TY - JOUR
T1 - Molecular characterization of known and novel ACVR1 variants in phenotypes of aberrant ossification
AU - Gupta, Aditi
AU - Zimmermann, Michael T.
AU - Wang, Haitao
AU - Broski, Stephen M.
AU - Sigafoos, Ashley N.
AU - Macklin, Sarah K.
AU - Urrutia, Raul A.
AU - Clark, Karl J.
AU - Atwal, Paldeep S.
AU - Pignolo, Robert J.
AU - Klee, Eric W.
N1 - Funding Information:
The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about. The authors would like to thank the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found at http://gnomad.broadinstitute.org/about. The authors would like to thank the patient for participation in this study. The authors would like to thank the Center for Individualized Medicine at Mayo Clinic, the Radiant Hope Foundation, and the Robert and Arlene Kogod professorship for funding.
Funding Information:
The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute. org/about. The authors would like to thank the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found at http://gnomad.broadinstitute.org/about. The authors would like to thank the patient for participation in this study. The authors would like to thank the Center for Individualized Medicine at Mayo Clinic, the Radiant Hope Foundation, and the Robert and Arlene Kogod professorship for funding.
Publisher Copyright:
© 2019 Wiley Periodicals, Inc.
PY - 2019/9
Y1 - 2019/9
N2 - 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.
AB - 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.
KW - ACVR1
KW - diffuse idiopathic skeletal hyperostosis
KW - fibrodysplasia ossificans progressiva
KW - whole exome sequencing
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UR - http://www.scopus.com/inward/citedby.url?scp=85068139246&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.61274
DO - 10.1002/ajmg.a.61274
M3 - Article
C2 - 31240838
AN - SCOPUS:85068139246
SN - 1552-4825
VL - 179
SP - 1764
EP - 1777
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 9
ER -