Haploinsufficiency of the HIRA gene located in the 22q11 deletion syndrome region is associated with abnormal neurodevelopment and impaired dendritic outgrowth

Jeanne, Médéric; Vuillaume, Marie‐Laure; Ung, Dévina C.; Vancollie, Valerie E.; Wagner, Christel; Collins, Stephan C.; Vonwill, Sandrine; Haye, Damien; Chelloug, Nora; Pfundt, Rolph; Kummeling, Joost; Moizard, Marie‐Pierre; Marouillat, Sylviane; Kleefstra, Tjitske; Yalcin, Binnaz; Laumonnier, Frédéric; Toutain, Annick

doi:10.1007/s00439-020-02252-1

Cited by 14 publications

(11 citation statements)

References 38 publications

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“…It regulates neural progenitor proliferation and neurogenesis, and it belongs to the WD40 Repeat (WDR) protein family involved in brain development and neuronal connectivity. Recent studies on HIRA knock-down mouse models demonstrated that its haploinsufficiency is associated with abnormal neurodevelopment and impaired dendritic outgrowth [31]. Other authors analysed hematopoietic cells with specific HIRA deletion in mice and showed that this dramatically reduces bone marrow hematopoietic stem cells (HSCs), resulting in anaemia, thrombocytopenia and lymphocytopenia [32].…”

Section: Discussionmentioning

confidence: 99%

Identification of a DNA Methylation Episignature in the 22q11.2 Deletion Syndrome

Rooney

Levy

Haghshenas

et al. 2021

IJMS

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The 22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder in humans and is the result of a recurrent 1.5 to 2.5 Mb deletion, encompassing approximately 20–40 genes, respectively. The clinical presentation of the typical deletion includes: Velocardiofacial, Di George, Opitz G/BBB and Conotruncalanomaly face syndromes. Atypical deletions (proximal, distal or nested) are rare and characterized mainly by normal phenotype or mild intellectual disability and variable clinical features. The pathogenetic mechanisms underlying this disorder are not completely understood. Because the 22q11.2 region harbours genes coding for transcriptional factors and chromatin remodelers, in this study, we performed analysis of genome-wide DNA methylation of peripheral blood from 49 patients with 22q11.2DS using the Illumina Infinium Methylation EPIC bead chip arrays. This cohort comprises 43 typical, 2 proximal and 4 distal deletions. We demonstrated the evidence of a unique and highly specific episignature in all typical and proximal 22q11.2DS. The sensitivity and specificity of this signature was further confirmed by comparing it to over 1500 patients with other neurodevelopmental disorders with known episignatures. Mapping the 22q11.2DS DNA methylation episignature provides both novel insights into the molecular pathogenesis of this disorder and an effective tool in the molecular diagnosis of 22q11.2DS.

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Section: Discussionmentioning

confidence: 99%

Identification of a DNA Methylation Episignature in the 22q11.2 Deletion Syndrome

Rooney

Levy

Haghshenas

et al. 2021

IJMS

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“…Tbx1 and Dgcr8 are two individual genes within the locus that have garnered attention since they are intolerant to loss of function and have widespread effects on gene regulation; Tbx1 is a transcription factor and Dgcr8 is a protein involved in a microRNA processing complex [52,53]. Numerous murine models targeting genes in the human 22q11.2 locus have been developed to better understand the contribution of single and multiple 22q11.2 genes to developmental, cell-specific, and behavioral deviations relative to wild-type littermates [54][55][56][57][58][59]. For example, Tbx1 heterozygous mice showed significant alterations of myelinated axons in the fimbria, lower mRNA levels of oligodendrocyte-related genes, and postnatal progenitor cells from the subventricular zone produced fewer oligodendrocytes in vitro [60].…”

Section: Genetic Heterogeneity the Value Of Focusing On A Genetically...mentioning

confidence: 99%

A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome

et al. 2022

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Recently, increasing numbers of rare pathogenic genetic variants have been identified that are associated with variably elevated risks of a range of neurodevelopmental outcomes, notably including Autism Spectrum Disorders (ASD), Schizophrenia Spectrum Disorders (SSD), and Intellectual Disability (ID). This review is organized along three main questions: First, how can we unify the exclusively descriptive basis of our current psychiatric diagnostic classification system with the recognition of an identifiable, highly penetrant genetic risk factor in an increasing proportion of patients with ASD or SSD? Second, what can be learned from studies of individuals with ASD or SSD who share a common genetic basis? And third, what accounts for the observed variable penetrance and pleiotropy of neuropsychiatric phenotypes in individuals with the same pathogenic variant? In this review, we focus on findings of clinical and preclinical studies of the 22q11.2 deletion syndrome (22q11DS). This particular variant is not only one of the most common among the increasing list of known rare pathogenic variants, but also one that benefits from a relatively long research history. Consequently, 22q11DS is an appealing model as it allows us to: (1) elucidate specific genotype–phenotype associations, (2) prospectively study behaviorally defined classifications, such as ASD or SSD, in the context of a known, well-characterized genetic basis, and (3) elucidate mechanisms underpinning variable penetrance and pleiotropy, phenomena with far-reaching ramifications for research and clinical practice. We discuss how findings from animal and in vitro studies relate to observations in human studies and can help elucidate factors, including genetic, environmental, and stochastic, that impact the expression of neuropsychiatric phenotypes in 22q11DS, and how this may inform mechanisms underlying neurodevelopmental expression in the general population. We conclude with research priorities for the field, which may pave the way for novel therapeutics.

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“…Furthermore, in bivalent genes that evolve to become transcriptionally active, H3.3 is kept around the TSS and is incorporated into the gene body and in those that become transcriptionally inactive, the H3.3 is lost around the TSS ( Goldberg et al, 2010 ). Additionally, haploinsufficiency of HIRA leads to abnormal defects involved in the regulation of neuronal differentiation and maturation ( Jeanne et al, 2021 ). This places histone variants and their chaperones as important regulators of neuronal development and maturation.…”

Section: Histones Their Chaperones and Their Involvement In Agingmentioning

confidence: 99%

“…The phenotype seen in these patients is very heterogeneous, including heart defects, parathyroid hypoplasia, immune deficiency, and hypocalcemia ( Jeanne et al, 2021 ). Given this, the altered mechanisms that lead to its heterogeneous pathogenesis might depend on the cellular type analyzed, whether it is a neuronal or a hematopoietic stem cell defect.…”

Section: Chromatin Remodelers and Histone Chaperones As Targets In Sy...mentioning

confidence: 99%

Histones and their chaperones: Adaptive remodelers of an ever-changing chromatinic landscape

et al. 2022

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Chromatin maintenance and remodeling are processes that take place alongside DNA repair, replication, or transcription to ensure the survival and adaptability of a cell. The environment and the needs of the cell dictate how chromatin is remodeled; particularly where and which histones are deposited, thus changing the canonical histone array to regulate chromatin structure and gene expression. Chromatin is highly dynamic, and histone variants and their chaperones play a crucial role in maintaining the epigenetic regulation at different genomic regions. Despite the large number of histone variants reported to date, studies on their roles in physiological processes and pathologies are emerging but continue to be scarce. Here, we present recent advances in the research on histone variants and their chaperones, with a focus on their importance in molecular mechanisms such as replication, transcription, and DNA damage repair. Additionally, we discuss the emerging role they have in transposable element regulation, aging, and chromatin remodeling syndromes. Finally, we describe currently used methods and their limitations in the study of these proteins and highlight the importance of improving the experimental approaches to further understand this epigenetic machinery.

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Haploinsufficiency of the HIRA gene located in the 22q11 deletion syndrome region is associated with abnormal neurodevelopment and impaired dendritic outgrowth

Cited by 14 publications

References 38 publications

Identification of a DNA Methylation Episignature in the 22q11.2 Deletion Syndrome

Identification of a DNA Methylation Episignature in the 22q11.2 Deletion Syndrome

A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome

Histones and their chaperones: Adaptive remodelers of an ever-changing chromatinic landscape

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