scholarly journals An Autism-Associated de novo Mutation in GluN2B Destabilizes Growing Dendrites by Promoting Retraction and Pruning

2021 ◽  
Vol 15 ◽  
Author(s):  
Jacob A. Bahry ◽  
Karlie N. Fedder-Semmes ◽  
Michael P. Sceniak ◽  
Shasta L. Sabo
Keyword(s):  
De Novo ◽  
Time Lapse ◽  
Autism Spectrum ◽  
Dendrite Growth ◽  
De Novo Mutation ◽  
Neocortical Neurons ◽  
Spectrum Disorders ◽  
Dendritic Branches ◽  
Dendrite Morphogenesis ◽  
Time Lapse Imaging

Mutations in GRIN2B, which encodes the GluN2B subunit of NMDA receptors, lead to autism spectrum disorders (ASD), but the pathophysiological mechanisms remain unclear. Recently, we showed that a GluN2B variant that is associated with severe ASD (GluN2B724t) impairs dendrite morphogenesis. To determine which aspects of dendrite growth are affected by GluN2B724t, we investigated the dynamics of dendrite growth and branching in rat neocortical neurons using time-lapse imaging. GluN2B724t expression shifted branch motility toward retraction and away from extension. GluN2B724t and wild-type neurons formed new branches at similar rates, but mutant neurons exhibited increased pruning of dendritic branches. The observed changes in dynamics resulted in nearly complete elimination of the net expansion of arbor size and complexity that is normally observed during this developmental period. These data demonstrate that ASD-associated mutant GluN2B interferes with dendrite morphogenesis by reducing rates of outgrowth while promoting retraction and subsequent pruning. Because mutant dendrites remain motile and capable of growth, it is possible that reducing pruning or promoting dendrite stabilization could overcome dendrite arbor defects associated with GRIN2B mutations.

scholarly journals Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kohei Kitagawa ◽  
Kensuke Matsumura ◽  
Masayuki Baba ◽  
Momoka Kondo ◽  
Tomoya Takemoto ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Behavior ◽  
Mouse Model ◽  
Mouse Models ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutation ◽  
Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

scholarly journals CACNA1D De Novo Mutations in Autism Spectrum Disorders Activate Cav1.3 L-Type Calcium Channels

2015 ◽  
Vol 77 (9) ◽  
pp. 816-822 ◽  
Author(s):  
Alexandra Pinggera ◽  
Andreas Lieb ◽  
Bruno Benedetti ◽  
Michaela Lampert ◽  
Stefania Monteleone ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Calcium Channels ◽  
De Novo ◽  
Autism Spectrum ◽  
De Novo Mutations ◽  
Spectrum Disorders

scholarly journals Patterns and rates of exonic de novo mutations in autism spectrum disorders

Nature ◽  
2012 ◽  
Vol 485 (7397) ◽  
pp. 242-245 ◽  
Author(s):  
Benjamin M. Neale ◽  
Yan Kou ◽  
Li Liu ◽  
Avi Ma’ayan ◽  
Kaitlin E. Samocha ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
De Novo ◽  
Autism Spectrum ◽  
De Novo Mutations ◽  
Spectrum Disorders

scholarly journals An autism spectrum disorder-related de novo mutation hotspot discovered in the GEF1 domain of Trio

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Anastasiia Sadybekov ◽  
Chen Tian ◽  
Cosimo Arnesano ◽  
Vsevolod Katritch ◽  
Bruce E. Herring
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutation

scholarly journals Progress Towards Simple and Direct Detection of Adenylosuccinate Lyase Deficiency in Human Urine

2011 ◽  
Vol 64 (11) ◽  
pp. 1470 ◽  
Author(s):  
Soojin Lim ◽  
Mark Lowry ◽  
Robert M. Strongin
Keyword(s):  
Autism Spectrum Disorders ◽  
Human Urine ◽  
Boronic Acid ◽  
De Novo ◽  
Direct Detection ◽  
Autism Spectrum ◽  
Purine Synthesis ◽  
Adenylosuccinate Lyase ◽  
Adenylosuccinate Lyase Deficiency ◽  
Spectrum Disorders

A rhodamine based boronic acid linearly responds to increasing 5-aminoimidazole-4-carboxamide riboside (AICAr) concentrations in human urine. This method is thus an advance in detecting adenylosuccinate lyase (ADSL) deficiency as AICAr is a model riboside for the ADSL substrates succinyladenosine (S-Ado) and succinylaminoimidazolecarboxamide riboside (SAICAr). ADSL deficiency is a rare but devastating disease of de novo purine synthesis in infants. Its diagnosis is also significant as it is one of the autism spectrum disorders.

scholarly journals Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Nadja T. Hofer ◽  
Petronel Tuluc ◽  
Nadine J. Ortner ◽  
Yuliia V. Nikonishyna ◽  
Monica L. Fernándes-Quintero ◽  
...  
Keyword(s):  
High Risk ◽  
Neurodevelopmental Disorders ◽  
Developmental Disorder ◽  
De Novo ◽  
Disease Risk ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
De Novo Mutation ◽  
Loss Of Function ◽  
Gain Of Function

Abstract Background There is increasing evidence that de novo CACNA1D missense mutations inducing increased Cav1.3 L-type Ca2+-channel-function confer a high risk for neurodevelopmental disorders (autism spectrum disorder with and without neurological and endocrine symptoms). Electrophysiological studies demonstrating the presence or absence of typical gain-of-function gating changes could therefore serve as a tool to distinguish likely disease-causing from non-pathogenic de novo CACNA1D variants in affected individuals. We tested this hypothesis for mutation S652L, which has previously been reported in twins with a severe neurodevelopmental disorder in the Deciphering Developmental Disorder Study, but has not been classified as a novel disease mutation. Methods For functional characterization, wild-type and mutant Cav1.3 channel complexes were expressed in tsA-201 cells and tested for typical gain-of-function gating changes using the whole-cell patch-clamp technique. Results Mutation S652L significantly shifted the voltage-dependence of activation and steady-state inactivation to more negative potentials (~ 13–17 mV) and increased window currents at subthreshold voltages. Moreover, it slowed tail currents and increased Ca2+-levels during action potential-like stimulations, characteristic for gain-of-function changes. To provide evidence that only gain-of-function variants confer high disease risk, we also studied missense variant S652W reported in apparently healthy individuals. S652W shifted activation and inactivation to more positive voltages, compatible with a loss-of-function phenotype. Mutation S652L increased the sensitivity of Cav1.3 for inhibition by the dihydropyridine L-type Ca2+-channel blocker isradipine by 3–4-fold. Conclusions and limitations Our data provide evidence that gain-of-function CACNA1D mutations, such as S652L, but not loss-of-function mutations, such as S652W, cause high risk for neurodevelopmental disorders including autism. This adds CACNA1D to the list of novel disease genes identified in the Deciphering Developmental Disorder Study. Although our study does not provide insight into the cellular mechanisms of pathological Cav1.3 signaling in neurons, we provide a unifying mechanism of gain-of-function CACNA1D mutations as a predictor for disease risk, which may allow the establishment of a more reliable diagnosis of affected individuals. Moreover, the increased sensitivity of S652L to isradipine encourages a therapeutic trial in the two affected individuals. This can address the important question to which extent symptoms are responsive to therapy with Ca2+-channel blockers.

scholarly journals High-throughput sequencing of autism spectrum disorders comes of age

2013 ◽  
Vol 95 (4) ◽  
pp. 121-129 ◽  
Author(s):  
MINGBANG WANG ◽  
XIAOMEI FAN ◽  
TAO WANG ◽  
JINYU WU
Keyword(s):  
Autism Spectrum Disorders ◽  
High Throughput ◽  
High Throughput Sequencing ◽  
De Novo ◽  
Autism Spectrum ◽  
Disease Gene Discovery ◽  
The Usa ◽  
High Heritability ◽  
Spectrum Disorders ◽  
Promising Perspective

SummaryAutism spectrum disorders (ASDs) are lifelong neurodevelopmental disabilities that affect 1 in 88 children in the USA. Despite the high heritability, the genetic basis for a majority of the ASDs remains elusive. The considerable clinical and genetic heterogeneity pose a significant challenge technically. State-of-the-art high-throughput sequencing (HTS), which makes the analyses of any specific single/multiple genes or whole exomes feasible, has shown a promising perspective in disease gene discovery. To date, numerous genetic studies using HTS have been reported and many rare inherited or de novo mutations have been identified. This review will focus on the progress and prospective of genome studies of ASDs using HTS.

scholarly journals Adducted Thumb and Peripheral Polyneuropathy: Diagnostic Supports in Suspecting White–Sutton Syndrome: Case Report and Review of the Literature

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 950
Author(s):  
Gabriele Trimarchi ◽  
Stefano Giuseppe Caraffi ◽  
Francesca Clementina Radio ◽  
Sabina Barresi ◽  
Gianluca Contrò ◽  
...  
Keyword(s):  
De Novo ◽  
Clinical Signs ◽  
Autism Spectrum ◽  
Chromosome 1 ◽  
Clinical Feature ◽  
Feeding Difficulties ◽  
Brain Malformations ◽  
Peripheral Polyneuropathy ◽  
Spectrum Disorders ◽  
Sleep Difficulties

One of the recently described syndromes emerging from the massive study of cohorts of undiagnosed patients with autism spectrum disorders (ASD) and syndromic intellectual disability (ID) is White–Sutton syndrome (WHSUS) (MIM #616364), caused by variants in the POGZ gene (MIM *614787), located on the long arm of chromosome 1 (1q21.3). So far, more than 50 individuals have been reported worldwide, although phenotypic features and natural history have not been exhaustively characterized yet. The phenotypic spectrum of the WHSUS is broad and includes moderate to severe ID, microcephaly, variable cerebral malformations, short stature, brachydactyly, visual abnormalities, sensorineural hearing loss, hypotonia, sleep difficulties, autistic features, self-injurious behaviour, feeding difficulties, gastroesophageal reflux, and other less frequent features. Here, we report the case of a girl with microcephaly, brain malformations, developmental delay (DD), peripheral polyneuropathy, and adducted thumb—a remarkable clinical feature in the first years of life—and heterozygous for a previously unreported, de novo splicing variant in POGZ. This report contributes to strengthen and expand the knowledge of the clinical spectrum of WHSUS, pointing out the importance of less frequent clinical signs as diagnostic handles in suspecting this condition.

Sign in / Sign up

Export Citation Format

Share Document