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

Abstract

Abstract 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.