New gene discoveries highlight functional convergence in autism and related neurodevelopmental disorders

Moysés-Oliveira, Mariana; Yadav, Rachita; Erdin, Serkan; Talkowski, Michael E.

doi:10.1016/j.gde.2020.07.001

Cited by 35 publications

(33 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…From the last few decades, the molecular study of neurodevelopmental disorders revealed the involvement of numerous genes essential in neuronal developmental processes like morphogenesis or neuronal plasticity and synaptogenesis (Bourgeron, 2015 ; Gilman et al, 2011 ; Krishnan et al, 2016 ; Laumonnier et al, 2007 ; Moyses‐Oliveira et al, 2020 ; Parenti et al, 2020 ). Among them, microdeletions and mutations in the X‐chromosomal PTCHD1 (patched domain containing 1) gene were described in patients with autism spectrum disorders (ASDs) and/or intellectual disability (ID; Chaudhry et al, 2015 ; Filges et al, 2011 ; Marshall et al, 2008 ; Noor et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

Novel missense mutations in PTCHD1 alter its plasma membrane subcellular localization and cause intellectual disability and autism spectrum disorder

et al. 2021

View full text Add to dashboard Cite

The X‐linked PTCHD1 gene, encoding a synaptic membrane protein, has been involved in neurodevelopmental disorders with the description of deleterious genomic microdeletions or truncating coding mutations. Missense variants were also identified, however, without any functional evidence supporting their pathogenicity level. We investigated 13 missense variants of PTCHD1, including eight previously described (c.152G>A,p.(Ser51Asn); c.217C>T,p.(Leu73Phe); c.517A>G,p.(Ile173Val); c.542A>C,p.(Lys181Thr); c.583G>A,p.(Val195Ile); c.1076A>G,p.(His359Arg); c.1409C>A,p.(Ala470Asp); c.1436A>G,p.(Glu479Gly)), and five novel ones (c.95C>T,p.(Pro32Leu); c.95C>G,p.(Pro32Arg); c.638A>G,p.(Tyr213Cys); c.898G>C,p.(Gly300Arg); c.928G>C,p.(Ala310Pro)) identified in male patients with intellectual disability (ID) and/or autism spectrum disorder (ASD). Interestingly, several of these variants involve amino acids localized in structural domains such as transmembrane segments. To evaluate their potentially deleterious impact on PTCHD1 protein function, we performed in vitro overexpression experiments of the wild‐type and mutated forms of PTCHD1‐GFP in HEK 293T and in Neuro‐2a cell lines as well as in mouse hippocampal primary neuronal cultures. We found that six variants impaired the expression level of the PTCHD1 protein, and were retained in the endoplasmic reticulum suggesting abnormal protein folding. Our functional analyses thus provided evidence of the pathogenic impact of missense variants in PTCHD1, which reinforces the involvement of the PTCHD1 gene in ID and in ASD.

show abstract

Section: Introductionmentioning

confidence: 99%

Novel missense mutations in PTCHD1 alter its plasma membrane subcellular localization and cause intellectual disability and autism spectrum disorder

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Although significant JOINT DEGs and DEL DEGs had minimal overlap, gene annotations of JOINT DEGs were also enriched for terms related to neuron development (e.g., neural tube development FDR 0.02, Figure 3A ) and overrepresented with genes exhibiting selective pressure and loss-of-function intolerance (FDR 0.01, using genes with upper bound of the observed/expected confidence interval < 0.25 in gnomAD) that are enriched in neurodevelopmental disease. 45,60,61 Further, query for overrepresented transcription factor binding motifs in JOINT DEGs identified not only the THAP1 motif, but also elements for YY1 and REX-1 (both FDR < 0.05, Figure 3A ), both of which have roles in neurodevelopment. 62–65 Taken together, functional enrichment analyses suggest that convergent pathways and networks related to development characterized both JOINT DEGs and DEL DEGs, and imply neurodevelopmental consequences resulting from diverse classes of THAP1 mutations and across different levels of THAP1 dysregulation.…”

Section: Resultsmentioning

confidence: 99%

Dystonia-specific mutations in THAP1 alter transcription of genes associated with neurodevelopment and myelin

Domingo

Yadav

Shah

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Dystonia is a neurologic disorder associated with an increasingly large number of variants in many genes, resulting in characteristic disturbances in volitional movement. Dissecting the relationships between these mutations and their functional outcomes is a critical step in understanding the key pathways that drive dystonia pathogenesis. Here we established a pipeline for characterizing an allelic series of dystonia-specific mutations in isogenic induced pluripotent stem cells (iPSCs). We used this strategy to investigate the molecular consequences of variation in THAP1, which encodes a transcription factor that has been linked to neural differentiation. Multiple pathogenic mutations that have been associated with dystonia cluster within distinct THAP1 functional domains and are predicted to alter its DNA binding properties and/or protein interactions differently, yet the relative impact of these varied changes on molecular signatures and neural deficits is unclear. To determine the effects of these mutations on THAP1 transcriptional activity, we engineered an allelic series of eight mutations in a common iPSC background and differentiated these lines into a panel of near-isogenic neural stem cells (n = 94 lines). Transcriptome profiling of these neural derivatives followed by joint analysis of the most robust individual signatures across mutations identified a convergent pattern of dysregulated genes functionally related to neurodevelopment, lysosomal lipid metabolism, and myelin. Based on these observations, we examined mice bearing Thap1-disruptive alleles and detected significant changes in myelin gene expression and reduction of myelin structural integrity relative to tissue from control mice. These results suggest that deficits in neurodevelopment and myelination are common consequences of dystonia-associated THAP1 mutations and highlight the potential role of neuron-glial interactions in the pathogenesis of dystonia.

show abstract

“…When new and old genes pinpointed by CMA studies were combined in functional modules using IPA and ToppGene Suite, we observed an enrichment in genes involved in synaptic function and transmission, which are well-established biological processes involved in autism and NDDs [94].…”

Section: Discussionmentioning

confidence: 96%

Evaluation of Chromosome Microarray Analysis in a Large Cohort of Females with Autism Spectrum Disorders: A Single Center Italian Study

Calderoni

Ricca

Balboni

et al. 2020

JPM

View full text Add to dashboard Cite

Autism spectrum disorders (ASD) encompass a heterogeneous group of neurodevelopmental disorders resulting from the complex interaction between genetic and environmental factors. Thanks to the chromosome microarray analysis (CMA) in clinical practice, the accurate identification and characterization of submicroscopic deletions/duplications (copy number variants, CNVs) associated with ASD was made possible. However, the widely acknowledged excess of males on the autism spectrum reflects on a paucity of CMA studies specifically focused on females with ASD (f-ASD). In this framework, we aim to evaluate the frequency of causative CNVs in a single-center cohort of idiopathic f-ASD. Among the 90 f-ASD analyzed, we found 20 patients with one or two potentially pathogenic CNVs, including those previously associated with ASD (located at 16p13.2 16p11.2, 15q11.2, and 22q11.21 regions). An exploratory genotype/phenotype analysis revealed that the f-ASD with causative CNVs had statistically significantly lower restrictive and repetitive behaviors than those without CNVs or with non-causative CNVs. Future work should focus on further understanding of f-ASD genetic underpinnings, taking advantage of next-generation sequencing technologies, with the ultimate goal of contributing to precision medicine in ASD.

show abstract

New gene discoveries highlight functional convergence in autism and related neurodevelopmental disorders

Cited by 35 publications

References 73 publications

Novel missense mutations in PTCHD1 alter its plasma membrane subcellular localization and cause intellectual disability and autism spectrum disorder

Novel missense mutations in PTCHD1 alter its plasma membrane subcellular localization and cause intellectual disability and autism spectrum disorder

Dystonia-specific mutations in THAP1 alter transcription of genes associated with neurodevelopment and myelin

Evaluation of Chromosome Microarray Analysis in a Large Cohort of Females with Autism Spectrum Disorders: A Single Center Italian Study

Contact Info

Product

Resources

About