2. Academic Validation
  3. FSHD2- and BAMS-associated mutations confer opposing effects on SMCHD1 function

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

  • J Biol Chem. 2018 Jun 22;293(25):9841-9853. doi: 10.1074/jbc.RA118.003104.
Alexandra D Gurzau 1 2,  Kelan Chen 1 2,  Shifeng Xue 3 4,  Weiwen Dai 1,  Isabelle S Lucet 1 2,  Thanh Thao Nguyen Ly 3 4,  Bruno Reversade 3 4 5 6 7,  Marnie E Blewitt 8 2 9,  James M Murphy 10 2
Affiliations

Affiliations

  • 1 From the Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.
  • 2 the Departments of Medical Biology and.
  • 3 the Institute of Molecular and Cell Biology and.
  • 4 Human Genetics and Embryology Laboratory, Institute of Medical Biology, A*STAR, Singapore.
  • 5 the Department of Medical Genetics, Koç University School of Medicine (KUSoM), 34450 Sarıyer/Istanbul, Turkey.
  • 6 the Department of Paediatrics, School of Medicine, National University of Singapore, Singapore, and.
  • 7 Amsterdam Reproduction and Development, Academic Medical Centre and VU University Medical Center, 1105 AZ Amsterdam, The Netherlands.
  • 8 From the Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia, blewitt@wehi.edu.au.
  • 9 Genetics, University of Melbourne, Parkville, Victoria 3052, Australia.
  • 10 From the Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia, jamesm@wehi.edu.au.
PMID: 29748383 DOI: 10.1074/jbc.RA118.003104
Abstract

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.

Keywords

ATPase; SMC; Xenopus; craniofacial development; epigenetics; hinge domain; muscular dystrophy; small-angle X-ray scattering (SAXS).

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