Neurodevelopment and Genetic Evaluation of Sotos Syndrome Cases with a Novel Mutation: a Single-Center Experience

Elmas, Muhsin; Gogus, Basak; Değirmenci, Banu; Gezdirici, Alper; Solak, Mustafa

doi:10.1007/s12031-021-01897-5

Cited by 5 publications

(2 citation statements)

References 22 publications

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“…We find evidence that VPA modulates genes encoding histone methyltransferases that methylate H3K36, such as NSD1 63 and SETD5 64 . NSD1 has been associated with syndromic ASD 65 , and modulates the mono- and di-methylation of H3K36 (H3K36me1/2) 63 . Human neurons treated with VPA showed significantly decreased expression of NSD1 in this study.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of The Chromatin Environment Leads to Differential Alternative Splicing as A Mechanism Of Disease In a Human Model of Autism Spectrum Disorders

Leung

Rosenzweig

Yoon

et al. 2022

Preprint

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Autism spectrum disorder (ASD) affects 1 in 44 children. Chromatin regulatory proteins are overrepresented among genes that contain high risk variants in ASD. Disruption of the chromatin environment leads to widespread dysregulation of gene expression, which is traditionally thought as a mechanism of disease pathogenesis associated with ASD. Alternatively, alterations in chromatin dynamics could also lead to dysregulation of alternative splicing, which is understudied as a mechanism of ASD pathogenesis. The anticonvulsant valproic acid (VPA) is a well-known environmental risk factor for ASD that acts as a class I histone deacetylase (HDAC) inhibitor. However, the precise molecular mechanisms underlying defects in human neuronal development associated with exposure to VPA are understudied. To dissect how VPA exposure and subsequent chromatin hyperacetylation influence molecular signatures involved in ASD pathogenesis, we conducted RNA sequencing (RNA-seq) in human cortical neurons that were treated with VPA. We observed that differentially expressed genes (DEGs) were enriched for mRNA splicing, mRNA processing, histone modification, and metabolism related gene sets. Furthermore, we observed widespread increase in the number and the type of alternative splicing events. Analysis of differential transcript usage (DTU) showed that exposure to VPA induces extensive alterations in transcript isoform usage across neurodevelopmentally important genes. Finally, we find that DEGs and genes that display DTU overlap with known ASD-risk genes. Together, these findings suggest that, in addition to differential gene expression, changes in alternative splicing correlated with alterations in the chromatin environment could act as an additional mechanism of disease in ASD.

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Section: Discussionmentioning

confidence: 99%

Dysregulation of The Chromatin Environment Leads to Differential Alternative Splicing as A Mechanism Of Disease In a Human Model of Autism Spectrum Disorders

Leung

Rosenzweig

Yoon

et al. 2022

Preprint

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show abstract

“…Loss of function mutations in NSD1 are a major cause of Sotos Syndrome (Kurotaki et al, 2002(Kurotaki et al, , 2005 which presents with macrocephaly, pre-and postnatal overgrowth, facial dysmorphism, ID, autistic features, developmental delay, and in some cases seizures (Sotos et al, 1964;Fortin et al, 2021). The macrocephaly phenotype associated with NSD1 mutations in Sotos syndrome has variable penetrance as 72-95% of patients present with larger head circumference (Cecconi et al, 2005;Faravelli, 2005;Saugier-Veber et al, 2007;Fortin et al, 2021;Muhsin et al, 2022). In contrast, duplication of NSD1 in the microduplication 5q35 syndrome leads to microcephaly in 74% of cases, with undergrowth, and developmental delay in close to 90% of the cases (Chen et al, 2006;Franco et al, 2010;Dikow et al, 2013;Rosenfeld et al, 2013;Quintero-Rivera et al, 2021).…”

Section: Nsd1 Gene Dosage and The Balancing Act Of Large Vs Small Brainsmentioning

confidence: 99%

The role of histone methyltransferases in neurocognitive disorders associated with brain size abnormalities

Ritchie

Lizarraga

2023

Front. Neurosci.

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Brain size is controlled by several factors during neuronal development, including neural progenitor proliferation, neuronal arborization, gliogenesis, cell death, and synaptogenesis. Multiple neurodevelopmental disorders have co-morbid brain size abnormalities, such as microcephaly and macrocephaly. Mutations in histone methyltransferases that modify histone H3 on Lysine 36 and Lysine 4 (H3K36 and H3K4) have been identified in neurodevelopmental disorders involving both microcephaly and macrocephaly. H3K36 and H3K4 methylation are both associated with transcriptional activation and are proposed to sterically hinder the repressive activity of the Polycomb Repressor Complex 2 (PRC2). During neuronal development, tri-methylation of H3K27 (H3K27me3) by PRC2 leads to genome wide transcriptional repression of genes that regulate cell fate transitions and neuronal arborization. Here we provide a review of neurodevelopmental processes and disorders associated with H3K36 and H3K4 histone methyltransferases, with emphasis on processes that contribute to brain size abnormalities. Additionally, we discuss how the counteracting activities of H3K36 and H3K4 modifying enzymes vs. PRC2 could contribute to brain size abnormalities which is an underexplored mechanism in relation to brain size control.

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Sotos syndrome: A study of antenatal presentation

Zhang¹,

Jing²,

Chen

et al. 2022

European Journal of Obstetrics & Gynecology and Reproductiv

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Neurodevelopment and Genetic Evaluation of Sotos Syndrome Cases with a Novel Mutation: a Single-Center Experience

Cited by 5 publications

References 22 publications

Dysregulation of The Chromatin Environment Leads to Differential Alternative Splicing as A Mechanism Of Disease In a Human Model of Autism Spectrum Disorders

Dysregulation of The Chromatin Environment Leads to Differential Alternative Splicing as A Mechanism Of Disease In a Human Model of Autism Spectrum Disorders

The role of histone methyltransferases in neurocognitive disorders associated with brain size abnormalities

Sotos syndrome: A study of antenatal presentation

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