Recurrent and founder mutations in the Netherlands: cardiac Troponin I (TNNI3) gene mutations as a cause of severe forms of hypertrophic and restrictive cardiomyopathy

Wijngaard, Arthur van den; Volders, Paul G.A.; Tintelen, J Peter van; Jongbloed, Jan D. H.; Berg, Maarten P. van den; Deprez, R. H. Lekanne; Mannens, Marcel M.A.M.; Hofmann, Natalia K.; Slegtenhorst, Marjon van; Dooijes, Dennis; Michels, Michelle; Arens, Yvonne; Jongbloed, Roselie; Smeets, Boudewijn J. J.

doi:10.1007/s12471-011-0135-z

Cited by 51 publications

(33 citation statements)

References 20 publications

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“…In addition, Iceland's remote, rugged terrain and harsh environment may have produced negative effects on deleterious HCM mutations and may have contributed to the lower population prevalence of HCM in Iceland (1:1600) compared with the United States (1:500). 7 The founder mutation in the Icelandic population, similar to previously described founding mutations in Finland, 29 the Netherlands, 30 India, 31,32 Japan, 33 South Africa, 24 Spain, 34 France, 35 and the United States, 36 affects the MYBPC3 gene. Unlike deleterious HCM mutations, founder MYBPC3 mutations have a minimal effect on overall survival, particularly during the reproductive years of life.…”

Section: Discussionsupporting

confidence: 75%

Nationwide Study on Hypertrophic Cardiomyopathy in Iceland

et al. 2014

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Background-The geographic isolation and homogeneous population of Iceland are ideally suited to ascertain clinical and genetic characteristics of hypertrophic cardiomyopathy (HCM) at the population level. Methods and Results-Medical records and cardiac imaging studies obtained between 1997 and 2010 were reviewed to identify Icelandic patients with HCM. Surviving patients were recruited for clinical and genetic studies. A previously identified Icelandic mutation, MYBPC3 c.927-2A>G, was genotyped, and mutation-negative samples were sequenced for HCM genes and other hypertrophic genes. Record review identified 180 patients with HCM. Genetic analyses of 151 patients defined pathogenic mutations in 101 (67%), including MYBPC3 c.927-2A>G (88 patients, 58%), 4 other MYBPC3 or MYH7 mutations (5 patients, 3.3%), and 2 GLA mutations (8 patients, 5.3%). Haplotype and genetic genealogical data defined MYBPC3 c.927-2A>G as a founder mutation, introduced into the Icelandic population in the 15th century, with a current population prevalence of 0.36%. MYBPC3 c.927-2A>G mutation carriers exhibited phenotypic diversity but were younger at diagnosis (42 versus 49 years; P=0.001) and sustained more adverse events (15% versus 2%; P=0.02) than mutation-negative patients. All-cause mortality for patients with HCM was similar to that of an age-matched Icelandic population (hazard ratio, 0.98; P=0.9). HCM-related mortality (0.78%/y) occurred at a mean age of 68 compared with 81 years for non-HCM-related mortality (P=0.02). Conclusions-A founder MYBPC3 mutation that arose >550 years ago is the predominant cause of HCM in Iceland. The MYBPC3 c.927-2A>G mutation is associated with low adverse event rates but earlier cardiovascular mortality, illustrating the impact of genotype on outcomes in HCM.

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Section: Discussionsupporting

confidence: 75%

Nationwide Study on Hypertrophic Cardiomyopathy in Iceland

et al. 2014

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“…Out of these mutations, the missense mutation D190G was found in 12 patients of the same family and showed a clinical phenotype of mixed appearance of RCM and HCM. In addition, the R145W mutation of cTnI which is responsible for RCM in that study was also observed in patients presenting the HCM phenotype [63]. Such mutation is also located at the same residue as HCM causing mutations R145G and R145Q [64].…”

Section: Molecular Etiology Of Rcmsupporting

confidence: 51%

Insights into restrictive cardiomyopathy from clinical and animal studies

Jean-Charles¹,

Li²,

Nan³

et al. 2011

Journal of Geriatric Cardiology

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Cardiomyopathies are diseases that primarily affect the myocardium, leading to serious cardiac dysfunction and heart failure. Out of the three major categories of cardiomyopathies (hypertrophic, dilated and restrictive), restrictive cardiomyopathy (RCM) is less common and also the least studied. However, the prognosis for RCM is poor as some patients dying in their childhood. The molecular mechanisms behind the disease development and progression are not very clear and the treatment of RCM is very difficult and often ineffective. In this article, we reviewed the recent progress in RCM research from the clinical studies and the translational studies done on diseased transgenic animal models. This will help for a better understanding of the mechanisms underlying the etiology and development of RCM and for the design of better treatments for the disease.

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“…Since the discovery of cTnI as a HCM associated gene, five HCM mutations (K206Q [7], K206I [18], K207T [9], E209A [10] and E209K [11]) have been found to occur within the last 5 C-terminal residues of human cTnI [12]. Although the effect of these HCM mutations on Tn function are unknown, the presence of these mutations in this region of cTnI and the high sequence conservation in this region of cTnI both suggest that the last 5 C-terminal residues of cTnI are important in cTnI function.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations within this region of cTnI are associated with hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), and dilated cardiomyopathy (DCM). At least five mutations associated with HCM (K206Q [7], K206I [8], K207T [9], E209A [10] and E209K [11]) occur within the last 5 C-terminal residues of human cTnI [12]. The K207T mutation was discovered in an American patient and was classified as likely pathogenic but little data is available about patients with this mutation [9].…”

Section: Introductionmentioning

confidence: 99%

“…The K207T mutation was discovered in an American patient and was classified as likely pathogenic but little data is available about patients with this mutation [9]. The E209A mutation was found in five index patients in the Netherlands and is currently considered an unclassified variant of unknown pathological significance [10]. The E209K was found during genetic testing of 2,912 probands with HCM [11].…”

Section: Introductionmentioning

confidence: 99%

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The functional significance of the last 5 residues of the C-terminus of cardiac troponin I

Gilda

Martinez

et al. 2016

Archives of Biochemistry and Biophysics

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The C-terminal region of cardiac troponin I (cTnI) is known to be important in cardiac function, as removal of the last 17 C-terminal residues of human cTnI has been associated with myocardial stunning. To investigate the C-terminal region of cTnI, three C-terminal deletion mutations in human cTnI were generated: Δ1 (deletion of residue 210), Δ3 (deletion of residues 208-210), and Δ5 (deletion of residues 206-210). Mammalian two-hybrid studies showed that the interactions between cTnI mutants and cardiac troponin C (cTnC) or cardiac troponin T (cTnT) were impaired in Δ3 and Δ5 mutants when compared to wild-type cTnI. Troponin complexes containing 2-[4’-(iodoacetamido) anilino] naphthalene-6-sulfonic acid (IAANS) labeled cTnC showed that the troponin complex containing cTnI Δ5 had a small increase in Ca2+ affinity (P < 0.05); while the cTnI Δ1- and Δ3 troponin complexes showed no difference in Ca2+ affinity when compared to wild-type troponin. In vitro motility assays showed that all truncation mutants had increased Ca2+ dependent motility relative to wild-type cTnI. These results suggest that the last 5 C-terminal residues of cTnI influence the binding of cTnI with cTnC and cTnT, affects the Ca2+-dependence of filament sliding, and demonstrate the importance of this region of cTnI.

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Recurrent and founder mutations in the Netherlands: cardiac Troponin I (TNNI3) gene mutations as a cause of severe forms of hypertrophic and restrictive cardiomyopathy

Cited by 51 publications

References 20 publications

Nationwide Study on Hypertrophic Cardiomyopathy in Iceland

Nationwide Study on Hypertrophic Cardiomyopathy in Iceland

Insights into restrictive cardiomyopathy from clinical and animal studies

The functional significance of the last 5 residues of the C-terminus of cardiac troponin I

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