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.

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

2020 ◽  
Author(s):  
Felix Marbach ◽  
Georgi Stoyanov ◽  
Florian Erger ◽  
Jill A. Rosenfeld ◽  
Erin Torti ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
In Vivo Studies ◽  
Global Developmental Delay ◽  
Missense Variants ◽  
Significant Enrichment

Purpose: We characterize the phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder, who carry heterozygous missense-variants of the PRKAR1B gene. Methods: Variants of PRKAR1B were identified by single-exome or trio-exome analysis. We contacted the families and physicians of the six individuals in order to collect clinical and phenotypic information. Results: PRKAR1B encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA), and is predominantly expressed in the central nervous system. Recent studies of patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B, and in vivo studies of the murine ortholog demonstrated altered hippocampal function and reduced neurogenic inflammation and long-term nociceptive pain in R1β-deficient mice. In our study, de novo origin of the PRKAR1B-variants could be confirmed in five out 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 has been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. Conclusion: Our study provides strong evidence for a novel, PRKAR1B-related neurodevelopmental disorder.

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 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

25. Identification of De novo, Deleterious Mutations through Exome Sequencing of Sporadic Autism Spectrum Disorder Trios

2018 ◽  
Author(s):  
Shalandra Wood
Keyword(s):  
Autism Spectrum Disorder ◽  
Exome Sequencing ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutations ◽  
Genetic Etiology ◽  
Affected Child ◽  
Biological Relevance

  Autism Spectrum Disorder (ASD) is a prevalent neurodevelopmental disorder that has a strong genetic component consisting of many genes contributing to its cause. To help understand this complex genetic etiology, we are looking for novel genes that may be involved in the reason individuals develop ASD. We are doing this by using 5 sporadic ASD cases to determine de novo mutations (mutations new to the affected child that are not previously found in the family). These sporadic cases ensure that the disorder is not likely to arise through any inherited mutations, but through a new mutation found solely in the affected child. We use a trio analysis in which the genes of the affected child are compared to those of their mother and father, so pure de novo single nucleotide polymorphisms (SNPs) can be determined. These SNPs are then filtered based on predicted deleterious effect, quality and biological relevance. Using whole-exome sequencing on these 5 sporadic trios numerous deleterious, de novo mutations have been determined. These are being reviewed for biological relevance, and will be validated using Sanger Sequencing. Of these proposed SNPs being validated a few, such as SHANK3 and DVL1, have previously been linked to ASD. Whereas others, such as C11orf31, are novel candidate genes for the disorder. Through this experiment our understanding of the genetic etiology of ASD continues to grow and evolve, leading to greater insight into this disorder and new directions for possible treatments

scholarly journals Evolutionary Action of de novo Missense Variants across Pathways Prioritizes Genes Linked to Autism and Predicts Patient Phenotypic Severity

2017 ◽  
Author(s):  
Amanda Koire ◽  
Christie Buchovecky ◽  
Panagiotis Katsonis ◽  
Young Won Kim ◽  
Stephen J. Wilson ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Synaptic Transmission ◽  
De Novo ◽  
Missense Variant ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Integrative Approach ◽  
Missense Mutations ◽  
Functional Impact ◽  
Missense Variants

AbstractThe pathogenicity of individual de novo missense mutations in autism spectrum disorder remains difficult to validate. Here we asked in 2,384 probands whether these variants exhibited collective functional impact biases across pathways. As measured with Evolutionary Action (EA) in 368 gene groupings, we found significant biases in axonogenesis, synaptic transmission, and other neurodevelopmental pathways. Strikingly, both de novo and inherited missense variants in prioritized genes correlated with patient IQ. This general integrative approach thus detects missense variants most likely to contribute to autism pathogenesis and is the first, to our knowledge, to link missense variant impact to autism phenotypic severity.

scholarly journals An Overview of Genetic and Environmental Risk of Autism Spectrum Disorder

2019 ◽  
pp. 37-44 ◽  
Author(s):  
Jianjun Ou ◽  
Ruiting Liu ◽  
Yidong Shen ◽  
Kun Xia ◽  
Jingping Zhao
Keyword(s):  
Autism Spectrum Disorder ◽  
Environmental Factors ◽  
Rare Variants ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Spectrum Disorder ◽  
Nucleotide Polymorphisms ◽  
Genetic And Environmental Factors

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder typically diagnosed in children in the first few years of life. Genetic studies have demonstrated a moderate to high heritability of ASD, but only a limited number of single nucleotide polymorphisms (SNPs) have been identified. Meanwhile, numerous single de novo rare variants and copy number variations have been detected in patients with ASD, which are likely caused by environmental factors. Here we provide an overview of genetic and environmental factors that may contribute to the risk of ASD and we recommend that further study should be focused on both genes and environmental factors, as well as their interactions with the expectation that epigenetic studies will lead to understanding the link between the environment and risk of ASD.

scholarly journals Autism spectrum disorder trios from consanguineous populations are enriched for rare biallelic variants, identifying 32 new candidate genes

2021 ◽  
Author(s):  
Ricardo Harripaul ◽  
Ansa Rabia ◽  
Nasim Vasli ◽  
Anna Mikhailov ◽  
Ashlyn Rodrigues ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Rare Variants ◽  
De Novo ◽  
Splice Variants ◽  
Neurodevelopmental Disorder ◽  
Point Mutations ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Loss Of Function ◽  
Candidate Sequence

Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder that affects about 1 in 55 children worldwide and imposes enormous economic and socioemotional burden on families and communities. Genetic studies of ASD have identified de novo copy number variants (CNVs) and point mutations that contribute significantly to the genetic architecture of ASD, but the majority of these studies were conducted in outbred populations, which are not ideal for detecting autosomal recessive (AR) inheritance. However, several studies have investigated ASD genetics in consanguineous populations and point towards AR as an under-appreciated source of ASD variants. Here, we used trio whole exome sequencing (WES) to look for rare variants for ASD in 115 proband-mother-father trios from populations with high rates of consanguinity, namely Pakistan, Iran, and Saudi Arabia. In total, we report 87 candidate sequence variants, with 57% biallelic, 21% autosomal dominant/de novo, and the rest X-linked. 52% of the variants were loss of function (LoF) or putative LoF (splice site, stop loss) and 47% non-synonymous. Our analysis indicates an enrichment of previously identified and candidate AR genes. These include variants in genes previously reported for AR ASD and/or intellectual disability (ID), such as AGA, ASL, ASPA, BTN3A2, CC2D1A, DEAF1, HTRA2, KIF16B, LINS1, MADD, MED25, MTHFR, RSRC1, TECPR2, VPS13B, ZNF335, and 32 previously unreported candidates, including 15 LoF or splice variants, in genes such as DAGLA, EFCAB8, ENPP6, FAXDC2, ILDR2, PKD1L1, SCN10A, and SLC36A1. We also identified candidate biallelic exonic loss CNVs a number of trios, implicating genes including DNAH7, and DHRS4/DHRS4L2.

scholarly journals De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder

2019 ◽  
Vol 22 (3) ◽  
pp. 538-546 ◽  
Author(s):  
Ghayda M. Mirzaa ◽  
◽  
Jessica X. Chong ◽  
Amélie Piton ◽  
Bernt Popp ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder

scholarly journals Autism Spectrum Disorder Risk Factor Met Regulates the Organization of Inhibitory Synapses

2021 ◽  
Vol 14 ◽  
Author(s):  
Pauline Jeckel ◽  
Martin Kriebel ◽  
Hansjürgen Volkmer
Keyword(s):  
Autism Spectrum Disorder ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Scaffolding Protein ◽  
Inhibitory Synapses ◽  
Gabaergic Synapses ◽  
The Impact

A common hypothesis explains autism spectrum disorder (ASD) as a neurodevelopmental disorder linked to excitatory/inhibitory (E/I) imbalance in neuronal network connectivity. Mutation of genes including Met and downstream signaling components, e.g., PTEN, Tsc2 and, Rheb are involved in the control of synapse formation and stabilization and were all considered as risk genes for ASD. While the impact of Met on glutamatergic synapses was widely appreciated, its contribution to the stability of inhibitory, GABAergic synapses is poorly understood. The stabilization of GABAergic synapses depends on clustering of the postsynaptic scaffolding protein gephyrin. Here, we show in vivo and in vitro that Met is necessary and sufficient for the stabilization of GABAergic synapses via induction of gephyrin clustering. Likewise, we provide evidence for Met-dependent gephyrin clustering via activation of mTOR. Our results support the notion that deficient GABAergic signaling represents a pathomechanism for ASD.

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