| 1. |
- Dalin, Martin, 1982, et al.
(författare)
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Massive parallel sequencing questions the pathogenic role of missense variants in dilated cardiomyopathy
- 2017
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 228, s. 742-748
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Tidskriftsartikel (refereegranskat)abstract
- Background: Germline genetic variants are an important cause of dilated cardiomyopathy (DCM). However, recent sequencing studies have revealed rare variants in DCM-associated genes also in individuals without known heart disease. In this study, we investigate variant prevalence and genotype-phenotype correlations in Swedish DCM patients, and compare their genetic variants to those detected in reference cohorts. Methods and results: We sequenced the coding regions of 41 DCM-associated genes in 176 unrelated patients with idiopathic DCM and found 102 protein-altering variants with an allele frequency of <0.04% in reference cohorts; the majority were missense variants not previously described in DCM. Fifty-five (31%) patients had one variant, and 24 (14%) patients had two or more variants in the analysed genes. Detection of genetic variants in any gene, and in LMNA, MYII7 or TTN alone, was associated with early onset disease and reduced transplant-free survival. As expected, nonsense and frameshift variants were more common in DCM patients than in healthy individuals of the reference cohort 1000 Genomes Europeans. Surprisingly however, the prevalence, conservation and pathogenicity scores, and localization of missense variants were similar in DCM patients and healthy reference individuals. Conclusion: To our knowledge, this is the first study to identify correlations between genotype and prognosis when sequencing a large number of genes in unselected DCM patients. The similar distribution of missense variants in DCM patients and healthy reference individuals questions the pathogenic role of many variants, and suggests that results from genetic testing of DCM patients should be interpreted with caution.
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| 2. |
- Akula, Murali K, et al.
(författare)
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Protein prenylation restrains innate immunity by inhibiting Rac1 effector interactions
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Rho family proteins are prenylated by geranylgeranyltransferase type I (GGTase-I), which normally target proteins to membranes for GTP-loading. However, conditional deletion of GGIase-I in mouse macrophages increases GTP-loading of Rho proteins, leading to enhanced inflammatory responses and severe rheumatoid arthritis. Here we show that heterozygous deletion of the Rho family gene Rac1, but not Rhoa and Cdc42, reverses inflammation and arthritis in GGTase-I-deficient mice. Non-prenylated Rac1 has a high affinity for the adaptor protein Ras GTPase-activating-like protein 1 (Iqgap1), which facilitates both GTP exchange and ubiquitination-mediated degradation of Rac1. Consistently, inactivating lagapl normalizes Rac1 GTP-loading, and reduces inflammation and arthritis in GGTase-I-deficient mice, as well as prevents statins from increasing Rac1 GTP-loading and cytokine production in macrophages. We conclude that blocking prenylation stimulates Rac1 effector interactions and unleashes proinflammatory signaling. Our results thus suggest that prenylation normally restrains innate immune responses by preventing Rac1 effector interactions.
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| 3. |
- Ivarsson, Emil G., 1989
(författare)
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Statins, Lipids, and Mutations: Consequences for the Heart and Immune System
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- CAAX proteins are a group of proteins that undergo a three-step protein maturation process that renders the proteins carboxyl-terminus hydrophobic and prone to localize to cellular membranes, where they have their primary function. The first step in this process is called prenylation, which is the covalent attachment of a lipid, either a 15-carbon farnesyl or a 20-carbon geranylgeranyl lipid, to the carboxyl-terminal cysteine residue by the enzymes farnesyltransferase (FTase) and geranylgeranyltransferase type I (GGTase-I), respectively. Statins are inhibitors of HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthesis pathway, and are widely used in the treatment of hypercholesterolemia. They are thought to improve myocardial function by inhibiting GGTase-I- and FTase-mediated prenylation of the CAAX proteins RHOA and RAC1, two known mediators of cardiomyopathy. In the first paper of this thesis, we show that, contrary to popular belief, long-term statin administration causes reduced heart function, hypertrophic cardiomyopathy, and hyperactive RHOA in the hearts of wild-type mice. Similarly, we show that inactivation of the prenylation enzymes GGTase-I, FTase, or both, in heart muscle cells causes severe dilated cardiomyopathy. These findings indicate that statins and prenylation inhibitors might have the capacity to cause heart problems. In the second paper, we define the mechanism underlying a previous finding that inactivation of GGTase-I in mouse macrophages prevents prenylation of RHO family proteins, paradoxically causes them to become hyperactive, and that this leads to severe rheumatoid arthritis. We find that the RHO-protein RAC1 is responsible for the development of rheumatoid arthiritis. We further show that non-prenylated RAC1 exhibit an increased interaction with the effector proteins TIAM1 and IQGAP1 which trigger GTP loading, activation, excessive inflammatory signaling, and arthritis. Inactivation of RAC1 or IQGAP1 reduces the inflammatory signaling and markedly improves rheumatoid arthritis in GGTase-I deficient mice. We conclude that inhibiting prenylation of RAC1 stimulates effector interactions and cause excessive inflammatory signaling. This finding suggests that prenylation normally restrains innate immunity by limiting RAC1 effector interactions and its activation. Protein-altering germline mutations are a major cause of dilated cardiomyopathy (DCM). However, recent sequencing studies have shown that rare protein-altering variants are also present in individuals without reported DCM. This complicates the interpretation of genetic testing in the clinic, which is increasingly used for diagnosis. In the third paper, we analyzed genotype-phenotype correlations and variant prevalence in 41 DCM-associated genes in a cohort of 176 Swedish DCM patients, and compared the variants to those of healthy reference individuals. We found 102 rare protein-altering variants, many of which were not previously reported, and further analysis revealed that harboring any variant was correlated with earlier onset of disease and reduced transplant-free survival. Comparing the number of variants found in DCM patients to rare variants in a healthy population showed that, while frameshift and nonsense variant were more common in DCM patients, the prevalence, pathogenicity scores, and location of missense variants were similar in both groups. These findings question the role of many putatively disease-causing variants and suggest that results from genetic testing should be interpreted with caution.
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