Molecular characterization of known and novel ACVR1 variants in phenotypes of aberrant ossification. Am J Med Genet A 2019 Sep;179(9):1764-1777
Date
06/27/2019Pubmed ID
31240838DOI
10.1002/ajmg.a.61274Scopus ID
2-s2.0-85068139246 (requires institutional sign-in at Scopus site) 12 CitationsAbstract
Diffuse idiopathic skeletal hyperostosis (DISH) is a disorder principally characterized by calcification and ossification of spinal ligaments and entheses. Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disabling disorder characterized by progressive ossification of skeletal muscle, fascia, tendons, and ligaments. These conditions manifest phenotypic overlap in the ossification of tendons and ligaments. We describe herein a patient with DISH, exhibiting heterotopic ossification of the posterior longitudinal ligament where clinical whole exome sequencing identified a variant within ACVR1, a gene implicated in FOP. This variant, p.K400E, is a novel variant, not identified previously, and occurs in a highly conserved region across orthologs. We used sequence-based predicative algorithms, molecular modeling, and molecular dynamics simulations, to test the potential for p.K400E to alter the structure and dynamics of ACVR1. We applied the same modeling and simulation methods to established FOP variants, to identify the detailed effects that they have on the ACVR1 protein, as well as to act as positive controls against which the effects of p.K400E could be evaluated. Our in silico molecular analyses support p.K400E as altering the behavior of ACVR1. In addition, functional testing to measure the effect of this variant on BMP-pSMAD 1/5/8 target genes was carried out which revealed this variant to cause increased ID1 and Msx2 expression compared with the wild-type receptor. This analysis supports the potential for the variant of uncertain significance to contribute to the patient's phenotype.
Author List
Gupta A, Zimmermann MT, Wang H, Broski SM, Sigafoos AN, Macklin SK, Urrutia RA, Clark KJ, Atwal PS, Pignolo RJ, Klee EWAuthors
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of WisconsinMichael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Activin Receptors, Type IAdolescent
Adult
Algorithms
Computer Simulation
Female
Humans
Longitudinal Ligaments
Male
Molecular Dynamics Simulation
Muscle, Skeletal
Mutation
Myositis Ossificans
Ossification of Posterior Longitudinal Ligament
Ossification, Heterotopic
Phenotype
Signal Transduction
Smad Proteins
