FSHD2- and BAMS-associated mutations confer opposing effects on SMCHD1 function Thao Nguyen Ly, Bruno Reversade, Marnie E. Blewitt and James M. Murphy Alexandra D. Gurzau, Kelan Chen, Shifeng Xue, Weiwen Dai, Isabelle S. Lucet, Thanh J. Biol. Chem. 2018, 293:9841-9853. doi: 10.1074/jbc.RA118.003104 originally published online May 10, 2018
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.
This study was supported by an Australian Research Training Program scholarship (to A. D. G.), a Cancer Council Victoria fellowship (to K. C.), the Bellberry-Viertel Senior Medical Research Fellowship (to M. E. B.), Australian National Health and Medical Research Council Fellowship 1105754 (to J. M. M.) and Grant 1098290 (to M. E. B. and J. M. M.), A*STAR BMRC YIG (to S. X.), NMRC YIRG (to S. X.), and a Strategic Positioning Fund on Genetic Orphan Diseases from the BMRC, A*STAR, Singapore (to B. R.). Additional support was provided by Victorian State Government Operational Infrastructure Support, Australian National Health and Medical Research Council IRIISS Grant 9000433, and the Australian Cancer Research Foundation. BMRC, Young Investigator Grant (1610151036), BMRC, Strategic Positioning Fund on Genetic Orphan Diseases NMRC, Open Fund- Young Investigator Research Grant (NMRC/OFYIRG/062/2017).