Mackay MR/J000329/1 Identifying factors required for genomic DNA methylation

We each inherit one copy of every gene from our mothers, and one copy from our fathers, and generally we only develop a genetic disease if both copies are damaged. However, about 1% of our genes are imprinted - though the genes from both parents have the same sequence, they are controlled differently, so that only one parent's copy can be used. An imprinted gene is in special danger of mutation, because it has only one active copy. If either its sequence or its control is disrupted, that one copy will not work, and the result is an imprinting disorder. Imprinting disorders often show themselves in early childhood - the affected children may be strikingly big or small, or very weak, or unable to feed or thrive, and they have learning or behavioural difficulties. Doctors currently find imprinting disorders hard to diagnose, because often there's nothing wrong with the genes themselves, just with the way they are controlled. But a lot of children have the same kind of problems that occur in imprinting disorders - problems with growth, feeding and learning - so if we can find out more about imprinting, we may be able to diagnose and help many more children. We recently found that mutation of a gene called ZFP57 causes imprinting disorders. We believe that ZFP57 binds to special sequences of DNA in some genes and marks them out to be imprinted. Therefore, we want to use ZFP57 as leverage to find out new things about imprinting. (A) We will find out exactly what DNA sequences ZFP57 binds to, because that will tell us just what DNA is important for imprinting and how it be mutated in imprinting disorders. (B) We will study the DNA of people with ZFP57 mutation and similar imprinting disorders, to find out exactly what imprinted genes are affected, because this will help us identify new imprinting mutations that affect growth and development. (C). We will find out what factors work with ZFP57 to help it control imprinting, because that will tell us about how the whole process normally works and how it can go wrong in disease. We will work closely with doctors and NHS scientists so that our findings can be used to diagnose, support and treat children with these disorders.