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Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome.

ABSTRACT: L-type calcium channel CaV1.2 plays an essential role in cardiac function. The gain-of-function mutations in CaV1.2 have been reported to be associated with Timothy syndrome, a disease characterized by QT prolongation and syndactyly. Previously we demonstrated that roscovitine, a cyclin-dependent kinase (CDK) inhibitor, could rescue the phenotypes in induced pluripotent stem cell-derived cardiomyocytes from Timothy syndrome patients. However, exactly how roscovitine rescued the phenotypes remained unclear. Here we report a mechanism potentially underlying the therapeutic effects of roscovitine on Timothy syndrome cardiomyocytes. Our results using roscovitine analogs and CDK inhibitors and constructs demonstrated that roscovitine exhibits its therapeutic effects in part by inhibiting CDK5. The outcomes of this study allowed us to identify a molecular mechanism whereby CaV1.2 channels are regulated by CDK5. This study provides insights into the regulation of cardiac calcium channels and the development of future therapeutics for Timothy syndrome patients.

SUBMITTER: Song L

PROVIDER: S-EPMC5511105 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome.

Song LouJin L Park Seon-Hye E SE Isseroff Yehuda Y Morikawa Kumi K Yazawa Masayuki M

Stem cell reports 20170622 1

L-type calcium channel Ca<sub>V</sub>1.2 plays an essential role in cardiac function. The gain-of-function mutations in Ca<sub>V</sub>1.2 have been reported to be associated with Timothy syndrome, a disease characterized by QT prolongation and syndactyly. Previously we demonstrated that roscovitine, a cyclin-dependent kinase (CDK) inhibitor, could rescue the phenotypes in induced pluripotent stem cell-derived cardiomyocytes from Timothy syndrome patients. However, exactly how roscovitine rescued ...[more]

PMID: 28648896

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Project description:BackgroundMutations in the CACNA1C gene-encoding for the major Ca2+ channel of the heart-may exhibit a variety of clinical manifestations. These include typical or atypical Timothy syndromes (TS) which are associated with multiple organ manifestations, and cardiac involvement in form of malignant arrhythmias, QTc prolongation, or AV block. "Cardiac only" Timothy syndrome (COTS) shows no extracardiac manifestation, whereas some CACNA1C gene mutations are associated with QTc prolongation alone (isolated long QT syndrome 8, LQT8).MethodsA systematic search of the literature reporting cases of CACNA1C gene mutation associated syndromes, including TS, COTS and isolated LQT8 via major databases published from 2004 through 2019 was performed. Detailed patient-level phenotypic and genotypic characteristics, as well as long-term outcome measures were collected and compared between pre-specified patient groups, defined both on phenotype and genotype.ResultsA total of 59 TS, 6 COTS, and 20 isolated LQT8 index cases were identified. Apart of syndactyly or baldness, there were no major differences regarding clinical manifestations or outcome measures between TS subtypes, either defining TS subtypes on the genotype or based on the phenotype. Both subtypes were characterized by an extreme degree of QTc prolongation (median ≥600 ms) which were reflected in high major adverse cardiac event rate. On the other hand, there were marked differences between TS, COTS, and isolated LQT8. Timothy syndrome was characterized by a much earlier disease onset, much more pronounced QTc prolongation and much higher mortality rate than COTS or isolated LQT8. Similar differences were observed comparing CACNA1C exon 8/8A vs. non-exon 8/8A mutation carriers. TS showed a high degree of genetic homogeneity, as the p.Gly406Arg mutation either in exon 8 or exon 8A alone was responsible for 70% of the cases.ConclusionsClinical phenotypes associated with mutations in the CACNA1C gene show important clinical differences. Timothy syndrome is associated with the most severe clinical phenotype and with the highest risk of morbidity and mortality. However, distinguishing TS subtypes, in any form, are not supported by our data.Systematic review registration[https://www.crd.york.ac.uk/prospero/], identifier [CRD42020184737].

Dataset Information

Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome.

Publications

Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome.

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