title: Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease.
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.
authors.affiliation: Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA.
authors.forename: Dong-Chuan
authors.initials: DC
authors.lastname: Guo
authors.affiliation: Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA.
authors.forename: Xue-Yan
authors.initials: XY
authors.lastname: Duan
authors.affiliation: Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA.
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Regalado
authors.affiliation: Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Mellor-Crummey
authors.affiliation: Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA.
authors.forename: Callie S
authors.initials: CS
authors.lastname: Kwartler
authors.affiliation: Department of Neurosurgery, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Kim
authors.affiliation: Pediatric Nephrology, Joseph M. Sanzari Children's Hospital, Hackensack, NJ 07601, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lieberman
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Center, 6525 Nijmegen, the Netherlands.
authors.forename: Bert B A
authors.initials: BBA
authors.lastname: de Vries
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Center, 6525 Nijmegen, the Netherlands.
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.affiliation: Institute of Medical Genetics, University of Zurich, 8006 Zurick, Switzerland.
authors.forename: Albert
authors.initials: A
authors.lastname: Schinzel
authors.affiliation: Department of Medical Genetics, Molecular and Clinical Pharmacology of the Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Dieter
authors.initials: D
authors.lastname: Kotzot
authors.affiliation: Department of Epigenetics &Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xuetong
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Min-Lee
authors.initials: ML
authors.lastname: Yang
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Department of Cardiovascular Medicine, Cleveland Clinic Heart and Vascular Institute, Cleveland, OH 44195, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Gornik
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Santhi K
authors.initials: SK
authors.lastname: Ganesh
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Braverman
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Dorothy K
authors.initials: DK
authors.lastname: Grange
authors.affiliation: Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA. Electronic address: dianna.m.milewicz@uth.tmc.edu.
authors.forename: Dianna M
authors.initials: DM
authors.lastname: Milewicz
mesh_terms: D000293:Adolescent; D000328:Adult; D001842:Bone and Bones / Q000473:pathology; D059327:Brachydactyly / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics; D018797:Cell Cycle Proteins; D059472:Exome / Q000235:genetics; D005260:Female; D005352:Fibromuscular Dysplasia / Q000235:genetics*; D005808:Genes, Recessive; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007859:Learning Disabilities / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D013576:Syndactyly / Q000235:genetics; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C456659:YY1AP1 protein, human