FSHD2- and BAMS-associated mutations confer opposing effects on SMCHD1 function

Alexandra D. Gurzau, Kelan Chen, Shifeng Xue, Weiwen Dai, Isabelle S. Lucet, Thanh Thao Nguyen Ly, Bruno Reversade, Marnie E. Blewitt, James M. Murphy

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Structural maintenance of chromosomes flexible hinge domain-containing 1 (Smchd1) plays important roles in epigenetic silencing and normal mammalian development. Recently, heterozygous mutations in SMCHD1 have been reported in two disparate disorders: facioscapulohumeral muscular dystrophy type 2 (FSHD2) and Bosma arhinia microphthalmia syndrome (BAMS). FSHD2-associated mutations lead to loss of function; however, whether BAMS is associated with loss- or gain-of-function mutations in SMCHD1 is unclear. Here, we have assessed the effect of SMCHD1 missense mutations from FSHD2 and BAMS patients on ATP hydrolysis activity and protein conformation and the effect of BAMS mutations on craniofacial development in a Xenopus model. These data demonstrated that FSHD2 mutations only result in decreased ATP hydrolysis, whereas many BAMS mutations can result in elevated ATPase activity and decreased eye size in Xenopus. Interestingly, a mutation reported in both an FSHD2 patient and a BAMS patient results in increased ATPase activity and a smaller Xenopus eye size. Mutations in the extended ATPase domain increased catalytic activity, suggesting critical regulatory intramolecular interactions and the possibility of targeting this region therapeutically to boost SMCHD1’s activity to counter FSHD.
Original languageEnglish (US)
Pages (from-to)9841-9853
Number of pages13
JournalJournal of Biological Chemistry
Issue number25
StatePublished - Jun 22 2018
Externally publishedYes

Bibliographical note

Generated from Scopus record by KAUST IRTS on 2023-02-15

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology


Dive into the research topics of 'FSHD2- and BAMS-associated mutations confer opposing effects on SMCHD1 function'. Together they form a unique fingerprint.

Cite this