Zebrafish <i>sin3b</i> mutants are viable but have size, skeletal, and locomotor defects

Moravec, Cara E.; Yousef, Hakeem; Kinney, Brian A.; Salerno-Eichenholz, Ryan; Monestime, Camillia M.; Martin, Benjamin L.; Sirotkin, Howard I.

doi:10.1002/dvdy.24581

Cited by 8 publications

(7 citation statements)

References 57 publications

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“…Zebrafish mutants harboring truncating mutations in sin3b display locomotion defects, delayed ossification, and shortened body length. 26 With the exception of variable growth phenotypes in our cohort (Table 1), these aberrant zebrafish mutant phenotypes did not have discrete anatomical correlates with features of our human cohort. To test whether we could link anatomical phenotypes observed in individuals with SIN3B haploinsufficiency, we disrupted the SIN3B ortholog in zebrafish (Ensembl: ENSDARG00000062472, GRCz10; 63% identity, 74% similarity versus human [GenBank: NP_056075.1]; Figure S2A).…”

mentioning

confidence: 56%

Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder

Latypova

Vincent

Mollé

et al. 2021

The American Journal of Human Genetics

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mentioning

confidence: 56%

Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder

Latypova

Vincent

Mollé

et al. 2021

The American Journal of Human Genetics

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“…The SIN3B gene encodes a transcription corepressor which has an important role in histone deacetylation and transcriptional repression ( Latypova et al, 2021 ). An animal model showed that Sin3b knockout mice and zebrafish sin3b mutants express skeletal and growth defects ( David et al, 2008 ; Moravec et al, 2017 ). Sin3b knockout mice also showed defects in blood differentiation, whereas zebrafish sin3b mutants showed locomotor defects ( Cantor and David, 2017 ; Moravec et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

“…An animal model showed that Sin3b knockout mice and zebrafish sin3b mutants express skeletal and growth defects ( David et al, 2008 ; Moravec et al, 2017 ). Sin3b knockout mice also showed defects in blood differentiation, whereas zebrafish sin3b mutants showed locomotor defects ( Cantor and David, 2017 ; Moravec et al, 2017 ). Although STRING analysis did not show any correlation with a specific phenotype (data available online), both g:Profiler analysis and the literature have reported that haploinsufficiency of SIN3B causes an ID and ASD phenotypes ( Latypova et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Impaired Neurodevelopmental Genes in Slovenian Autistic Children Elucidate the Comorbidity of Autism With Other Developmental Disorders

Krgovic

Gorenjak

Rihar

et al. 2022

Front. Mol. Neurosci.

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Autism spectrum disorders (ASD) represent a phenotypically heterogeneous group of patients that strongly intertwine with other neurodevelopmental disorders (NDDs), with genetics playing a significant role in their etiology. Whole exome sequencing (WES) has become predominant in molecular diagnostics for ASD by considerably increasing the diagnostic yield. However, the proportion of undiagnosed patients still remains high due to complex clinical presentation, reduced penetrance, and lack of segregation analysis or clinical information. Thus, reverse phenotyping, where we first identified a possible genetic cause and then determine its clinical relevance, has been shown to be a more efficient approach. WES was performed on 147 Slovenian pediatric patients with suspected ASD. Data analysis was focused on identifying ultrarare or “single event” variants in ASD-associated genes and further expanded to NDD-associated genes. Protein function and gene prioritization were performed on detected clinically relevant variants to determine their role in ASD etiology and phenotype. Reverse phenotyping revealed a pathogenic or likely pathogenic variant in ASD-associated genes in 20.4% of patients, with subsequent segregation analysis indicating that 14 were de novo variants and 1 was presumed compound heterozygous. The diagnostic yield was further increased by 2.7% by the analysis of ultrarare or “single event” variants in all NDD-associated genes. Protein function analysis established that genes in which variants of unknown significance (VUS) were detected were predominantly the cause of intellectual disability (ID), and in most cases, features of ASD as well. Using such an approach, variants in rarely described ASD-associated genes, such as SIN3B, NR4A2, and GRIA1, were detected. By expanding the analysis to include functionally similar NDD genes, variants in KCNK9, GNE, and other genes were identified. These would probably have been missed by classic genotype–phenotype analysis. Our study thus demonstrates that in patients with ASD, analysis of ultrarare or “single event” variants obtained using WES with the inclusion of functionally similar genes and reverse phenotyping obtained a higher diagnostic yield despite limited clinical data. The present study also demonstrates that most of the causative genes in our cohort were involved in the syndromic form of ASD and confirms their comorbidity with other developmental disorders.

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“…In the vertebrate lineage, a duplication event gave rise to two Sin3 genes, Sin3a and Sin3b . In zebrafish, however, there are three Sin3 genes, sin3aa , sin3ab, and sin3b, as a result of a second gene duplication event specific to teleost fish [ 36 ]. The paralogs Sin3aa and Sin3ab are 78% identical to each other and 50% identical to their ortholog Sin3b, exhibiting high levels of similarity between the PAH and HID domains.…”

Section: Sin3 Isoform Conservation Across Speciesmentioning

confidence: 99%

Same agent, different messages: insight into transcriptional regulation by SIN3 isoforms

Chaubal

Pile

2018

Epigenetics & Chromatin

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SIN3 is a global transcriptional coregulator that governs expression of a large repertoire of gene targets. It is an important player in gene regulation, which can repress or activate diverse gene targets in a context-dependent manner. SIN3 is required for several vital biological processes such as cell proliferation, energy metabolism, organ development, and cellular senescence. The functional flexibility of SIN3 arises from its ability to interact with a large variety of partners through protein interaction domains that are conserved across species, ranging from yeast to mammals. Several isoforms of SIN3 are present in these different species that can perform common and specialized functions through interactions with distinct enzymes and DNA-binding partners. Although SIN3 has been well studied due to its wide-ranging functions and highly conserved interaction domains, precise roles of individual SIN3 isoforms have received less attention. In this review, we discuss the differences in structure and function of distinct SIN3 isoforms and provide possible avenues to understand the complete picture of regulation by SIN3.

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Zebrafish sin3b mutants are viable but have size, skeletal, and locomotor defects

Cited by 8 publications

References 57 publications

Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder

Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder

Impaired Neurodevelopmental Genes in Slovenian Autistic Children Elucidate the Comorbidity of Autism With Other Developmental Disorders

Same agent, different messages: insight into transcriptional regulation by SIN3 isoforms

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