Disruption of the gene Euchromatin Histone Methyl Transferase1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome

Kleefstra, Tjitske; Smidt, Marten P.; Banning, Martijn J.G.; Oudakker, Astrid R.; Esch, Hilde Van; Brouwer, Arjan P.M. de; Nillesen, Willy M.; Sistermans, Erik A.; Hamel, B.C.J.; Bruijn, Diederik R.H. de; Fryns, Jean‐Pierre; Yntema, Helger G.; Brunner, Hans; Vries, L.B.A. de; Bokhoven, Hans van

doi:10.1136/jmg.2004.028464

Cited by 171 publications

(131 citation statements)

References 42 publications

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“…GLP is most notably associated with Kleefstra syndrome, an intellectual disability multi-system syndrome associated with congenital heart defects, hypotonia, and dysmorphisms [32]. Kleefstra syndrome is caused by the haploinsufficiency of GLP, either through single mutations or 9q34.3 microdeletions [32,33].…”

Section: Intellectual Disabilitymentioning

confidence: 99%

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EHMT1/GLP; Biochemical Function and Association with Brain Disorders

Adam

Isles

2017

Epigenomes

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Abstract:The gene EHMT1 that encodes the Euchromatic Histone Methyltransferase-1, also known as GLP (G9a-like protein), has been associated with a number of neurodevelopmental and neurodegenerative disorders. GLP is a member of the euchromatic lysine histone methyltransferase family, along with EHMT2 or G9A. As its name implies, Ehmt1/GLP is involved in the addition of methyl groups to histone H3 lysine 9, a generally repressive mark linked to classical epigenetic process such as genomic imprinting, X-inactivation, and heterochromatin formation. However, GLP also plays both a direct and indirect role in regulating DNA-methylation. Here, we discuss what is currently known about the biochemical function of Ehmt1/GLP and its association, via various genetic studies, with brain disorders.

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Section: Intellectual Disabilitymentioning

confidence: 99%

“…Kleefstra syndrome is caused by the haploinsufficiency of GLP, either through single mutations or 9q34.3 microdeletions [32,33]. More recently, a sub-group of patients suffering from Kleefstra syndrome that do not have the deletion or mutation of GLP have been identified.…”

Section: Intellectual Disabilitymentioning

confidence: 99%

EHMT1/GLP; Biochemical Function and Association with Brain Disorders

Adam

Isles

2017

Epigenomes

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“…The behavioral changes triggered by G9a/GLP deficiency are similar to key symptoms of the human 9q34 mental retardation syndrome that is associated with the deletion or disruption of one copy of the EHMT1/GLP gene in 9q34.3 subtelomeric region (59,60). The potential causal role of the GLP gene alterations in the human 9q34 mental retardation syndrome has been further underscored by the identification of various intragenic GLP/EHMT1 mutations in patients with a mental retardation syndrome clinically indistinguishable from 9q34 deletion syndrome (60a, 63a).…”

Section: Neuro-associated Disordersmentioning

confidence: 70%

Functional Crosstalk Between Lysine Methyltransferases on Histone Substrates: The Case of G9A/GLP and Polycomb Repressive Complex 2

Mozzetta

Pontis

Ait‐Si‐Ali

2015

Antioxidants & Redox Signaling

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Significance: Methylation of histone H3 on lysine 9 and 27 (H3K9 and H3K27) are two epigenetic modifications that have been linked to several crucial biological processes, among which are transcriptional silencing and cell differentiation. Recent Advances: Deposition of these marks is catalyzed by H3K9 lysine methyltransferases (KMTs) and polycomb repressive complex 2, respectively. Increasing evidence is emerging in favor of a functional crosstalk between these two major KMT families. Critical Issues: Here, we review the current knowledge on the mechanisms of action and function of these enzymes, with particular emphasis on their interplay in the regulation of chromatin states and biological processes. We outline their crucial roles played in tissue homeostasis, by controlling the fate of embryonic and tissue-specific stem cells, highlighting how their deregulation is often linked to the emergence of a number of malignancies and neurological disorders. Future Directions: Histone methyltransferases are starting to be tested as drug targets. A new generation of highly selective chemical inhibitors is starting to emerge. These hold great promise for a rapid translation of targeting epigenetic drugs into clinical practice for a number of aggressive cancers and neurological disorders.

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“…With respect to the behavioural phenotype, in addition to intellectual disability, an amiable, friendly disposition was described [65]. Cognitive phenotyping of a small number of patients disclosed hypersociability accompanied by high levels of frustration tolerance to [67] and in some by a mutation in the euchromatin histione methyltransferase 1 (EHMT1) gene [68,69]. In all cases, however, loss of function of the EHMT1 gene is the causative factor.…”

Section: Q2131 Microdeletion Syndrome (Koolen-de Vries Syndrome; Omentioning

confidence: 99%

Aetiology Based Diagnosis and Treatment Selection in Intellectually Disabled People with Challenging Behaviours

Verhoeven¹,

Egger

2014

J. Intellect. Disabl. Diagn. Treat.

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Since both intellectual disability and challenging behaviour are entities encompassing heterogeneous clinical conditions and current taxonomies are of limited use in this field of psychiatry, diagnosing psychiatric symptoms in intellectually disabled patients is still very complex. In the diagnostic process of psychiatric symptoms and behavioural abnormalities, the first step should be genome profiling using the latest techniques in order to detect pathogenic CNVs or single gene mutations that are causative for the developmental delay. Their importance can be derived from the scientific observation that several genetic syndromes are associated with a specific behavioural, psychiatric, neuropsychological or neurological symptom profile, relevant for both choice of treatment and prognosis. Second, it has to be stressed that psychiatric disorders, especially from the depression and anxiety spectrum, frequently manifest with atypical symptoms that may hamper adequate pharmacological treatment. With respect to challenging behaviours in general, it should be emphasized that these are essentially dependent on contextual variables for which no rational pharmacological treatment is available and behavioural interventions are primarily warranted. Prescription of psychotropics has been demonstrated to be marginally effective only and to induce regularly unwanted side effects or even an increase of abnormal behaviours. It is therefore recommended to measure always the plasma concentration of psychotropics and antiepileptics and to perform, preferably prior to the start of treatment, genotyping of relevant cytochrome isoenzymes.In is concluded that, apart from the a priori genetic analysis, careful investigation of the here described data sources is needed to formulate a diagnostic hypothesis and treatment proposal.

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Disruption of the gene Euchromatin Histone Methyl Transferase1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome

Cited by 171 publications

References 42 publications

EHMT1/GLP; Biochemical Function and Association with Brain Disorders

EHMT1/GLP; Biochemical Function and Association with Brain Disorders

Functional Crosstalk Between Lysine Methyltransferases on Histone Substrates: The Case of G9A/GLP and Polycomb Repressive Complex 2

Aetiology Based Diagnosis and Treatment Selection in Intellectually Disabled People with Challenging Behaviours

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