Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026827 (hypotonia)
 5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chromosome 9q subtelomere deletion syndrome (9qSTDS) is among the first and most common clinically recognizable syndromes to arise from widespread testing by fluorescent in situ hybridization (FISH) of subtelomere deletions. There are about 50 reported cases worldwide. Affected individuals invariably have severe hypotonia with speech and gross motor delay. The facial gestalt is distinct and features absolute or relative micro- or brachycephaly, hypertelorism, synophrys, and/or arched eyebrows, mid-face hypoplasia, a short nose with upturned nares, a protruding tongue with everted lower lip and down-turned corners of the mouth. Approximately half of affected individuals have congenital heart defects (primarily ASD or VSD). A significant minority have epilepsy and/or behavioral and sleep disturbances. A variety of other major and minor eye, ear, genital, and limb anomalies have been reported. Most patients have sub-microscopic deletions of the subtelomere region of chromosome 9q34.3 that range from <400 kb to >3 Mb. The 9qSTDS is caused by haplo-insufficiency of EHMT1, a gene whose protein product (Eu-HMTase1) is a histone H3 Lys 9 (H3-K9) methyltransferase. This was established by identification of three patients with features of the syndrome and either mutations or a balanced translocation in EHMT1. H3-K9 histone methylation is restricted to the euchromatin of mammals and functions to silence individual genes. Deletion size does not correlate with the severity of the 9qSTDS since patients with mutations in EHMT1 are as severely affected as those with submicroscopic deletions. Patients clinically suspected of having the 9qSTDS but with normal subtelomere deletion testing by FISH or MLPA should be considered for detailed 9q MLPA analysis and/or sequencing of EHMT1. EHMT1 is another example in the growing list of genes responsible for brain development that appear to play a role in chromatin remodeling. Published 2007 Wiley-Liss, Inc.
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PMID:The chromosome 9q subtelomere deletion syndrome. 1791 72

Haploinsufficiency of Euchromatin histone methyltransferase 1 (EHMT1), a chromatin modifying enzyme, is the cause of Kleefstra syndrome (KS). KS is an intellectual disability (ID) syndrome, with general developmental delay, hypotonia, and craniofacial dysmorphisms as additional core features. Recent studies have been focused on the role of EHMT1 in learning and memory, linked to the ID phenotype of KS patients. In this study we used the Ehmt1(+/-) mouse model, and investigated whether the core features of KS were mimicked in these mice. When comparing Ehmt1(+/-) mice to wildtype littermates we observed delayed postnatal growth, eye opening, ear opening, and upper incisor eruption, indicating a delayed postnatal development. Furthermore, tests for muscular strength and motor coordination showed features of hypotonia in young Ehmt1(+/-) mice. Lastly, we found that Ehmt1(+/-) mice showed brachycephalic crania, a shorter or bent nose, and hypertelorism, reminiscent of the craniofacial dysmorphisms seen in KS. In addition, gene expression analysis revealed a significant upregulation of the mRNA levels of Runx2 and several other bone tissue related genes in P28 Ehmt1(+/-) mice. Runx2 immunostaining also appeared to be increased. The mRNA upregulation was associated with decreased histone H3 lysine 9 dimethylation (H3K9me2) levels, the epigenetic mark deposited by Ehmt1, in the promoter region of these genes. Together, Ehmt1(+/-) mice indeed recapitulate KS core features and can be used as an animal model for Kleefstra syndrome. The increased expression of bone developmental genes in the Ehmt1(+/-) mice likely contributes to their cranial dysmorphisms and might be explained by diminished Ehmt1-induced H3K9 dimethylation.
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PMID:Reduced Euchromatin histone methyltransferase 1 causes developmental delay, hypotonia, and cranial abnormalities associated with increased bone gene expression in Kleefstra syndrome mice. 2436 66

Prader-Willi syndrome (PWS), a disorder of genomic imprinting, is characterized by neonatal hypotonia, hypogonadism, small hands and feet, hyperphagia and obesity in adulthood. PWS results from the loss of paternal copies of the cluster of SNORD116 C/D box snoRNAs and their host transcript, 116HG, on human chromosome 15q11-q13. We have investigated the mechanism of repression of the maternal SNORD116 cluster and 116HG. Here, we report that the zinc-finger protein ZNF274, in association with the histone H3 lysine 9 (H3K9) methyltransferase SETDB1, is part of a complex that binds to the silent maternal but not the active paternal alleles. Knockdown of SETDB1 in PWS-specific induced pluripotent cells (iPSCs) causes a decrease in the accumulation of H3K9 trimethylation (H3K9me3) at 116HG and corresponding accumulation of the active chromatin mark histone H3 lysine 4 dimethylation (H3K4me2). We also show that upon knockdown of SETDB1 in PWS-specific iPSCs, expression of maternally silenced 116HG RNA is partially restored. SETDB1 knockdown in PWS iPSCs also disrupts DNA methylation at the PWS-IC where a decrease in 5-methylcytosine is observed in association with a concomitant increase in 5-hydroxymethylcytosine. This observation suggests that the ZNF274/SETDB1 complex bound to the SNORD116 cluster may protect the PWS-IC from DNA demethylation during early development. Our findings reveal novel epigenetic mechanisms that function to repress the maternal 15q11-q13 region.
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PMID:Reactivation of maternal SNORD116 cluster via SETDB1 knockdown in Prader-Willi syndrome iPSCs. 2476 Jul 66

Kleefstra syndrome (KS; OMIM #610253), formerly known as the 9q subtelomeric deletion syndrome, is an autosomal dominant cause of intellectual disability (ID) characterized by hypotonia and facial dysmorphisms.(1,2) The cause of KS is attributed to haploinsufficiency of the euchromatin histone methyltransferase 1 (EHMT1) gene (OMIM *607001) located at chromosome 9q34.3 (i.e., distal long arm of chromosome 9), either by microdeletion or point mutation. EHMT1 encodes a histone H3 methyltransferase at position Lys-9 (H3K9).(1-3).
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PMID:Reversible white matter lesions associated with mutant EHMT1 and Kleefstra syndrome. 2712 77

Identification of over 500 epigenetic regulators in humans raises an interesting question regarding how chromatin dysregulation contributes to different diseases. Bromodomain and PHD finger-containing protein 1 (BRPF1) is a multivalent chromatin regulator possessing three histone-binding domains, one non-specific DNA-binding module, and several motifs for interacting with and activating three lysine acetyltransferases. Genetic analyses of fish brpf1 and mouse Brpf1 have uncovered an important role in skeletal, hematopoietic, and brain development, but it remains unclear how BRPF1 is linked to human development and disease. Here, we describe an intellectual disability disorder in ten individuals with inherited or de novo monoallelic BRPF1 mutations. Symptoms include infantile hypotonia, global developmental delay, intellectual disability, expressive language impairment, and facial dysmorphisms. Central nervous system and spinal abnormalities are also seen in some individuals. These clinical features overlap with but are not identical to those reported for persons with KAT6A or KAT6B mutations, suggesting that BRPF1 targets these two acetyltransferases and additional partners in humans. Functional assays showed that the resulting BRPF1 variants are pathogenic and impair acetylation of histone H3 at lysine 23, an abundant but poorly characterized epigenetic mark. We also found a similar deficiency in different lines of Brpf1-knockout mice. These data indicate that aberrations in the chromatin regulator gene BRPF1 cause histone H3 acetylation deficiency and a previously unrecognized intellectual disability syndrome.
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PMID:Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation. 2793 40

Prader-Willi syndrome (PWS) is characterized by neonatal hypotonia, developmental delay and hyperphagia/obesity and is caused by the absence of paternal contribution to chromosome 15q11-q13. Using induced pluripotent stem cell (iPSC) models of PWS, we previously discovered an epigenetic complex that is comprised of the zinc-finger protein ZNF274 and the SET domain bifurcated 1 (SETDB1) histone H3 lysine 9 (H3K9) methyltransferase and that silences the maternal alleles at the PWS locus. Here, we have knocked out ZNF274 and rescued the expression of silent maternal alleles in neurons derived from PWS iPSC lines, without affecting DNA methylation at the PWS-Imprinting Center (PWS-IC). This suggests that the ZNF274 complex is a separate imprinting mark that represses maternal PWS gene expression in neurons and is a potential target for future therapeutic applications to rescue the PWS phenotype.
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PMID:Zinc finger protein 274 regulates imprinted expression of transcripts in Prader-Willi syndrome neurons. 2922 78