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

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.

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

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.709228 ◽

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.

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

10.21203/rs.3.rs-77513/v1 ◽

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.

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

Frontiers in Genetics ◽

10.3389/fgene.2020.00972 ◽

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.

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Early differences in auditory processing relate to Autism Spectrum Disorder traits in infants with Neurofibromatosis Type I

Journal of Neurodevelopmental Disorders ◽

10.1186/s11689-021-09364-3 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Jannath Begum-Ali ◽

◽

Anna Kolesnik-Taylor ◽

Isabel Quiroz ◽

Luke Mason ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Auditory Processing ◽

Neurofibromatosis Type ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Type I ◽

Sensory Reactivity ◽

Auditory Responses ◽

Repetition Suppression ◽

Age Related

Abstract Background Sensory modulation difficulties are common in children with conditions such as Autism Spectrum Disorder (ASD) and could contribute to other social and non-social symptoms. Positing a causal role for sensory processing differences requires observing atypical sensory reactivity prior to the emergence of other symptoms, which can be achieved through prospective studies. Methods In this longitudinal study, we examined auditory repetition suppression and change detection at 5 and 10 months in infants with and without Neurofibromatosis Type 1 (NF1), a condition associated with higher likelihood of developing ASD. Results In typically developing infants, suppression to vowel repetition and enhanced responses to vowel/pitch change decreased with age over posterior regions, becoming more frontally specific; age-related change was diminished in the NF1 group. Whilst both groups detected changes in vowel and pitch, the NF1 group were largely slower to show a differentiated neural response. Auditory responses did not relate to later language, but were related to later ASD traits. Conclusions These findings represent the first demonstration of atypical brain responses to sounds in infants with NF1 and suggest they may relate to the likelihood of later ASD.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22010118 ◽

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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A loss-of-function variant in SUV39H2 identified in autism-spectrum disorder causes altered H3K9 trimethylation and dysregulation of protocadherin β-cluster genes in the developing brain

Molecular Psychiatry ◽

10.1038/s41380-021-01199-7 ◽

2021 ◽

Author(s):

Shabeesh Balan ◽

Yoshimi Iwayama ◽

Tetsuo Ohnishi ◽

Mikiko Fukuda ◽

Atsuko Shirai ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Autism Spectrum ◽

Developing Brain ◽

Spectrum Disorder ◽

Loss Of Function ◽

H3k9 Trimethylation

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Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings

Genes ◽

10.3390/genes12071053 ◽

2021 ◽

Vol 12 (7) ◽

pp. 1053

Author(s):

Jasleen Dhaliwal ◽

Ying Qiao ◽

Kristina Calli ◽

Sally Martell ◽

Simone Race ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Rare Variants ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Compound Heterozygous ◽

Variable Effect ◽

Gabaergic Neurotransmission ◽

High Heritability ◽

Compound Heterozygous Variants

Autism Spectrum Disorder (ASD) is the most common neurodevelopmental disorder in children and shows high heritability. However, how inherited variants contribute to ASD in multiplex families remains unclear. Using whole-genome sequencing (WGS) in a family with three affected children, we identified multiple inherited DNA variants in ASD-associated genes and pathways (RELN, SHANK2, DLG1, SCN10A, KMT2C and ASH1L). All are shared among the three children, except ASH1L, which is only present in the most severely affected child. The compound heterozygous variants in RELN, and the maternally inherited variant in SHANK2, are considered to be major risk factors for ASD in this family. Both genes are involved in neuron activities, including synaptic functions and the GABAergic neurotransmission system, which are highly associated with ASD pathogenesis. DLG1 is also involved in synapse functions, and KMT2C and ASH1L are involved in chromatin organization. Our data suggest that multiple inherited rare variants, each with a subthreshold and/or variable effect, may converge to certain pathways and contribute quantitatively and additively, or alternatively act via a 2nd-hit or multiple-hits to render pathogenicity of ASD in this family. Additionally, this multiple-hits model further supports the quantitative trait hypothesis of a complex genetic, multifactorial etiology for the development of ASDs.

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2288 Neural correlates of face processing in autism spectrum disorder: A quantitative meta-analysis of current literature and future directions

Journal of Clinical and Translational Science ◽

10.1017/cts.2018.100 ◽

2018 ◽

Vol 2 (S1) ◽

pp. 21-22

Author(s):

Carla J. Ammons ◽

Mary-Elizabeth Winslett ◽

Rajesh K. Kana

Keyword(s):

Autism Spectrum Disorder ◽

Face Processing ◽

Repetitive Behavior ◽

Autism Spectrum ◽

Small Sample ◽

Spectrum Disorder ◽

Future Research ◽

Healthy Controls ◽

Specific Level

OBJECTIVES/SPECIFIC AIMS: Autism spectrum disorder (ASD) affects 1 in 68 people and includes restricted, repetitive behavior, and social communication deficits. Aspects of face processing (i.e., identity, emotion perception) are impaired in some with ASD. Neuroimaging studies have shown aberrant patterns of brain activation and connectivity of face processing regions. However, small sample sizes and inconsistent results have hindered clinical utility of these findings. The study aims to establish consistent patterns of brain responses to faces in ASD and provide directions for future research. METHODS/STUDY POPULATION: Neuroimaging studies were identified through a multi-database search according to PRISMA guidelines. In total, 23 studies were retained for a sample size of 383 healthy controls and 345 ASD. Peak coordinates were extracted for activation likelihood estimation (ALE) in GingerALE v2.3.6. Follow-up ALE analyses investigated directed Versus undirected gaze, static Versus dynamic, emotional Versus neutral, and familiar Versus unfamiliar faces. RESULTS/ANTICIPATED RESULTS: Faces produced bilateral activation of the fusiform gyrus (FG) in healthy controls (−42 −52 −20; 22 −74 −12, p<0.05, FDR) and left FG activation in ASD (−42 −54 −16, p<0.05, FDR). Activation in both groups was lateral to the mid-fusiform sulcus. Follow-up results pending. DISCUSSION/SIGNIFICANCE OF IMPACT: Reduced right FG activation to faces may inform biomarker or response to intervention studies. Mid-fusiform sulcus proved a reliable predictor of functional divides should be investigated on a subject-specific level.

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