Professor of Clinical Genetics
- Consultant Physician
Chromatin remodelling factors in human genetic disease.
The principal aim of the group is to characterise the ATRX protein; germline mutations in the underlying gene give rise to a severe X-linked form of syndromal intellectual disability one feature of which is alpha thalassaemia. We run a clinical and molecular diagnostic service through which we have collected over 200 affected families. We identify the underlying mutations and through microarray gene expression analysis, methylation studies, enzyme assays and protein structure studies we are defining their functional consequences. This clinical work also informs our research which is to both understand the function of this protein and understand how mutations lead to disease. Recent work has shown that ATRX with the histone chaperone DAXX remodels chromatin by replacing canonical histones with the histone variant H3.3 and that this role is important in maintaining epigenetic memory and patterns of gene expression.
In the last 5 years it has been shown that ATRX acts as a tumour suppressor. Somatic mutations in ATRX are observed in a group of cancers which maintain their telomere length not by reactivating telomerase as is seen in 85% of cancers, but using homology directed repair, a process known as Alternative Lengthening of Telomeres (ALT). We have shown that re-expressing ATRX leads to repression of ALT and this has opened up a new area of research which we are exploring in collaboration with Dr David Clynes (Dept of Oncology)
Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.
O'Donnell-Luria AH. et al, (2019), Am J Hum Genet
Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.
Gorman KM. et al, (2019), Am J Hum Genet, 104, 948 - 956
The macroH2A1.2 histone variant links ATRX loss to alternative telomere lengthening.
Kim J. et al, (2019), Nat Struct Mol Biol
Refining the Primrose syndrome phenotype: A study of five patients with ZBTB20 de novo variants and a review of the literature.
Cleaver R. et al, (2019), Am J Med Genet A, 179, 344 - 349
The Loss of ATRX Increases Susceptibility to Pancreatic Injury and Oncogenic KRAS in Female But Not Male Mice
Young CC. et al, (2019), Cellular and Molecular Gastroenterology and Hepatology, 7, 93 - 113