Loss-of-Function Mutations in YY1Ap1 Lead to Grange Syndrome and a Fibrouscular Dysplasia-Like Vascular Disease
Dong-chuan Guo13, Xue-Yan Duan13, Ellen S. Regalado, Lauren Mellor-Crummey, Callie S. Kwartler, Dong Kim, Kenneth Lieberman, Bert B.A. de Vries, Rolph Pfundt, Albert Schinzel, Dieter Kotzot, Xuetong Shen, Min-Lee Yang, University of Washington Center for Mendelian Genomics, Michael J. Bamshad, Deborah A. Nickerson, Heather L. Gornik, Santhi K. Ganesh, Alan C. Braverman, Dorothy K. Grange, Dianna M. Milewicz
The American Journal of Human Genetics. Volume 100, Issue 1, 21 – 30. 2017
DOI: http://dx.doi.org/10.1016/j.ajhg.2016.11.008
Fibromuscular dysplasia (FMD) is a heterogeneous group of non-atherosclerotic and non-inflammatory arterial diseases that primarily involves the renal and cerebrovascular arteries. Grange syndrome is an autosomal-recessive condition characterized by severe and early-onset vascular disease similar to FMD and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Exome-sequencing analysis of DNA from three affected siblings with Grange syndrome identified compound heterozygous nonsense variants in YY1AP1, and homozygous nonsense or frameshift YY1AP1 variants were subsequently identified in additional unrelated probands with Grange syndrome. YY1AP1 encodes yin yang 1 (YY1)-associated protein 1 and is an activator of the YY1 transcription factor. We determined that YY1AP1 localizes to the nucleus and is a component of the INO80 chromatin remodeling complex, which is responsible for transcriptional regulation, DNA repair, and replication. Molecular studies revealed that loss of YY1AP1 in vascular smooth muscle cells leads to cell cycle arrest with decreased proliferation and increased levels of the cell cycle regulator p21/WAF/CDKN1A and disrupts TGF-β-driven differentiation of smooth muscle cells. Identification of YY1AP1 mutations as a cause of FMD indicates that this condition can result from underlying genetic variants that significantly alter the phenotype of vascular smooth muscle cells.
Since ancient times and across many cultures, the tree has long been a symbol of many things, including wisdom, protection, strength, inter-connectivity, and life itself. We’ve chosen the tree to represent the Fibromuscular Dysplasia Society of America for these reasons, and because the tree’s branches and roots signify the arteries affected by this disease. The tree’s branches, reaching upward and outward, provide protection and shelter, and represent our mission to help those who’ve been diagnosed with FMD. Trees, strengthened by their continuously spreading roots, symbolize how as we grow together we are stronger and more resilient. As with its growth from a delicate sapling to a giant robust tree, and as its branches and roots grow and spread, the tree symbol represents how we’ve evolved and continue to promote research, education and patient support throughout the years. Together we can achieve much, as we strive to reach for the sky.