Genetics of childhood-onset hypertension

National Human Genome Research Institute

Investigators

Linked publications, trials & patents

Abstract

Our previous studies using exome sequencing of 76 probands with COEH identified 5 probands from 4 families with rare, predicted protein-damaging, biallelic variation in trans in SYNE1. We showed that this proportion is significantly more than expected by chance, and that the frequency of rare variants in SYNE1 is highest among individuals with African ancestries. Subsequent studies in which we performed siRNA knockdown (KD) of SNYE1 transcripts in vascular smooth muscle cells, reduced cellular stiffness on atomic force microscopy and resulted in abnormal actin filament contraction, both consistent with the pathophysiology of COEH. We also showed that administration of Fausidil, a pharmacologic inhibitor of the Rho-Kinase/ROCK activity that is regulated by SYNE1 and regulates actin filament formation and contractility, was able to reduce the stiffness of SYNE1 KD cells. The current reporting period has focused on the dissemination of these findings, including the drafting and submission of the manuscript describing our findings. We continue to revise and refine the results, ahead of expanded analyses of sequenced individuals and commencement of prospective recruitment.