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Mutations in the lamin A/C gene (LMNA) cause dilated cardiomyopathy associated with increased activity of ERK1/2 in the heart. We recently showed that ERK1/2 phosphorylates cofilin-1 on threonine 25 (phospho(T25)-cofilin-1) that in turn disassembles the actin cytoskeleton. Here, we show that in muscle cells carrying a cardiomyopathy-causing LMNA mutation, phospho(T25)-cofilin-1 binds to myocardin-related transcription factor A (MRTF-A) in the cytoplasm, thus preventing the stimulation of serum response factor (SRF) in the nucleus. Inhibiting the MRTF-A/SRF axis leads to decreased α-tubulin acetylation by reducing the expression of ATAT1 gene encoding α-tubulin acetyltransferase 1. Hence, tubulin acetylation is decreased in cardiomyocytes derived from male patients with LMNA mutations and in heart and isolated cardiomyocytes from Lmnap.H222P/H222P male mice. In Atat1 knockout mice, deficient for acetylated α-tubulin, we observe left ventricular dilation and mislocalization of Connexin 43 (Cx43) in heart. Increasing α-tubulin acetylation levels in Lmnap.H222P/H222P mice with tubastatin A treatment restores the proper localization of Cx43 and improves cardiac function. In summary, we show for the first time an actin-microtubule cytoskeletal interplay mediated by cofilin-1 and MRTF-A/SRF, promoting the dilated cardiomyopathy caused by LMNA mutations. Our findings suggest that modulating α-tubulin acetylation levels is a feasible strategy for improving cardiac function. Lamin A/C gene mutations cause dilated cardiomyopathy associated with cofilin-1 phosphorylation and actin destabilization. Here, the authors show that phosphorylated cofilin-1 blunts the MRTF-A/SRF axis, leading to decreased tubulin acetylation and altered cardiac structure and function. [ABSTRACT FROM AUTHOR]

Background: Transthyretin amyloidosis (ATTR) is an occasional incidental finding on bone scintigraphy. We studied its prognostic impact in elderly patients. Methods: The study population consisted of 2000 patients aged over 70 years who underwent bone scintigraphies with clinical indications in three nuclear medicine departments (Kymenlaakso, Jorvi and Meilahti hospitals) in Finland. All studies were performed using 99mTechnetium labeled hydroxymethylene diphosphonate (HMDP). ATTR was suspected in patients with ≥grade 2 Perugini grade uptake (grade 0-3). Heart-to-contralateral ratio (H/CL) of ≥ 1.30 was considered positive for ATTR. The overall and cardiovascular mortality were obtained from the Finnish National Statistical Service. Results: There were a total of 1014 deaths (51%) and 177 cardiovascular deaths (9%) during median follow-up of 4 ± 2 years. ATTR was suspected in 69 patients (3.6%) of which 54 (2.7%) had grade 2 and 15 (.8%) had grade 3 uptake and in 47 patients (2.4%) by H/CL ratio. In multivariate analyses age, bone metastasis, H/CL ratio and grade 3 uptake were independent predictors of overall and cardiovascular mortality. Grade 2 uptake was a predictor of cardiovascular mortality. Conclusions: A suspected ATTR as an incidental finding on bone scintigraphy predicts elevated overall and cardiovascular mortality in elderly patients. [ABSTRACT FROM AUTHOR]

Approximately 20–35% of cases of idiopathic dilated cardiomyopathy are familial. DCM-associated mutations have been reported in 13 genes including the desmin, δ-sarcoglycan, and metavinculin genes. This study screened for variants in these genes in Finnish patients with DCM. All coding regions of the desmin and δ-sarcoglycan genes and the metavinculin-specific exon of the vinculin gene were screened in 52 DCM patients from eastern Finland by PCR-SSCP. We detected a novel mutation, Arg71Thr, in the δ-sarcoglycan gene in two members of a small DCM family. One of the mutation carriers fulfills diagnostic criteria for DCM and is also symptomatic. The other mutation carrier has slightly dilated left ventricle and well preserved systolic function. Therefore carriers of the Arg71Thr mutation had a relatively mild phenotype and a late onset of the disease. Disease-associated mutations were not found in the desmin gene or the metavinculin-specific exon of the vinculin gene. We conclude that the desmin and δ-sarcoglycan genes are not predominant disease-causing genes in patients with DCM in eastern Finland. [ABSTRACT FROM AUTHOR]

In inflammatory bowel diseases (IBD), certain chromosomal candidate loci have been repeatedly identified by independent studies in different populations. To investigate the contribution of the loci on chromosomes 1, 3, 7, 12, 14, and 16 to the susceptibility of IBD in Finnish population, where the predominant feature is the excess of ulcerative colitis (UC) families compared to Crohn's disease (CD) families, we carried out linkage analyses using 93 Finnish, multiply-affected IBD families. We observed nominal evidence for linkage to chromosome 3p21, consistent with earlier reports. The lod scores peaked at D3S2432, with a maximum two-point lod score of 1.68 (P=0.0027). In addition, we studied whether risk of IBD is associated with functional variants of two positional candidate genes; the chemokine receptor CCR5 gene on chromosome 3p21 and the interleukin-4 receptor α-subunit gene (IL4RA) on chromosome 16. We did not find any significant correlation between a 32bp deletion variant of CCR5 or a single nucleotide change A1902G (Gln576Arg) of IL4RA, and IBD phenotypes, with the exception that in the UC group homozygosity for the G 1902 allele of IL4RA was less frequent (0.019 vs 0.049, P=0.038). In conclusion, our study, carried out in a genetically homogenous population, suggests that chromosome 3 may contain a susceptibility gene for IBD. [ABSTRACT FROM AUTHOR]

Familial hypertriglyceridemia has been suggested to be an autosomal dominant condition with age-dependent penetrance, but so far the underlying defective gene has not been elucidated. We examined the possible role of three candidate gene loci by linkage analysis in six Finnish families with familial clustering of hypertriglyceridemia. The probands were initially recruited from a group of hyperlipidemic outpatients after measurement of serum triglyceride concentrations exceeding 2.00 mmol/l on two occasions. Altogether, 71 subjects were included in the linkage analyses. Bior multiallelic DNA polymorphisms were used as markers for the apolipoprotein B gene (chromosome 2), lipoprotein lipase gene (chromosome 8), and apolipoprotein A-I/C-III/A-IV gene cluster (chromosome 11). Linkage analysis was performed by applying two alternative phenotyping models, one adopting quantitative serum triglyceride concentrations and another using qualitative classification of the subjects into hypertriglyceridemic, normotriglyceridemic, and borderline hypertriglyceridemic groups. Using either approach, the cumulative lod scores of each of the three candidate genes in the six families were less than -2.0 at the recombination fraction 0.0. These results suggest that none of the candidate genes investigated is involved in familial clustering of hypertriglyceridemia in our study. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

This manuscript has not been published before and is not currently being considered for publication elsewhere. Increased septal convexity of left ventricle has been described in subjects with hypertrophic cardiomyopathy (HCM) -causing mutations without left ventricular hypertrophy (LVH). Our objective was to study septal convexity by cardiac magnetic resonance (CMR) in subjects with the Finnish founder mutation Q1016X in the myosin-binding protein C gene (MYBPC3). Septal convexity was measured in end-diastolic 4-chamber CMR image in 67 study subjects (47 subjects with the MYBPC3-Q1061X mutation and 20 healthy relatives without the mutation). Septal convexity was significantly increased in subjects with the MYBPC3-Q1061X mutation and LVH (n = 32) compared to controls (11.4 ± 4.3 vs 2.7 ± 3.2 mm, P < 0.001). In mutation carriers without LVH, there was a trend for increased septal convexity compared to controls (4.9 ± 2.5 vs 2.7 ± 3.2 mm, P = 0.074). When indexed for BSA, septal convexity in mutation carriers without LVH was 2.8 ± 1.4 mm/m2 and 1.5 ± 1.6 mm/m2 in controls (P = 0.036). In all mutation carriers, septal convexity correlated significantly with body surface area, age, maximal LV wall thickness, LV mass, and late gadolinium enhancement. Subjects with the MYBPC3–Q10961X mutation have increased septal convexity irrespective of the presence of LVH. Septal convexity appears to reflect septal remodeling, and could be useful in recognizing LVH negative mutation carriers. [ABSTRACT FROM AUTHOR]