scholarly journals A new homozygous CACNB2 mutation has functional relevance and supports a role for calcium channels in autism spectrum disorder

2019 ◽  
Author(s):  
Claudio Graziano ◽  
Patrick Despang ◽  
Flavia Palombo ◽  
Giulia Severi ◽  
Annio Posar ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Calcium Channels ◽  
Calcium Channel ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Site Directed Mutagenesis ◽  
Global Developmental Delay ◽  
Whole Cell ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels

Abstract BackgroundDiagnostic yield in patients with autism spectrum disorder (ASD) has improved over the last years, thanks to the introduction of whole genome arrays and next generation sequencing, but etiology is still unknown for the majority of cases. Among distinct cellular pathways, evidence implicating dysregulation of cellular calcium homeostasis in ASD pathogenesis has been accumulating, and specific mutations in voltage-gated calcium channels found in patients with autism were shown to be functionally relevant.MethodsWhole exome sequencing and Sanger sequencing were performed to identify and confirm variants in a girl with ASD, global developmental delay and precocious puberty, born of first-degree cousins. Site-directed mutagenesis was used to generate a human CaVβ2d calcium channel subunit carrying a CACNB2 mutation. Whole-cell patch-clamp recordings were performed to reveal functional effects of mutant CaVβ2d on Ba2+-currents mediated by L-type (CaV1.2) calcium channels in transiently transfected HEK-293 cells.ResultsIn an ASD patient, we identified a rare homozygous variant (p.Arg70Cys) in the CACNB2 gene coding for the auxiliary CaVβ2subunit of voltage-gated calcium channels. In a recombinant system, the CaVβ2 variant, which was not previously associated to ASD, was found to alter CaV1.2 calcium channel function by significantly affecting activation and inactivation of whole-cell Ba2+-currents.LimitationsAlthough the evidence of CACNB2 involvement in ASD is slowly accumulating, the number of reported patients is very limited. Deep clinical phenotyping and functional studies in larger sets of subjects will be instrumental to fully understand the penetrance and outcome of CACNB2 variants.ConclusionsThe p.Arg70Cys variant in CACNB2 shows functional consequences similar to other ASD-associated CaVβ2 mutations. These results support the idea of CACNB2 variations contributing to the development of ASD and hint to a rare form of Mendelian recessive autism with possible specific comorbidities.

scholarly journals Voltage-gated calcium channel blockers for psychiatric disorders: genomic reappraisal

2019 ◽  
Vol 216 (5) ◽  
pp. 250-253 ◽  
Author(s):  
Paul J. Harrison ◽  
Elizabeth M. Tunbridge ◽  
Annette C. Dolphin ◽  
Jeremy Hall
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Psychiatric Disorders ◽  
Calcium Channel Blockers ◽  
Channel Blockers ◽  
Risk Genes ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Voltage Gated Calcium Channel ◽  
Second Use

SummaryWe reappraise the psychiatric potential of calcium channel blockers (CCBs). First, voltage-gated calcium channels are risk genes for several disorders. Second, use of CCBs is associated with altered psychiatric risks and outcomes. Third, research shows there is an opportunity for brain-selective CCBs, which are better suited to psychiatric indications.

OP312 Developing A Tool-kit For Assessment Of Autism Spectrum Disorder

2021 ◽  
Vol 37 (S1) ◽  
pp. 12-12
Author(s):  
Leah Watson ◽  
Shirley Jonathan
Keyword(s):  
Autism Spectrum Disorder ◽  
Language Disorder ◽  
Autism Spectrum ◽  
Early Years ◽  
Spectrum Disorder ◽  
Global Developmental Delay ◽  
Evidence Based ◽  
Speech And Language ◽  
Autism Symptoms ◽  
Therapy Assessment

IntroductionBefore the coronavirus pandemic, children who were on the Early Years Neurodevelopment (EYND) assessment pathway and suspected to have possible Autism Spectrum Disorder (ASD), received clinic based appointments. This process included a parental interview by a doctor, a specialist speech and language therapy assessment, autism diagnostic observation schedule (ADOS), which were all carried out on hospital sites. These were postponed in March following national guidance. Our aim was to continue providing accurate evidence-based service for ASD diagnosis.MethodsWe utilised evidence-based telehealth methods to perform a specialist speech and language assessment in a child's home via video call. Parents were also invited to share videos of everyday activities via a secure portal. We could observe the child in a meaningful setting and witness functional impact of their needs. Each case is discussed by a multiagency panel based on DSM-V criteria.Online training was undertaken by professionals to deliver the Brief Observation of Autism Symptoms (BOSA) based on the ADOS for COVID times. Parents were coached by the therapist to enable them to become the administrator, rather than a professional.ResultsTelephonic feedback from the first ten parents whose children underwent a telehealth assessment has been positive; the home was deemed more natural and for some less distressing than clinic. Formal patient surveys have been devised for both the telehealth and BOSA clinic assessments. Analysis is expected by the end of March.To date we have been able to reach an outcome for thirty children, the diagnosis of ASD for twenty-four children and the other six received a diagnosis of global developmental delay or language disorder.ConclusionsWe expect that telehealth will reduce the number of assessments before an ASD diagnosis is made resulting in more prudent healthcare. The new methods have demonstrated clear increased parental participation.

A homozygous missense mutation inHERC2associated with global developmental delay and autism spectrum disorder

2012 ◽  
Vol 33 (12) ◽  
pp. 1639-1646 ◽  
Author(s):  
Erik G. Puffenberger ◽  
Robert N. Jinks ◽  
Heng Wang ◽  
Baozhong Xin ◽  
Christopher Fiorentini ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Missense Mutation ◽  
Developmental Delay ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Global Developmental Delay ◽  
Homozygous Missense Mutation

scholarly journals A de novo TOP2B variant associated with global developmental delay and autism spectrum disorder

2020 ◽  
Vol 8 (3) ◽  
Author(s):  
Takuya Hiraide ◽  
Seiji Watanabe ◽  
Tomoko Matsubayashi ◽  
Kumiko Yanagi ◽  
Mitsuko Nakashima ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Developmental Delay ◽  
De Novo ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Global Developmental Delay

Modeling ion permeation through a bacterial voltage-gated calcium channel CaVAb using molecular dynamics simulations

2017 ◽  
Vol 13 (1) ◽  
pp. 208-214 ◽  
Author(s):  
Jamal Adiban ◽  
Yousef Jamali ◽  
Hashem Rafii-Tabar
Keyword(s):  
Molecular Dynamics ◽  
Calcium Channels ◽  
Calcium Channel ◽  
Molecular Dynamics Simulations ◽  
Selectivity Filter ◽  
Ion Permeation ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Voltage Gated Calcium Channel ◽  
Dynamics Simulations

Ca2+ion binds tightly to the center of the selectivity filter of voltage-gated calcium channels.

scholarly journals Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

2021 ◽  
Author(s):  
Felix Marbach ◽  
◽  
Georgi Stoyanov ◽  
Florian Erger ◽  
Constantine A. Stratakis ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Global Developmental Delay ◽  
Missense Variants ◽  
Large Patient ◽  
Significant Enrichment

Abstract Purpose We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). Methods Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Results Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.

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