brain hemorrhage, cystatin C, parent-of-origin effect, environmental effect, phenotypic plasticity
dermal fibroblast, zebrafish
cell culture, molecular biology, RNA sequencing, proteomics, Immunohistochemsitry
The Hertie Institute, University of Tubingen, Germany. Group of Mathias Jucker. University of Manchester UK. Group of Garth Cooper. Center for Applied Genomics, Childrens´Hospital of Philadelphia, USA. Group of Hakon Hakonarson
We are studying a dominantly inherited disease caused by a mutation in the cystatin C gene. The mutated protein gets deposited as amyloid in brain arterioles. Carriers get brain hemorrhages as young adults but few have late onset. A maternal effect is seen where those who inherit the gene from the mother die 9.5 years younger compared to those who got it from their father. By tracing all subfamilies back in time an environmental effect became clear. Before 1820 carriers were not affected by the mutation but thereafter carriers started to the get brain hemorrhages. Around 1900 the lifespan was down to 30 years and has been stable since. Import records for the whole of Iceland showed a big increase in sugar/grain import after 1820 suggesting an environmental effect on penetrance. We have studied the transcriptosome of the dermal fibroblasts of carriers and controls and see more ECM production in carriers. This is supported by IHC of patients´ brains. We are studying the effects of HDAC inhibitors on the gene activity of carriers. We are establishing a zebra fish model of the disease.