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Pathogenic ACVR1^R206H activation by Activin A-induced receptor clustering and autophosphorylation.

ABSTRACT: Fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) are debilitating diseases that share causal mutations in ACVR1, a TGF-β family type I receptor. ACVR1^R206H is a frequent mutation in both diseases. Pathogenic signaling via the SMAD1/5 pathway is mediated by Activin A, but how the mutation triggers aberrant signaling is not known. We show that ACVR1 is essential for Activin A-mediated SMAD1/5 phosphorylation and is activated by two distinct mechanisms. Wild-type ACVR1 is activated by the Activin type I receptors, ACVR1B/C. In contrast, ACVR1^R206H activation does not require upstream kinases, but is predominantly activated via Activin A-dependent receptor clustering, which induces its auto-activation. We use optogenetics and live-imaging approaches to demonstrate Activin A-induced receptor clustering and show it requires the type II receptors ACVR2A/B. Our data provide molecular mechanistic insight into the pathogenesis of FOP and DIPG by linking the causal activating genetic mutation to disrupted signaling.

SUBMITTER: Ramachandran A

PROVIDER: S-EPMC8280795 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Pathogenic ACVR1<sup>R206H</sup> activation by Activin A-induced receptor clustering and autophosphorylation.

Ramachandran Anassuya A Mehić Merima M Wasim Laabiah L Malinova Dessislava D Gori Ilaria I Blaszczyk Beata K BK Carvalho Diana M DM Shore Eileen M EM Jones Chris C Hyvönen Marko M Tolar Pavel P Hill Caroline S CS

The EMBO journal 20210518 14

Fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) are debilitating diseases that share causal mutations in ACVR1, a TGF-β family type I receptor. ACVR1<sup>R206H</sup> is a frequent mutation in both diseases. Pathogenic signaling via the SMAD1/5 pathway is mediated by Activin A, but how the mutation triggers aberrant signaling is not known. We show that ACVR1 is essential for Activin A-mediated SMAD1/5 phosphorylation and is activated by two distinct mechani ...[more]

PMID: 34003511

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Project description:BackgroundGenetic contributors to cardiac arrhythmias are often found in cardiovascular conduction pathways and ion channel proteins. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disease of massive heterotopic ossification caused by a highly recurrent R206H mutation in ACVR1/ALK2. This mutation causes abnormal activation of the bone morphogenetic protein (BMP) pathway in response to Activin A. Prior studies suggested increased risks of cardiopulmonary complications in FOP. We examined participants in a Natural History Study (NHS) of FOP (ClinicalTrials.gov #NCT02322255) to better understand their cardiovascular status.MethodsThe NHS is an ongoing 3 year international multi-center longitudinal study of 114 patients (ages 4-56 years) with genetically confirmed ACVR1/ALK2R206H FOP. Patients were clinically assessed at baseline and 12 months. Electrocardiograms (ECGs) were reviewed in a central ECG laboratory. Conduction abnormalities were compared against clinical data collected in the NHS, and echocardiograms collected from NHS and non-NHS patients.ResultsConduction abnormalities were present in 45.3% of baseline ECGs, with the majority of abnormalities classified as nonspecific intraventricular conduction delay (37.7%). More specifically, 22.2% of patients > 18 years old had conduction abnormalities, which was significantly higher than a prior published study of a healthy population (5.9%; n = 3978) (p < 0.00001). Patients with FOP < 18 years old also had a high prevalence of conduction abnormalities (62.3%). The 12-month follow up data was similar to baseline results. Conduction abnormalities did not correlate with chest wall deformities, scoliosis, pulmonary function test results, or increased Cumulative Analog Joint Involvement Scale scores. Echocardiograms from 22 patients with FOP revealed 8 with structural cardiac abnormalities, only 1 of which correlated with a conduction abnormality.ConclusionsWe found that patients with FOP may have subclinical conduction abnormalities manifesting on ECG, independent of heterotopic ossification. Although clinically significant heart disease is not typically associated with FOP, and the clinical implications for cardiovascular risk remain unclear, knowledge about ECG and echocardiogram changes is important for clinical care and research trials in patients with FOP. Further studies on how ACVR1/ALK2R206H affects cardiac health will help elucidate the underlying mechanism.

Dataset Information

Pathogenic ACVR1^R206H activation by Activin A-induced receptor clustering and autophosphorylation.

Publications

Pathogenic ACVR1<sup>R206H</sup> activation by Activin A-induced receptor clustering and autophosphorylation.

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Dataset Information

Pathogenic ACVR1R206H activation by Activin A-induced receptor clustering and autophosphorylation.

Publications

Pathogenic ACVR1<sup>R206H</sup> activation by Activin A-induced receptor clustering and autophosphorylation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Pathogenic ACVR1^R206H activation by Activin A-induced receptor clustering and autophosphorylation.