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Journal ArticleDOI

Dose dependent expression of HDAC4 causes variable expressivity in a novel inherited case of brachydactyly mental retardation syndrome.

TL;DR: Gene expression analyses lending evidence to the hypothesis that HDAC4 modulates severity of this disorder in a dosage‐dependent manner and a parent with mild symptoms of the disorder and a child exhibiting a more severe phenotype.
Abstract: Histone deacetylase 4 (HDAC4) serves important roles in multiple human systems, including neurological, cardiac, and skeletal functions. Mutation or deletion of HDAC4 causes brachydactyly mental retardation syndrome (BDMR), a disorder that includes intellectual disability, behavioral abnormalities, autism spectrum disorder, and craniofacial and skeletal anomalies, including brachydactyly type E. We present a case of familial BDMR, including a parent with mild symptoms of the disorder and a child exhibiting a more severe phenotype. Cytogenetic testing showed a cryptic balanced translocation in the mother that resulted in a 2q37.1 monosomy and a 10q26.1 trisomy in the son. Gene expression analyses demonstrated 67% HDAC4 expression in the mother and 23% HDAC4 expression in the son relative to normal controls, lending evidence to the hypothesis that HDAC4 modulates severity of this disorder in a dosage-dependent manner.
Citations
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Journal ArticleDOI
TL;DR: Interestingly, mutations in EZH2 and certain BAF complex components have roles in both neurodevelopmental disorders and cancer, and overlapping point mutations are suggesting functionally important residues and domains.
Abstract: Recent genome-sequencing studies in human neurodevelopmental and psychiatric disorders have revealed mutations in chromatin-modifying enzymes, such as chromatin remodellers and histone-modifying enzymes. Such studies are improving our understanding of the roles of these modifiers in human neurodevelopment, and this article discusses the emerging roles for several of these enzymes in development and disease.

420 citations

Journal ArticleDOI
TL;DR: The variety of germline mutations of epigenetic modifiers that are known to be associated with human disorders are described, and the therapeutic potential of epigenetics drugs as palliative care strategies in the treatment of such disorders are discussed.
Abstract: The orchestrated organization of epigenetic factors that control chromatin dynamism, including DNA methylation, histone marks, non-coding RNAs (ncRNAs) and chromatin-remodeling proteins, is essential for the proper function of tissue homeostasis, cell identity and development. Indeed, deregulation of epigenetic profiles has been described in several human pathologies, including complex diseases (such as cancer, cardiovascular and neurological diseases), metabolic pathologies (type 2 diabetes and obesity) and imprinting disorders. Over the last decade it has become increasingly clear that mutations of genes involved in epigenetic mechanism, such as DNA methyltransferases, methyl-binding domain proteins, histone deacetylases, histone methylases and members of the SWI/SNF family of chromatin remodelers are linked to human disorders, including Immunodeficiency Centromeric instability Facial syndrome 1, Rett syndrome, Rubinstein–Taybi syndrome, Sotos syndrome or alpha-thalassemia/mental retardation X-linked syndrome, among others. As new members of the epigenetic machinery are described, the number of human syndromes associated with epigenetic alterations increases. As recent examples, mutations of histone demethylases and members of the non-coding RNA machinery have recently been associated with Kabuki syndrome, Claes-Jensen X-linked mental retardation syndrome and Goiter syndrome. In this review, we describe the variety of germline mutations of epigenetic modifiers that are known to be associated with human disorders, and discuss the therapeutic potential of epigenetic drugs as palliative care strategies in the treatment of such disorders.

145 citations


Cites background from "Dose dependent expression of HDAC4 ..."

  • ...2 have been reported in BMRS subjects (Williams et al. 2010; Morris et al. 2012)....

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  • ...3 HDAC Brachydactyly-mental retardation syndrome (BDMR) 600430 Williams et al. (2010), Morris et al. (2012) EHMT1 79813 9q34....

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Journal ArticleDOI
TL;DR: This review brings up to date the knowledge of the physiological and pathological functions of class IIa HDACs, focusing in particular on the most recent discoveries from in vivo studies of mouse model systems.
Abstract: HDAC4, 5, 7 and 9 constitute the class IIa histone deacetylases (HDACs) within the large family of protein deacetylases. Class IIa HDACs have unique features that distinguish them from other HDACs. They contain an N-terminal domain that is required for their interaction with tissue-specific transcription factors and recruitment to their target genes. The N-terminal domain on class IIa HDACs also bears conserved serine residues that undergo signal-dependent phosphorylation, which brings about nuclear export of the enzymes and de-repression of their targets. One of the most important aspects of class IIa HDACs is their expression in specific tissues and organs within the organism, where they have crucial roles in development and differentiation processes. This review brings up to date our knowledge of the physiological and pathological functions of class IIa HDACs, focusing in particular on the most recent discoveries from in vivo studies of mouse model systems.

140 citations

Journal ArticleDOI
TL;DR: It is suggested that classifying disorders based on predicted effects on this balance would be informative regarding pathogenesis and strategies targeted at restoring this balance might offer novel therapeutic avenues, taking advantage of available agents such as histone deacetylase inhibitors and histone acetylation antagonists.
Abstract: Mendelian disorders of the epigenetic machinery are a newly delineated group of multiple congenital anomaly and intellectual disability syndromes resulting from mutations in genes encoding components of the epigenetic machinery. The gene products affected in these inherited conditions act in trans and are expected to have widespread epigenetic consequences. Many of these syndromes demonstrate phenotypic overlap with classical imprinting disorders and with one another. The various writer and eraser systems involve opposing players, which we propose must maintain a balance between open and closed chromatin states in any given cell. An imbalance might lead to disrupted expression of disease-relevant target genes. We suggest that classifying disorders based on predicted effects on this balance would be informative regarding pathogenesis. Furthermore, strategies targeted at restoring this balance might offer novel therapeutic avenues, taking advantage of available agents such as histone deacetylase inhibitors and histone acetylation antagonists.

116 citations


Cites background from "Dose dependent expression of HDAC4 ..."

  • ...Dose dependent expression of HDAC4 causes variable expressivity in a novel inherited case of brachydactyly mental retardation syndrome....

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  • ...In this condition, caused by haploinsufficiency of a histone deacetylase gene (HDAC4), patients have skeletal abnormalities, including brachycephaly and brachydactyly, as well as intellectual disability (128)....

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  • ...For instance, decreased amounts of HDAC4 appear to upregulate the MEF2 gene in neurons, offering a possible explanation for the intellectual disability seen in the syndrome (102)....

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  • ...F or p er so na l u se o nl y. GG15CH12-Bjornsson ARI 8 August 2014 12:35 DISORDERS ABOVE HISTONE TAILS TIP THE BALANCE TOWARD CLOSED CHROMATIN DISORDERS BELOW HISTONE TAILS TIP THE BALANCE TOWARD OPEN CHROMATIN Acetyl group binary system (0, 1) Methyl group quaternary system (0, 1, 2, 3) Open, active chromatin Acetyl group Methyl group Closed, inactive chromatin Methyl group H4 H4 H3 H3 H2A H2B HDAC4 KD M5 C HD AC 4 NS D1 EH MT 1 ML L2 EP 30 0 CR EB BP EP 30 0 CR EB BP KD M6 A EZ H2 ML L CLOSED OPEN CLOSED OPEN H4 tail BDMRKLFS K4 K9K9 or K14 K18 K23 K27 K36 K20 K16 K12 K8 K5 CJS WSS KS2 SS* WS* KS1 BDMR H3 tail RTS1,2RTS1,2 Era ser Era ser Era ser Era ser Hili ter NSD1 SS* Hili ter Hili ter Hili ter Hili ter Hili ter Hili ter Hili ter Hili ter Hi-li ter 276 Fahrner · Bjornsson A nn u....

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  • ...HDAC4 is an eraser of the same marks deposited by CREBBP/EP300 (127), tilting the balance toward closed chromatin states....

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Journal ArticleDOI
TL;DR: It is concluded that HDAC4 haploinsufficiency is responsible for psychomotor and behavioural abnormalities in combination with the BDMR syndrome-specific facial dysmorphism pattern and that these clinical features have a central diagnostic relevance.
Abstract: Deletions of the chromosomal region 2q37 cause brachydactyly-mental retardation syndrome (BDMR), also known as Albright hereditary osteodystrophy-like syndrome. Recently, histone deacetylase 4 (HDAC4) haploinsufficiency has been postulated to be the critical genetic mechanism responsible for the main clinical characteristics of the BDMR syndrome like developmental delay and behavioural abnormalities in combination with brachydactyly type E (BDE). We report here on the first three generation familial case of BDMR syndrome with inheritance of an interstitial microdeletion of chromosome 2q37.3. The deletion was detected by array comparative genomic hybridization and comprises the HDAC4 gene and two other genes. The patients of this pedigree show a variable severity of psychomotor and behavioural abnormalities in combination with a specific facial dysmorphism but without BDE. Given that only about half of the patients with 2q37 deletions have BDE; we compared our patients with other patients carrying 2q37.3 deletions or HDAC4 mutations known from the literature to discuss the diagnostic relevance of the facial dysmorphism pattern in 2q37.3 deletion cases involving the HDAC4 gene. We conclude that HDAC4 haploinsufficiency is responsible for psychomotor and behavioural abnormalities in combination with the BDMR syndrome-specific facial dysmorphism pattern and that these clinical features have a central diagnostic relevance.

46 citations

References
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Journal ArticleDOI
23 Aug 2002-Cell
TL;DR: It is shown that class II HDACs are substrates for a stress-responsive kinase specific for conserved serines that regulate MEF2-HDAC interactions, and act as signal-responsive suppressors of the transcriptional program governing cardiac hypertrophy and heart failure.

952 citations

Journal ArticleDOI
TL;DR: This study is a 20 fold increase in number over the previously reported largest study and represents an unbiased analysis of subtelomere rearrangements in a large, unselected patient population.
Abstract: Background: Subtelomere fluorescence in situ hybridisation (FISH) analysis has increasingly been used as an adjunct to routine cytogenetic testing in order to detect small rearrangements. Previous reports have estimated an overall abnormality rate of 6%, with a range of 2–29% because of different inclusion criteria. Methods: This study presents data compiled from 11 688 cases referred for subtelomere FISH testing in three clinical cytogenetic laboratories. Results: In this study population, the detection rate for clinically significant subtelomere abnormalities was approximately 2.5%, with an additional 0.5% detection of presumed familial variants. Approximately half of the clinically significant abnormalities identified were terminal deletions, the majority of which were de novo. Most of the remaining cases were unbalanced translocations between two chromosomes or two arms of the same chromosome. Approximately 60% of the unbalanced translocations were inherited from a parent carrying a balanced form of the rearrangement. Other abnormalities identified included tandem duplications, apparently balanced translocations, partial deletions, and insertions. Interestingly, 9 cases (0.08%) were found to have interstitial deletions of non-telomeric control loci, either BCR on 22q or PML on 15q. The most common clinically significant imbalances found were deletions of 1p, 22q, 4p, 9q, 8p, 2q and 20p. The most common familial variants were a deletion or duplication of 10q, deletion of 4q, deletion of Yq, and duplication of X/Yp onto Xq. Conclusions: This study of subtelomere rearrangements is a 20 fold increase in number over the previously reported largest study and represents an unbiased analysis of subtelomere rearrangements in a large, unselected patient population.

367 citations


Additional excerpts

  • ...[Ravnan et al., 2006]....

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Journal ArticleDOI
TL;DR: Data presented here show that deletion or mutation of HDAC4 results in reduced expression of RAI1, which causes Smith-Magenis syndrome when haploinsufficient, providing a link to the overlapping findings in these disorders.
Abstract: Brachydactyly mental retardation syndrome (BDMR) is associated with a deletion involving chromosome 2q37. BDMR presents with a range of features, including intellectual disabilities, developmental delays, behavioral abnormalities, sleep disturbance, craniofacial and skeletal abnormalities (including brachydactyly type E), and autism spectrum disorder. To date, only large deletions of 2q37 have been reported, making delineation of a critical region and subsequent identification of candidate genes difficult. We present clinical and molecular analysis of six individuals with overlapping deletions involving 2q37.3 that refine the critical region, reducing the candidate genes from >20 to a single gene, histone deacetylase 4 (HDAC4). Driven by the distinct hand and foot anomalies and similar cognitive features, we identified other cases with clinical findings consistent with BDMR but without a 2q37 deletion, and sequencing of HDAC4 identified de novo mutations, including one intragenic deletion probably disrupting normal splicing and one intragenic insertion that results in a frameshift and premature stop codon. HDAC4 is a histone deacetylase that regulates genes important in bone, muscle, neurological, and cardiac development. Reportedly, Hdac4−/− mice have severe bone malformations resulting from premature ossification of developing bones. Data presented here show that deletion or mutation of HDAC4 results in reduced expression of RAI1, which causes Smith-Magenis syndrome when haploinsufficient, providing a link to the overlapping findings in these disorders. Considering the known molecular function of HDAC4 and the mouse knockout phenotype, taken together with deletion or mutation of HDAC4 in multiple subjects with BDMR, we conclude that haploinsufficiency of HDAC4 results in brachydactyly mental retardation syndrome.

270 citations


"Dose dependent expression of HDAC4 ..." refers background in this paper

  • ...A previous study of simple deletions and mutations of HDAC4 showed approximately 50% expression in affected individuals [Williams et al., 2010]....

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  • ...Brachydactyly mental retardation syndrome (BDMR, OMIM 600430) is a rare genetic disorder caused by aberrations of chromosomal region 2q37 and associated with mutation or deletion of histone deacetylase 4 (HDAC4) [Williams et al., 2010]....

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  • ...%) is not typical of a heterozygous gene deletion; patients with BDMR, and deletions similar to that of patient 1 have not shown less than 50%expression [Williams et al., 2010; and data not shown]....

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  • ..., 2006], with recent reports demonstrating mutations in theHDAC4 gene in cases with theBDMRphenotype [Williams et al., 2010]....

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  • ...2qter [Aldred et al., 2004; Chaabouni et al., 2006], with recent reports demonstrating mutations in theHDAC4 gene in cases with theBDMRphenotype [Williams et al., 2010]....

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Journal ArticleDOI
09 Jan 2009-Science
TL;DR: Evidence is provided that HDAC4 plays an important role in promoting the survival of retinal neurons and relied at least partly on the activity of hypoxia-inducible factor 1α (HIF1α) in the cytoplasm.
Abstract: Histone deacetylase 4 (HDAC4) shuttles between the nucleus and cytoplasm and serves as a nuclear co-repressor that regulates bone and muscle development. We report that HDAC4 regulates the survival of retinal neurons in the mouse in normal and pathological conditions. Reduction in HDAC4 expression during normal retinal development led to apoptosis of rod photoreceptors and bipolar (BP) interneurons, whereas overexpression reduced naturally occurring cell death of the BP cells. HDAC4 overexpression in a mouse model of retinal degeneration prolonged photoreceptor survival. The survival effect was due to the activity of HDAC4 in the cytoplasm and relied at least partly on the activity of hypoxia-inducible factor 1α (HIF1α). These data provide evidence that HDAC4 plays an important role in promoting the survival of retinal neurons.

191 citations

Journal Article
TL;DR: Five patients with a combination of brachymetaphalangia and mental retardation, similar to that observed in Albright hereditary osteodystrophy (AHO), have cytogenetically visible de novo deletions of chromosome 2q37, suggesting genes important for skeletal and neurodevelopment lie within this region.
Abstract: We report five patients with a combination of brachymetaphalangia and mental retardation, similar to that observed in Albright hereditary osteodystrophy (AHO). Four patients had cytogenetically visible de novo deletions of chromosome 2q37. The fifth patient was cytogenetically normal and had normal bioactivity of the α subunit of Gs (Gsα), the protein that is defective in AHO. In this patient, we have used a combination of highly polymorphic molecular markers and FISH to demonstrate a microdeletion at 2q37. The common region of deletion overlap involves the most telomeric 2q marker, D2S125, and extends proximally for a maximum distance of 17.6 cM. We suggest this represents a consistent phenotype associated with some deletions at 2q37 and that genes important for skeletal and neurodevelopment lie within this region. Screening for deletions at this locus should be considered in individuals with brachymetaphalangia and mental retardation. Furthermore, 2q37 represents a candidate region for type E brachydactyly.

133 citations


"Dose dependent expression of HDAC4 ..." refers background in this paper

  • ...Individuals tend to have distinctive facies which may consist of low set ears, upslanting palpebral fissures, high arched eyebrows, smooth philtrum, thin upper lip vermilion, and underdeveloped or dysmorphic alae nasi and pinna; however, the most commonly associated clinical features of the disorder include developmental delay, behavioral issues, autism spectrum disorder, cardiac defects, obesity, and brachydactyly type E [Wilson et al., 1995; Aldred et al., 2004; Falk and Casas, 2007]....

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  • ...…or dysmorphic alae nasi and pinna; however, the most commonly associated clinical features of the disorder include developmental delay, behavioral issues, autism spectrum disorder, cardiac defects, obesity, and brachydactyly type E [Wilson et al., 1995; Aldred et al., 2004; Falk and Casas, 2007]....

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