Role of ATRX Chromatin Remodelling Factor in α‐Thalassaemia X‐Linked Mental Retardation


α‐Thalassaemia X‐linked mental retardation (ATR‐X syndrome) is a congenital disorder typified by intellectual disability, abnormalities in growth and genital formation, and mild anaemia. Mutations resulting in the reduced function of the ATRX chromatin remodelling protein underlie these symptoms. Variability in the severity of disease characteristics may be associated either with mutations that affect different regions of ATRX or with individual variability in the chromosome landscape targeted by it. ATRX associates with proteins involved in regulating chromatin structure and repression of gene expression in repetitive, transcriptionally silent regions of the genome. Loss of ATRX function can be associated with altered gene expression, including reduced α‐globin expression; impairment in DNA repair; and the maintenance of chromosome stability, which may most critically affect normal development within tissues such as the brain and testes. The current standard of care for ATR‐X syndrome focuses on the management of symptoms, with targeted therapeutics lacking.

Key Concepts

  • ATR‐X syndrome is caused by loss‐of‐function mutations that result in the diminished expression, or reduced functionality, of the ATRX protein.
  • Though clinical features of ATR‐X syndrome show variability, common characteristics include facial dysmorphism, stunted growth, hypotonia, microcephaly, intellectual disability, mild anaemia with detectable haemoglobin H (HbH) and genital abnormalities.
  • ATR‐X syndrome is a nonprogressive disorder, involving abnormal development.
  • ATRX is a widely expressed chromatin remodelling protein, whose function affects both genomic stability and gene expression.
  • The histone chaperone complex formed by DAXX and ATRX is critical for loading the histone variant H3.3 onto chromatin.
  • The function of ATRX may be most critical during the rapid expansion of cells that occurs during development within particular organs, such as the expansion of cortical neurons in the brain or Sertoli cells in the testes.

Keywords: ATR‐X syndrome; intellectual disability; HbH; neurodevelopmental disorder; SWI/SNF; histone H3.3; DAXX; HP1α/β; epigenetics; chromatin remodelling

Figure 1. Domain structure of ATRX. Two key domains, highly conserved within mammals, exist in ATRX. The N‐terminal ADD domain contains a PHD‐type zinc finger and is involved in histone 3 binding, heterochromatin maintenance and transcriptional repression. The C‐terminal SWI/SNF domain contains an ATPase domain and helicase domain repeats (black bars) and is involved in DNA recombination and repair, histone exchange and maintenance of heterochromatin. The bottom portion of the figure shows the amino acid similarity between human and mouse proteins.Adapted from Picketts et al.1998 © Springer.
Figure 2. ATRX complexes with multiple proteins to affect nucleosome structure at unique chromatin sites and participates in DNA repair. (a) ATRX interacts with DAXX, HP1α, MeCP2 and histone 3.3 at G‐rich and repetitive chromatin regions to maintain transcriptional silencing. ATRX and HP1α localise to telomeres in mouse ES cells, dependent upon an interaction with H3.3. HP1α binds to H3K9me3, and may help guide ATRX to certain target regions. ATRX helps to maintain the H3K9me3 modification, primarily within heterochromatin. DAXX envelopes H3.3, acting as a specific chaperone for this histone. Incorporation of H3.3 is mutually exclusive with the incorporation of mH2A. The ATRX interaction with histone 3 is through its ADD domain, which may also interact with double‐stranded DNA. ATRX interacts with DAXX and MeCP2 through its C‐terminal SWI/SNF helicase domain. MeCP2 may aid in ATRX localising to methylated DNA. (b) ATRX localises with SETDB1, TRIM28 and ZNF274 at 3′ zinc finger protein gene exons, in association with H3K9me3 and H3K36me3, to maintain chromatin stability at these loci. (c) ATRX is a binding partner of Mre11‐Rad50‐Nbs1 (MRN) complex. Its interaction with this complex facilitates DNA replication during S and G2 phases and prevents replication fork stalling.


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Further Reading

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Watson LA, Goldberg H and Bérubé NG (2015) Emerging roles of ATRX in cancer. Epigenomics 7 (8): 1365–1378.

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Young, Kevin G, and Picketts, David J(Nov 2016) Role of ATRX Chromatin Remodelling Factor in α‐Thalassaemia X‐Linked Mental Retardation. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026558]