6% of the patient population in Melbourne carries a genetic abnormality implicated in thalassemia. As well as causing blood disorders and severe mental retardation, boys with ATRX mutations have genital abnormalities. Our understanding of the genetic mutations which underlie this cluster of disorders has been advanced significantly by research performed by Dr. Anthony Argentaro.
Employing nuclear magnetic resonance while at Oxford and Cambridge Universities, he solved the three-dimensional structure of part of the huge ATRX protein that carries most of the clinical mutations. By comparing the structure of normal and mutated ATRX, he determined that too much OR too little ATRX leads to developmental disorders.
He has returned to Melbourne to Prince Henry’s Institute, where he will utilise his expertise to better understand how ATRX causes abnormalities in sexual development. He will work with international authority Associate Professor Vincent Harley to identify the genes and other proteins regulated by ATRX. In doing so, Dr. Argentaro aims to identify targets for treating these disabling and traumatic diseases.
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.
They 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.
