Hemoglobin H Disease and Mental Retardation

Weatherall, D. J.; Higgs, Douglas R.; Bunch, C; Old, Julie M.; Hunt, DM; Pressley, L.; Clegg, J. B.; Bethlenfalvay, Nicholas C.; Sjölin, Stig; Koler, Robert D.; Magenis, Ellen; Francis, Jackie; Bebbington, D

doi:10.1056/nejm198109103051103

Cited by 132 publications

(19 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…T he rare association of a-thalassemia and mental retardation (MR) was recognized over 25 years ago by Weatherall and colleagues (Weatherall et al 1981). It was known that athalassemia arises when there is a defect in the synthesis of the a globin chains of adult hemoglobin (HbA, a 2 b 2 ).…”

mentioning

confidence: 99%

-Thalassemia, Mental Retardation, and Myelodysplastic Syndrome

Gibbons

2012

Cold Spring Harbor Perspectives in Medicine

View full text Add to dashboard Cite

mentioning

confidence: 99%

-Thalassemia, Mental Retardation, and Myelodysplastic Syndrome

Gibbons

2012

Cold Spring Harbor Perspectives in Medicine

View full text Add to dashboard Cite

“…A TRX was identified when the gene encoding this protein was shown to be mutated in a form of X-linked mental retardation (ATR-X syndrome) in young males (1,2). Furthermore, null mutations in mice are lethal at the embryonic stage of development (3).…”

mentioning

confidence: 99%

Structural consequences of disease-causing mutations in the ATRX-DNMT3-DNMT3L (ADD) domain of the chromatin-associated protein ATRX

Argentaro

Yang

Chapman

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

140

120

View full text Add to dashboard Cite

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 ␣-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 ␣-helix that pack together to form a single globular domain. Interestingly, the ␣-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.ATR-X syndrome ͉ NMR structure ͉ zinc finger A TRX was identified when the gene encoding this protein was shown to be mutated in a form of X-linked mental retardation (ATR-X syndrome) in young males (1, 2). Furthermore, null mutations in mice are lethal at the embryonic stage of development (3). Because ATRX mutations reduce ␣-globin synthesis, causing ␣-thalassemia, it seems likely that ATRX normally plays a role in the regulation of globin gene expression (2, 4). The complexity of the disease also suggests that ATRX could be involved in the regulation of other as yet unidentified genes. ATRX is a large (2,492 residue; Ϸ280 kDa) nuclear protein predominantly localized to heterochromatin and nuclear PML bodies (5, 6). It contains two highly conserved domains, and missense mutations that give rise to ATR-X syndrome fall within these. At the C terminus is a helicase/ATPase domain, which characterizes ATRX as a member of the SNF2 (SWI/SNF) family of chromatin-associated proteins. Experimental evidence shows that ATRX acts as a DNA-dependent ATPase and as a DNA translocase, and it confers modest chromatin-remodeling activity in vitro (6). Thus, it seems likely that ATRX exerts its function by targeting chromatin.Of the missense mutations identified in the ATRX gene, 50% are located in the N terminus of the ATRX protein, which represents just 4% of the coding sequence (Fig. 1a) (7). This region is highly cysteine-rich and contains two different types of zinc-finger motif. It was first noticed that a region of the sequence shares homology with the plant homeodomain (PHD)-type zinc fingers (8). Mutations in other PHD-containing proteins (WSTF and AIRE) are also associated with human disease (9, 10). PHD fingers are found in nuclear proteins, and a...

show abstract

“…Alterations in the expression and/or activity of ATRX, both in rodents and humans, result in severe developmental defects, characterized by a number of negative clinical outcomes including psychomotor deficits, cognitive disability, congenital abnormalities, and a-thalassemia (Weatherall et al, 1981). Recent studies have also identified ATRX mutations in a number of cancers, including pancreatic neuroendocrine tumors and glioblastoma multiforme, suggesting that ATRX function is critically important to numerous aspect of cellular homeostasis (Heaphy et al, 2011;Schwartzentruber et al, 2012).…”

Section: Atrx: a Critical Regulator Of Chromatin State And Histone Dymentioning

confidence: 99%

Histone Regulation in the CNS: Basic Principles of Epigenetic Plasticity

Maze

Noh

Allis

2012

Neuropsychopharmacol

115

View full text Add to dashboard Cite

Postmitotic neurons are subject to a vast array of environmental influences that require the nuclear integration of intracellular signaling events to promote a wide variety of neuroplastic states associated with synaptic function, circuit formation, and behavioral memory. Over the last decade, much attention has been paid to the roles of transcription and chromatin regulation in guiding fundamental aspects of neuronal function. A great deal of this work has centered on neurodevelopmental and adulthood plasticity, with increased focus in the areas of neuropharmacology and molecular psychiatry. Here, we attempt to provide a broad overview of chromatin regulation, as it relates to central nervous system (CNS) function, with specific emphasis on the modes of histone posttranslational modifications, chromatin remodeling, and histone variant exchange. Understanding the functions of chromatin in the context of the CNS will aid in the future development of pharmacological therapeutics aimed at alleviating devastating neurological disorders.

show abstract

Hemoglobin H Disease and Mental Retardation

Cited by 132 publications

References 17 publications

-Thalassemia, Mental Retardation, and Myelodysplastic Syndrome

-Thalassemia, Mental Retardation, and Myelodysplastic Syndrome

Structural consequences of disease-causing mutations in the ATRX-DNMT3-DNMT3L (ADD) domain of the chromatin-associated protein ATRX

Histone Regulation in the CNS: Basic Principles of Epigenetic Plasticity

Contact Info

Product

Resources

About