Abstract BackgroundApart from the most prominent symptoms in Autism spectrum disorder (ASD), namely deficits in social interaction and repetitive behavior, patients often show abnormal sensory reactivity to environmental stimuli. Especially potentially painful stimuli are reported to be experienced in a different way compared to healthy persons.MethodsIn our present study, we present an ASD patient carrying compound heterozygous mutations in the voltage-gated sodium channel (VGSC) Nav1.8, which is preferentially expressed in sensory neurons. We expressed both identified mutations, p.I1511M and p.R512X, in a heterologous expression system and investigated their biophysical properties using patch-clamp recordings. ResultsThe results of these experiments suggest that both mutations lead to different degrees of loss-of-function of Nav1.8. Behavioral experiments in a Nav1.8 loss-of-function mouse model additionally revealed Nav1.8 may play a role in autistic behavior. LimitationsOur study did not verified the functions of p.I1511M and p.R512X mutations in vivo. The mice with these mutations can be constructed to verify the mutation functions in the future investigations. In addition, since we have only found one ASD patient which may relate to SCN10A mutations, the role of Nav1.8 in ASD needs to be confirmed in more cases. Moreover, the cellular mechanism underlying the effect of Nav1.8 on ASD needed to be explored in future studies.ConclusionsOur results present Nav1.8 as a protein potentially involved in ASD pathophysiology and may therefore offer new insights to the genetic basis of this disease.

scholarly journals The Gut-Brain Axis in Autism Spectrum Disorder: A Focus on the Metalloproteases ADAM10 and ADAM17

2020 ◽  
Vol 22 (1) ◽  
pp. 118
Author(s):  
Yuanpeng Zheng ◽  
Tessa A. Verhoeff ◽  
Paula Perez Pardo ◽  
Johan Garssen ◽  
Aletta D. Kraneveld
Keyword(s):  
Autism Spectrum Disorder ◽  
Intestinal Tract ◽  
Synapse Formation ◽  
Inflammatory Responses ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Protein Substrates ◽  
Specific Proteins ◽  
Membrane Bound

Autism Spectrum Disorder (ASD) is a spectrum of disorders that are characterized by problems in social interaction and repetitive behavior. The disease is thought to develop from changes in brain development at an early age, although the exact mechanisms are not known yet. In addition, a significant number of people with ASD develop problems in the intestinal tract. A Disintegrin And Metalloproteases (ADAMs) include a group of enzymes that are able to cleave membrane-bound proteins. ADAM10 and ADAM17 are two members of this family that are able to cleave protein substrates involved in ASD pathogenesis, such as specific proteins important for synapse formation, axon signaling and neuroinflammation. All these pathological mechanisms are involved in ASD. Besides the brain, ADAM10 and ADAM17 are also highly expressed in the intestines. ADAM10 and ADAM17 have implications in pathways that regulate gut permeability, homeostasis and inflammation. These metalloproteases might be involved in microbiota-gut–brain axis interactions in ASD through the regulation of immune and inflammatory responses in the intestinal tract. In this review, the potential roles of ADAM10 and ADAM17 in the pathology of ASD and as targets for new therapies will be discussed, with a focus on the gut–brain axis.

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