HDAC8‐deficiency causes an X‐linked dominant disorder with a wide range of severity

Mordaunt, Dylan; McLauchlan, A

doi:10.1111/cge.12588

Cited by 6 publications

(4 citation statements)

References 5 publications

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“…As concluded by Boyle et al (2015) as well as later by Mordaunt and McLauchlan (2015), the physical phenotype observed in patients with CDLS5 is very broad, similarly with intellectual disability. In some patients, facial features may not be characteristic for recognizable classical CDLS phenotype (caused by mutations in NIPBL gene on chromosome 5p13, referred to as CDLS1, MIM 122470), but may present a somewhat specific gestalt.…”

Section: Discussionmentioning

confidence: 70%

Novel variant in HDAC8 gene resulting in the severe Cornelia de Lange phenotype

Jezela‐Stanek¹,

Murcia

Jurkiewicz

et al. 2019

Clinical Dysmorphology

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syndrome (CDLS) is a clinically and genetically heterogeneous developmental disorder characterized by multiple malformations. Primarily, affected individuals have unique and recognizable dysmorphic facial features, cleft palate, distal limb defects, growth retardation, and developmental delay. However, also milder, as well as slightly phenotypically different forms exist. We described herein a patient with CDLS5, an X-linked form, caused by mutations in the HDAC8 gene inherited form the mosaic mother. Analysis of results from whole exome sequencing identified two variants with possible impact on the phenotype. Of them, hemizygous variant (c.938G>A, p.Arg313Gln) inherited from the mosaic mother, was further proved to lead to disease in the proband. Our intention was to delineate this syndrome but also point out the clinical course of the disease, which only in combination with a facial phenotype allow for verification of exome sequencing result. Clin Dysmorphol

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Section: Discussionmentioning

confidence: 70%

Novel variant in HDAC8 gene resulting in the severe Cornelia de Lange phenotype

Jezela‐Stanek¹,

Murcia

Jurkiewicz

et al. 2019

Clinical Dysmorphology

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“…Loss-of-function mutations in HDAC8, located on the X chromosome q13, have been linked to Cornelia de Lange Syndrome (CdLS) and CdLS-like features. 16,[45][46][47] These HDAC8 mutations are associated with severely skewed X inactivation in the PB of female patients. CdLS, a dominantly inherited congenital malformation disorder, is typically associated with mutations in the cohesin loading protein NIPBL or less frequently with mutations in the core cohesin components SMC1A and SMC3.…”

Section: Discussionmentioning

confidence: 99%

HDAC8 regulates long-term hematopoietic stem-cell maintenance under stress by modulating p53 activity

Hua

Cai

et al. 2017

Blood

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The maintenance and functional integrity of long-term hematopoietic stem cells (LT-HSCs) is critical for lifelong hematopoietic regeneration. Histone deacetylases (HDACs) modulate acetylation of lysine residues, a protein modification important for regulation of numerous biological processes. Here, we show that is most highly expressed in the phenotypic LT-HSC population within the adult hematopoietic hierarchy. Using an-floxed allele and a dual-fluorescence Cre reporter allele, largely normal hematopoietic differentiation capacity of deficient cells was observed. However, the frequency of phenotypic LT-HSC population was significantly higher shortly after deletion, and the expansion had shifted to the phenotypic multipotent progenitor population by 1 year. We show that -deficient hematopoietic progenitors are compromised in colony-forming cell serial replating in vitro and long-term serial repopulating activity in vivo. Mechanistically, we demonstrate that the HDAC8 protein interacts with the p53 protein and modulates p53 activity via deacetylation.-deficient LT-HSCs displayed hyperactivation of p53 and increased apoptosis under genotoxic and hematopoietic stress. Genetic inactivation of p53 reversed the increased apoptosis and elevated expression of proapoptotic targets and seen in -deleted LT-HSCs. Dramatically compromised hematopoietic recovery and increased lethality were seen in-deficient mice challenged with serial 5-fluorouracil treatment. This hypersensitivity to hematopoietic ablation was completely rescued by inactivation of p53. Altogether, these results indicate that HDAC8 functions to modulate p53 activity to ensure LT-HSC maintenance and cell survival under stress.

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“…One was on chromosome Xq13.1-q13.2 carrying a deletion of 121kb including gene HDAC8 and PHKA1. Mutations in HDAC8 may cause the rare multisystem disorder Cornelia deLange syndrome (CdLS) characterized by somatic defects and mental retardation [9]. Mutations in PHKA1 may myasthenia, amyotrophy and spasm [10].…”

Section: Discussionmentioning

confidence: 99%

Prenatal diagnosis of a complex chromosomal rearrangement involving five chromosomes

Wang¹,

Lü²,

ZuLiang³

et al. 2018

Clin. Exp. Obstet. Gynecol.

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The present authors report an exceptional complex chromosomal rearrangement involving five chromosomes. Cytogenetic analysis of cultured amniocytes revealed a unique karyotype of 46,X,t(X;13;9)(q13;q14;p22),t(3;6)(p13;q23) in 35/35 cultured amniocytes. Microarray-based comparative genomic hybridization (aCGH) revealed two microdeletions on chromosome Xq13.1-q13.2 and 13q14.2-q21.1 respectively. This study demonstrates the feasibility of using aCGH for prenatal diagnosis, especially in detecting subtle chromosomal abnormalities in high risk pregnancies.

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HDAC8‐deficiency causes an X‐linked dominant disorder with a wide range of severity

Cited by 6 publications

References 5 publications

Novel variant in HDAC8 gene resulting in the severe Cornelia de Lange phenotype

Novel variant in HDAC8 gene resulting in the severe Cornelia de Lange phenotype

HDAC8 regulates long-term hematopoietic stem-cell maintenance under stress by modulating p53 activity

Prenatal diagnosis of a complex chromosomal rearrangement involving five chromosomes

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