2. Academic Validation
  3. Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease

Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease

  • Am J Hum Genet. 2017 Jan 5;100(1):21-30. doi: 10.1016/j.ajhg.2016.11.008.
Dong-Chuan Guo 1,  Xue-Yan Duan 1,  Ellen S Regalado 1,  Lauren Mellor-Crummey 1,  Callie S Kwartler 1,  Dong Kim 2,  Kenneth Lieberman 3,  Bert B A de Vries 4,  Rolph Pfundt 4,  Albert Schinzel 5,  Dieter Kotzot 6,  Xuetong Shen 7,  Min-Lee Yang 8,  University of Washington Center for Mendelian Genomics,  Michael J Bamshad 9,  Deborah A Nickerson 9,  Heather L Gornik 10,  Santhi K Ganesh 8,  Alan C Braverman 11,  Dorothy K Grange 12,  Dianna M Milewicz 13
Affiliations

Affiliations

  • 1 Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA.
  • 2 Department of Neurosurgery, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA.
  • 3 Pediatric Nephrology, Joseph M. Sanzari Children's Hospital, Hackensack, NJ 07601, USA.
  • 4 Department of Human Genetics, Radboud University Nijmegen Medical Center, 6525 Nijmegen, the Netherlands.
  • 5 Institute of Medical Genetics, University of Zurich, 8006 Zurick, Switzerland.
  • 6 Department of Medical Genetics, Molecular and Clinical Pharmacology of the Medical University of Innsbruck, 6020 Innsbruck, Austria.
  • 7 Department of Epigenetics &Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 8 Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • 9 Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
  • 10 Department of Cardiovascular Medicine, Cleveland Clinic Heart and Vascular Institute, Cleveland, OH 44195, USA.
  • 11 Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 12 Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 13 Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA. Electronic address: [email protected].
PMID: 27939641 DOI: 10.1016/j.ajhg.2016.11.008
Abstract

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.

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