A novel αB-crystallin R123W variant drives hypertrophic cardiomyopathy by promoting maladaptive calcium-dependent signal transduction
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder affecting 1 in 500 people in the general population. Characterized by asymmetric left ventricular hypertrophy, cardiomyocyte disarray and cardiac fibrosis, HCM is a highly complex disease with heterogenous clinica...
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| Format: | Article |
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Frontiers Media S.A.
2023-06-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1223244/full |
| _version_ | 1797794975363104768 |
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| author | Chun Chou Gregory L. Martin Gayani Perera Junya Awata Amy Larson Robert Blanton Robert Blanton Michael T. Chin Michael T. Chin |
| author_facet | Chun Chou Gregory L. Martin Gayani Perera Junya Awata Amy Larson Robert Blanton Robert Blanton Michael T. Chin Michael T. Chin |
| author_sort | Chun Chou |
| collection | DOAJ |
| description | Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder affecting 1 in 500 people in the general population. Characterized by asymmetric left ventricular hypertrophy, cardiomyocyte disarray and cardiac fibrosis, HCM is a highly complex disease with heterogenous clinical presentation, onset and complication. While mutations in sarcomere genes can account for a substantial proportion of familial cases of HCM, 40%–50% of HCM patients do not carry such sarcomere variants and the causal mutations for their diseases remain elusive. Recently, we identified a novel variant of the alpha-crystallin B chain (CRYABR123W) in a pair of monozygotic twins who developed concordant HCM phenotypes that manifested over a nearly identical time course. Yet, how CRYABR123W promotes the HCM phenotype remains unclear. Here, we generated mice carrying the CryabR123W knock-in allele and demonstrated that hearts from these animals exhibit increased maximal elastance at young age but reduced diastolic function with aging. Upon transverse aortic constriction, mice carrying the CryabR123W allele developed pathogenic left ventricular hypertrophy with substantial cardiac fibrosis and progressively decreased ejection fraction. Crossing of mice with a Mybpc3 frame-shift model of HCM did not potentiate pathological hypertrophy in compound heterozygotes, indicating that the pathological mechanisms in the CryabR123W model are independent of the sarcomere. In contrast to another well-characterized CRYAB variant (R120G) which induced Desmin aggregation, no evidence of protein aggregation was observed in hearts expressing CRYABR123W despite its potent effect on driving cellular hypertrophy. Mechanistically, we uncovered an unexpected protein-protein interaction between CRYAB and calcineurin. Whereas CRYAB suppresses maladaptive calcium signaling in response to pressure-overload, the R123W mutation abolished this effect and instead drove pathologic NFAT activation. Thus, our data establish the CryabR123W allele as a novel genetic model of HCM and unveiled additional sarcomere-independent mechanisms of cardiac pathological hypertrophy. |
| first_indexed | 2024-03-13T03:10:50Z |
| format | Article |
| id | doaj.art-70a1450d9b0f468c9509965ddb5eba4e |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-03-13T03:10:50Z |
| publishDate | 2023-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-70a1450d9b0f468c9509965ddb5eba4e2023-06-26T12:11:16ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2023-06-011010.3389/fcvm.2023.12232441223244A novel αB-crystallin R123W variant drives hypertrophic cardiomyopathy by promoting maladaptive calcium-dependent signal transductionChun Chou0Gregory L. Martin1Gayani Perera2Junya Awata3Amy Larson4Robert Blanton5Robert Blanton6Michael T. Chin7Michael T. Chin8Department of Medicine, Tufts University School of Medicine, Boston, MA, United StatesMolecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, United StatesMolecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, United StatesMolecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, United StatesMolecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, United StatesDepartment of Medicine, Tufts University School of Medicine, Boston, MA, United StatesMolecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, United StatesDepartment of Medicine, Tufts University School of Medicine, Boston, MA, United StatesMolecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, United StatesHypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder affecting 1 in 500 people in the general population. Characterized by asymmetric left ventricular hypertrophy, cardiomyocyte disarray and cardiac fibrosis, HCM is a highly complex disease with heterogenous clinical presentation, onset and complication. While mutations in sarcomere genes can account for a substantial proportion of familial cases of HCM, 40%–50% of HCM patients do not carry such sarcomere variants and the causal mutations for their diseases remain elusive. Recently, we identified a novel variant of the alpha-crystallin B chain (CRYABR123W) in a pair of monozygotic twins who developed concordant HCM phenotypes that manifested over a nearly identical time course. Yet, how CRYABR123W promotes the HCM phenotype remains unclear. Here, we generated mice carrying the CryabR123W knock-in allele and demonstrated that hearts from these animals exhibit increased maximal elastance at young age but reduced diastolic function with aging. Upon transverse aortic constriction, mice carrying the CryabR123W allele developed pathogenic left ventricular hypertrophy with substantial cardiac fibrosis and progressively decreased ejection fraction. Crossing of mice with a Mybpc3 frame-shift model of HCM did not potentiate pathological hypertrophy in compound heterozygotes, indicating that the pathological mechanisms in the CryabR123W model are independent of the sarcomere. In contrast to another well-characterized CRYAB variant (R120G) which induced Desmin aggregation, no evidence of protein aggregation was observed in hearts expressing CRYABR123W despite its potent effect on driving cellular hypertrophy. Mechanistically, we uncovered an unexpected protein-protein interaction between CRYAB and calcineurin. Whereas CRYAB suppresses maladaptive calcium signaling in response to pressure-overload, the R123W mutation abolished this effect and instead drove pathologic NFAT activation. Thus, our data establish the CryabR123W allele as a novel genetic model of HCM and unveiled additional sarcomere-independent mechanisms of cardiac pathological hypertrophy.https://www.frontiersin.org/articles/10.3389/fcvm.2023.1223244/fullhypertrophic cardiomyopathycardiac hypertrophycryabcalcineurinNFATtransverse aortic constriction |
| spellingShingle | Chun Chou Gregory L. Martin Gayani Perera Junya Awata Amy Larson Robert Blanton Robert Blanton Michael T. Chin Michael T. Chin A novel αB-crystallin R123W variant drives hypertrophic cardiomyopathy by promoting maladaptive calcium-dependent signal transduction Frontiers in Cardiovascular Medicine hypertrophic cardiomyopathy cardiac hypertrophy cryab calcineurin NFAT transverse aortic constriction |
| title | A novel αB-crystallin R123W variant drives hypertrophic cardiomyopathy by promoting maladaptive calcium-dependent signal transduction |
| title_full | A novel αB-crystallin R123W variant drives hypertrophic cardiomyopathy by promoting maladaptive calcium-dependent signal transduction |
| title_fullStr | A novel αB-crystallin R123W variant drives hypertrophic cardiomyopathy by promoting maladaptive calcium-dependent signal transduction |
| title_full_unstemmed | A novel αB-crystallin R123W variant drives hypertrophic cardiomyopathy by promoting maladaptive calcium-dependent signal transduction |
| title_short | A novel αB-crystallin R123W variant drives hypertrophic cardiomyopathy by promoting maladaptive calcium-dependent signal transduction |
| title_sort | novel αb crystallin r123w variant drives hypertrophic cardiomyopathy by promoting maladaptive calcium dependent signal transduction |
| topic | hypertrophic cardiomyopathy cardiac hypertrophy cryab calcineurin NFAT transverse aortic constriction |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1223244/full |
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