Disruption of an EHMT1-Associated Chromatin-Modification Module Causes Intellectual Disability

Kleefstra, Tjitske; Kramer, Jamie M.; Neveling, Kornelia; Willemsen, Marjolein H.; Koemans, Tom S.; Vissers, Lisenka E.L.M.; Wissink-Lindhout, Willemijn M.; Fencková, Michaela; Akker, Willem M.R. van den; Kasri, Nael Nadif; Nillesen, Willy M.; Prescott, Trine; Clark, Robin D.; Devriendt, Koenraad; Reeuwijk, Jeroen van; Brouwer, Arjan P.M. de; Gilissen, Christian; Zhou, Huiqing; Brunner, Han G.; Veltman, Joris A.; Schenck, Annette; Bokhoven, Hans van

doi:10.1016/j.ajhg.2012.05.003

Cited by 232 publications

(198 citation statements)

References 54 publications

Supporting

Mentioning

191

Contrasting

Unclassified

Order By: Relevance

“…In total, mutations in six SWI/SNF complex members including SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily B, member 1 (SMARCB1), SMARCA4, SMARCA2, SMARCE1, AT rich interactive domain 1A (ARID1A) and ARID1B, were identified in individuals with CSS (85,86). Mutations in this complex are not exclusive to CSS, since mutations in SMARCA2, SMARCB1, and ARID1B have also been identified in other forms of syndromic ID and autism (73,(87)(88)(89) (Figure 2). …”

Section: Nuclear Receptor Signaling As An Epigenetic Mechanism In Undmentioning

confidence: 99%

“…Histone H3 lysine 4 trimethylation (H3K4me3), an activating modification, was found to be increased in the hippocampus 1 h after fear conditioning and returned to base line levels at 24 h after fear conditioning. Interestingly, heterozygous knockout mice, with loss of the H3K4-specific HMT Mll1, have defects in contextual fear conditioning (52) and heterozygous mutations in the two human homologues, MLL2 and MLL3, cause ID (69,73). Thus, H3K4me3 appears to be an important regulator of brain function in animal models and human disease.…”

Section: Histone Methylationmentioning

confidence: 99%

“…Mutations in nuclear receptor related chromatin modifiers were also identified in a group of individuals with Kleefstra syndrome phenotypic spectrum (KSS), a form of ID that is accompanied by childhood hypotonia and distinct facial features (73). Epigenetic regulators disrupted in KSS individuals include the SWI/SNF member SMARCB1, the histone methyltransferase MLL3, and the nuclear receptor subfamily 1, group I, member 3 (NR1I3), also known as the constitutive androstane receptor (CAR) (73) (Figure 2).…”

Section: Nuclear Receptor Signaling As An Epigenetic Mechanism In Undmentioning

confidence: 99%

“…For example, H3K9 tri-and di-methylation are associated with repressive heterochromatin, while H3K9 mono-methylation is found at active genes (66). Many different mediators of histone methylation have been implicated in ID, including the HDMs, Jumonji/ARID domain-containing protein 1c (JARID1c) and PHD finger protein 8 (PHF8), and the HMTs, euchromatin histone methyltransferase 1 (EHMT1), nuclear receptor binding SET domain protein 1 (NSD1), mixed lineage leukemia 2 (MLL2), and MLL3, suggesting that these modifications can play a role in human cognitive function (67)(68)(69)(70)(71)(72)(73).…”

Section: Histone Methylationmentioning

confidence: 99%

“…Epigenetic regulators disrupted in KSS individuals include the SWI/SNF member SMARCB1, the histone methyltransferase MLL3, and the nuclear receptor subfamily 1, group I, member 3 (NR1I3), also known as the constitutive androstane receptor (CAR) (73) (Figure 2). MLL3 tri methylates histone H3 at lysine 4 (H3K4me3) and is a critical member of the activating signal cointegrator-2 (ASC-2) complex (ASCOM), a large protein complex that is essential for transcriptional activation by many different nuclear receptors, including NR1I3 (Figure 1) (90)(91)(92)(93)(94)(95)(96).…”

Section: Nuclear Receptor Signaling As An Epigenetic Mechanism In Undmentioning

confidence: 99%

See 4 more Smart Citations

Epigenetic regulation of memory: implications in human cognitive disorders

Kramer

2013

BioMolecular Concepts

View full text Add to dashboard Cite

Epigenetic modification of chromatin structure is an important mechanism in the regulation of gene expression. Recent studies have shown that dynamic regulation of chromatin structure occurs in response to neuronal stimulation associated with learning and memory. Learning-induced chromatin modifications include DNA methylation, histone acetylation, histone phosphorylation and histone methylation. Studies in animal models have used genetic and pharmacological methods to manipulate the epigenetic machinery in the brain during learning and memory formation. In general, these studies suggest that epigenetic regulation of chromatin structure is essential for long term memory (LTM) consolidation, which is known to require new gene transcription. Analysis of animal models has also implicated epigenetic mechanisms in impaired cognition associated with aging, neurodegenerative disease, and intellectual disability (ID). Recently, it has been shown that a subset of ID disorders and autism are caused by disruption of specific chromatin modification complexes that are involved in nuclear hormone receptor mediated transcriptional regulation. This review provides an overview of chromatin modifications that are implicated in learning and memory and discusses the role of chromatin modifying proteins in learning-induced transcriptional regulation and human cognitive disorders.

show abstract

Section: Nuclear Receptor Signaling As An Epigenetic Mechanism In Undmentioning

confidence: 99%

Section: Histone Methylationmentioning

confidence: 99%

Section: Nuclear Receptor Signaling As An Epigenetic Mechanism In Undmentioning

confidence: 99%

Section: Histone Methylationmentioning

confidence: 99%

Section: Nuclear Receptor Signaling As An Epigenetic Mechanism In Undmentioning

confidence: 99%

See 3 more Smart Citations

Epigenetic regulation of memory: implications in human cognitive disorders

Kramer

2013

BioMolecular Concepts

View full text Add to dashboard Cite

show abstract

Distal 22q11.2 microduplication combined with typical 22q11.2 proximal deletion: A case report

Molck

Vieira

Simioni

et al. 2014

American J of Med Genetics Pt A

View full text Add to dashboard Cite

The 22q11 chromosomal region contains low copy repeats (LCRs) sequences that mediate non-allelic homologous recombination, which predisposes to copy number variations (CNVs) at this locus. Hemizygous deletions of the proximal 22q11.2 region result in the 22q11.2 deletion syndrome (22q11.2 DS). In addition, 22q11.2 duplications involving the distal LCR22s have been reported. This article describes a patient presenting a 2.5-Mb de novo deletion at proximal 22q11.21 region (between LCRs A-D), combined with a 1.3-Mb maternally inherited duplication at distal 22q11.23 region (between LCRs F-H). The presence of concomitant chromosomal imbalances found in this patient has not been reported previously. Clinical and molecular data were compared with literature, in order to contribute to genotype-phenotype correlation. These findings exemplify the complexity and genetic heterogeneity observed in 22q11.2 deletion syndrome and highlights the difficulty to make genetic counseling and predict phenotypic consequences in these situations.

show abstract

Genotype‐phenotype correlation of Coffin‐Siris syndrome caused by mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A

Kosho¹,

Okamoto²

2014

American J of Med Genetics Pt C

140

139

View full text Add to dashboard Cite

Coffin-Siris syndrome (CSS) is a rare congenital malformation syndrome, recently found to be caused by mutations in several genes encoding components of the BAF complex. To date, 109 patients have been reported with their mutations: SMARCB1 (12%), SMARCA4 (11%), SMARCE1 (2%), ARID1A (7%), ARID1B (65%), and PHF6 (2%). We review genotype-phenotype correlation of all previously reported patients with mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A through reassessment of their clinical and molecular findings. Cardinal features of CSS included variable degrees of intellectual disability (ID) predominantly affecting speech, sucking/feeding difficulty, and craniofacial (thick eyebrows, long eyelashes), digital (hypoplastic 5th fingers or toes, hypoplastic 5th fingernails or toenails), and other characteristics (hypertrichosis). In addition, patients with SMARCB1 mutations had severe neurodevelopmental deficits including severe ID, seizures, CNS structural abnormalities, and no expressive words as well as scoliosis. Especially, those with a recurrent mutation "p.Lys364del" represented strikingly similar phenotypes including characteristic facial coarseness. Patients with SMARCA4 mutations had less coarse craniofacial appearances and behavioral abnormalities. Patients with SMARCE1 mutations had a wide spectrum of manifestations from severe to moderate ID. Patients with ARID1A also had a wide spectrum of manifestations from severe ID and serous internal complications that could result in early death to mild ID. Mutations in SMARCB1, SMARCA4, and SMARCE1 are expected to exert dominant-negative or gain-of-function effects, whereas those in ARID1A are expected to exert loss-of-function effects.

show abstract

Disruption of an EHMT1-Associated Chromatin-Modification Module Causes Intellectual Disability

Cited by 232 publications

References 54 publications

Epigenetic regulation of memory: implications in human cognitive disorders

Epigenetic regulation of memory: implications in human cognitive disorders

Distal 22q11.2 microduplication combined with typical 22q11.2 proximal deletion: A case report

Genotype‐phenotype correlation of Coffin‐Siris syndrome caused by mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A

Contact Info

Product

Resources

About