Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chromatin-associated protein ATRX was originally identified because mutations in the ATRX gene cause a severe form of syndromal X-linked mental retardation associated with alpha-thalassemia. Half of all of the disease-associated missense mutations cluster in a cysteine-rich region in the N terminus of ATRX. This region was named the ATRX-DNMT3-DNMT3L (ADD) domain, based on sequence homology with a family of DNA methyltransferases. Here, we report the solution structure of the ADD domain of ATRX, which consists of an N-terminal GATA-like zinc finger, a plant homeodomain finger, and a long C-terminal alpha-helix that pack together to form a single globular domain. Interestingly, the alpha-helix of the GATA-like finger is exposed and highly basic, suggesting a DNA-binding function for ATRX. The disease-causing mutations fall into two groups: the majority affect buried residues and hence affect the structural integrity of the ADD domain; another group affects a cluster of surface residues, and these are likely to perturb a potential protein interaction site. The effects of individual point mutations on the folding state and stability of the ADD domain correlate well with the levels of mutant ATRX protein in patients, providing insights into the molecular pathophysiology of ATR-X syndrome.
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PMID:Structural consequences of disease-causing mutations in the ATRX-DNMT3-DNMT3L (ADD) domain of the chromatin-associated protein ATRX. 1760 77

X-linked alpha-thalassemia/mental retardation syndrome (ATR-X syndrome, OMIM #301040) is one of the syndromes associated with abnormal epigenetic gene regulation, including ICF(DNMT3B), Rett (MECP2), Rubinstein-Taybi (CBP), Coffin-Lowry (RSK2), and Sotos (NSD1) syndromes. It is a syndromic form of X-linked mental retardation, which affects males and is characterized by profound mental retardation, mild HbH disease (alpha-thalassemia), facial dysmorphism, skeletal abnormalities, and autistic behavior. ATR-X syndrome is caused by a mutation in the ATRX gene on the X chromosome (Xq13), which encodes ATRX protein, belonging to the SNF2 family of chromatin-remodeling proteins. The protein has two functionally important domains: an ADD (ATRX-DNMT3-DNMT3L) domain at the N-terminus, and chromatin-remodeling domain in the C-terminal half, where the ATRX gene mutations of most ATR-X patients reside. Perturbation in DNA methylation in the rDNA genes was repored in ATR-X patients, and ATRX protein is presumed to be involved in the establishment and maintenance of DNA methylation. Based on its various clinical phenotypes, the expressions of many genes, including alpha globin genes, seem to be abnormally regulated in ATR-X patients. However, the precise mechanism involving ATRX protein remains to be elucidated. Epigenetics can link environmental and genetic causes of many pathological conditions. The genes, which are abnormally regulated by a perturbed epigenetic mechanism, are, in themselves, structurally normal, and the elucidation of their mechanism may lead to the development of appropriate therapy.
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PMID:[X-linked alpha-thalassemia/mental retardation syndrome]. 1948 41

ATR-X (alpha-thalassemia/mental retardation, X-linked) syndrome is a human congenital disorder that causes severe intellectual disabilities. Mutations in the ATRX gene, which encodes an ATP-dependent chromatin-remodeler, are responsible for the syndrome. Approximately 50% of the missense mutations in affected persons are clustered in a cysteine-rich domain termed ADD (ATRX-DNMT3-DNMT3L, ADD(ATRX)), whose function has remained elusive. Here we identify ADD(ATRX) as a previously unknown histone H3-binding module, whose binding is promoted by lysine 9 trimethylation (H3K9me3) but inhibited by lysine 4 trimethylation (H3K4me3). The cocrystal structure of ADD(ATRX) bound to H3(1-15)K9me3 peptide reveals an atypical composite H3K9me3-binding pocket, which is distinct from the conventional trimethyllysine-binding aromatic cage. Notably, H3K9me3-pocket mutants and ATR-X syndrome mutants are defective in both H3K9me3 binding and localization at pericentromeric heterochromatin; thus, we have discovered a unique histone-recognition mechanism underlying the ATR-X etiology.
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PMID:ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome. 2166 79