Molecular characterization of known and novel ACVR1 variants in phenotypes of aberrant ossification

Aditi Gupta, Michael T. Zimmermann, Haitao Wang, Stephen Broski, Ashley N. Sigafoos, Sarah K. Macklin, Raul A. Urrutia, Karl J Clark, Paldeep S. Atwal, Robert Pignolo, Eric W Klee

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalAmerican Journal of Medical Genetics, Part A
DOIs
StatePublished - Jan 1 2019

Fingerprint

Myositis Ossificans
Diffuse Idiopathic Skeletal Hyperostosis
Ligaments
Osteogenesis
Phenotype
Tendons
Ossification of Posterior Longitudinal Ligament
Exome
Heterotopic Ossification
Fascia
Molecular Dynamics Simulation
Computer Simulation
Genes
Skeletal Muscle
Proteins

Keywords

  • ACVR1
  • diffuse idiopathic skeletal hyperostosis
  • fibrodysplasia ossificans progressiva
  • whole exome sequencing

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Molecular characterization of known and novel ACVR1 variants in phenotypes of aberrant ossification. / Gupta, Aditi; Zimmermann, Michael T.; Wang, Haitao; Broski, Stephen; Sigafoos, Ashley N.; Macklin, Sarah K.; Urrutia, Raul A.; Clark, Karl J; Atwal, Paldeep S.; Pignolo, Robert; Klee, Eric W.

In: American Journal of Medical Genetics, Part A, 01.01.2019.

Research output: Contribution to journalArticle

Gupta, Aditi ; Zimmermann, Michael T. ; Wang, Haitao ; Broski, Stephen ; Sigafoos, Ashley N. ; Macklin, Sarah K. ; Urrutia, Raul A. ; Clark, Karl J ; Atwal, Paldeep S. ; Pignolo, Robert ; Klee, Eric W. / Molecular characterization of known and novel ACVR1 variants in phenotypes of aberrant ossification. In: American Journal of Medical Genetics, Part A. 2019.
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abstract = "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.",
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