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Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5.

Abstract
Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher's exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.
AuthorsMargaret J McMillin, Anita E Beck, Jessica X Chong, Kathryn M Shively, Kati J Buckingham, Heidi I S Gildersleeve, Mariana I Aracena, Arthur S Aylsworth, Pierre Bitoun, John C Carey, Carol L Clericuzio, Yanick J Crow, Cynthia J Curry, Koenraad Devriendt, David B Everman, Alan Fryer, Kate Gibson, Maria Luisa Giovannucci Uzielli, John M Graham Jr, Judith G Hall, Jacqueline T Hecht, Randall A Heidenreich, Jane A Hurst, Sarosh Irani, Ingrid P C Krapels, Jules G Leroy, David Mowat, Gordon T Plant, Stephen P Robertson, Elizabeth K Schorry, Richard H Scott, Laurie H Seaver, Elliott Sherr, Miranda Splitt, Helen Stewart, Constance Stumpel, Sehime G Temel, David D Weaver, Margo Whiteford, Marc S Williams, Holly K Tabor, Joshua D Smith, Jay Shendure, Deborah A Nickerson, University of Washington Center for Mendelian Genomics, Michael J Bamshad
JournalAmerican journal of human genetics (Am J Hum Genet) Vol. 94 Issue 5 Pg. 734-44 (May 01 2014) ISSN: 1537-6605 [Electronic] United States
PMID24726473 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Ion Channels
  • PIEZO2 protein, human
Topics
  • Abnormalities, Multiple (genetics, pathology)
  • Arachnodactyly (genetics, pathology)
  • Arthrogryposis (genetics, pathology)
  • Blepharophimosis (genetics, pathology)
  • Child
  • Child, Preschool
  • Cleft Palate (genetics, pathology)
  • Clubfoot (genetics, pathology)
  • Connective Tissue Diseases (genetics, pathology)
  • Contracture (genetics, pathology)
  • Exome (genetics)
  • Female
  • Hand Deformities, Congenital (genetics, pathology)
  • Humans
  • Ion Channels (genetics)
  • Male
  • Mutation
  • Ophthalmoplegia (genetics, pathology)
  • Pedigree
  • Retinal Diseases (genetics, pathology)

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