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SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome

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  • Natalie D Shaw
  • Harrison Brand
  • Zachary A Kupchinsky
  • Lacey Plummer
  • Takako I Jones
  • Serkan Erdin
  • Alexei Stortchevoi
  • Kaitlin Samocha
  • Benjamin B Currall
  • Ryan L Collins
  • Jason R Willer
  • Angela Lek
  • Monkol Lek
  • Malik Nassan
  • Shahrin Pereira
  • Tammy Kammin
  • Diane Lucente
  • Alexandra Silva
  • Catarina M Seabra
  • Colby Chiang
  • Yu An
  • Jacqueline K Rainger
  • Shelagh Joss
  • Jill Clayton Smith
  • Margaret F Lippincott
  • Sylvia S Singh
  • Nirav Patel
  • Jenny W Jing
  • Jennifer R Law
  • Nalton Ferraro
  • Alain Verloes
  • Anita Rauch
  • Katharina Steindl
  • Markus Zweier
  • Ianina Scheer
  • Daisuke Sato
  • Nobuhiko Okamoto
  • Christina Jacobsen
  • Jeanie Tryggestad
  • Steven Chernausek
  • Lisa A Schimmenti
  • Benjamin Brasseur
  • Claudia Cesaretti
  • Jose E García-Ortiz
  • Tatiana Pineda Buitrago
  • Orlando Perez Silva
  • Jodi D Hoffman
  • Wolfgang Mühlbauer
  • Klaus W Ruprecht
  • Bart L Loeys
  • Masato Shino
  • Angela M Kaindl
  • Chie-Hee Cho
  • Cynthia C Morton
  • Eric C Liao
  • Ravikumar Balasubramanian
  • Janet E Hall
  • Stephanie B Seminara
  • Daniel Macarthur
  • Steven A Moore
  • Koh-ichiro Yoshiura
  • James F Gusella
  • John M Graham Jr
  • Angela E Lin
  • Nicholas Katsanis
  • Peter L Jones
  • William F Crowley Jr
  • Erica E Davis
  • Michael E Talkowski

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Original languageEnglish
Pages (from-to)238-248
Number of pages11
JournalNature Genetics
Volume49
Issue number2
Early online date9 Jan 2017
DOIs
Publication statusPublished - Feb 2017

Abstract

Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.

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