Recurrent and founder mutations in the Netherlands: mutation p.K217del in troponin T2, causing dilated cardiomyopathy*

Otten, E.; Deprez, R.H. Lekanne dit; Weiss, M.M.; Slegtenhorst, Marjon van; Joosten, M.; Smagt, Jasper J. van der; Jonge, N. de; Kerstjens-Frederikse, Wilhelmina S.; Roofthooft, M.T.R.; Balk, A.H.M.M.; Berg, Mandy; Ruiter, J.S.; Tintelen, J Peter van

doi:10.1007/978-90-368-0705-0_8

Cited by 3 publications

(5 citation statements)

References 26 publications

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“…; Otten et al . ). Mutations in the non‐sarcomeric gene LMNA , encoding the inner nuclear protein lamin A/C, have been found in 6% of DCM patients (Parks et al .…”

Section: Introductionmentioning

confidence: 97%

“…Truncation in this part of the protein would cause loss of the cTnC and two actin-binding domains of cTnI (Mogensen et al 2015). The p.K217del (also known as p.K210del; Otten et al 2010) mutation in the TNNT2 gene has been reported across the world in unrelated families and is associated with high mortality and disease onset at a young age (ß33 years) (Kamisago et al 2000;Mogensen et al 2004;Hershberger et al 2009;Otten et al 2010). Mutations in the non-sarcomeric gene LMNA, encoding the inner nuclear protein lamin A/C, have been found in 6% of DCM patients (Parks et al 2008).…”

Section: Introductionmentioning

confidence: 99%

“…The p.K217del (also known as p.K210del; Otten et al . ) mutation in the TNNT2 gene has been reported across the world in unrelated families and is associated with high mortality and disease onset at a young age (∼33 years) (Kamisago et al . ; Mogensen et al .…”

Section: Introductionmentioning

confidence: 99%

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Genotype‐specific pathogenic effects in human dilated cardiomyopathy

Bollen¹,

Schuldt²,

Harakaľová

et al. 2017

The Journal of Physiology

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Key points Mutations in genes encoding cardiac troponin I (TNNI3) and cardiac troponin T (TNNT2) caused altered troponin protein stoichiometry in patients with dilated cardiomyopathy. TNNI3p.98trunc resulted in haploinsufficiency, increased Ca2+‐sensitivity and reduced length‐dependent activation. TNNT2p.K217del caused increased passive tension.A mutation in the gene encoding Lamin A/C (LMNA p.R331Q) led to reduced maximal force development through secondary disease remodelling in patients suffering from dilated cardiomyopathy.Our study shows that different gene mutations induce dilated cardiomyopathy via diverse cellular pathways. AbstractDilated cardiomyopathy (DCM) can be caused by mutations in sarcomeric and non‐sarcomeric genes. In this study we defined the pathogenic effects of three DCM‐causing mutations: the sarcomeric mutations in genes encoding cardiac troponin I (TNNI3p.98truncation) and cardiac troponin T (TNNT2p.K217deletion; also known as the p.K210del) and the non‐sarcomeric gene mutation encoding lamin A/C (LMNAp.R331Q). We assessed sarcomeric protein expression and phosphorylation and contractile behaviour in single membrane‐permeabilized cardiomyocytes in human left ventricular heart tissue. Exchange with recombinant troponin complex was used to establish the direct pathogenic effects of the mutations in TNNI3 and TNNT2. The TNNI3p.98trunc and TNNT2p.K217del mutation showed reduced expression of troponin I to 39% and 51%, troponin T to 64% and 53%, and troponin C to 73% and 97% of controls, respectively, and altered stoichiometry between the three cardiac troponin subunits. The TNNI3p.98trunc showed pure haploinsufficiency, increased Ca2+‐sensitivity and impaired length‐dependent activation. The TNNT2p.K217del mutation showed a significant increase in passive tension that was not due to changes in titin isoform composition or phosphorylation. Exchange with wild‐type troponin complex corrected troponin protein levels to 83% of controls in the TNNI3p.98trunc sample. Moreover, upon exchange all functional deficits in the TNNI3p.98trunc and TNNT2p.K217del samples were normalized to control values confirming the pathogenic effects of the troponin mutations. The LMNAp.R331Q mutation resulted in reduced maximal force development due to disease remodelling. Our study shows that different gene mutations induce DCM via diverse cellular pathways.

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“…; Otten et al . ). Mutations in the non‐sarcomeric gene LMNA , encoding the inner nuclear protein lamin A/C, have been found in 6% of DCM patients (Parks et al .…”

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Genotype‐specific pathogenic effects in human dilated cardiomyopathy

Bollen¹,

Schuldt²,

Harakaľová

et al. 2017

The Journal of Physiology

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“…Recently, particular mutations in four other loci have been reported to partially phenocopy ARVC/D-DESMIN, TITIN, LAMIN A/C, and PHOSPHOLAMBAN [Klauke et al, 2010;Otten et al, 2010;Taylor et al, 2011;Quarta et al, 2012;Van Der Zwaag et al, 2012;Lorenzon et al, 2013] with fibro-fatty replacement being seen in the TITIN and LAMIN A/C cases, although most mutations in these four loci do not preferentially affect the RV.…”

Section: Introductionmentioning

confidence: 99%

Arrhythmogenic right ventricular cardiomyopathy/Dysplasia (ARVC/D)

Iyer¹,

Chin²

2013

American J of Med Genetics Pt C

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Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a progressive genetic cardiomyopathy characterized by progressive fatty and fibrous replacement of ventricular myocardium. The clinical presentation is marked by ventricular arrhythmias, some fatal. The disease has evolved from a primary electrical/electrophysiological disorder (in the 1980s-1990s) to a diagnostic imaging conundrum (in the 2000s) to the current day understanding of a genetic cardiomyopathy caused by defects in cell-cell adhesion proteins or intracellular signaling components. The pathogenesis, clinical presentation, and the genetics of the disease are discussed in this review.

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“…Por último, una variante de muy mal pronóstico (p.Lys210del), con una sobrevida ligeramente superior a 80% a los 20 años (casi un 20% de los individuos habían sufrido una muerte cardiovascular a esta edad); la sobrevida solo llegaba a 30% a los 60 años. Hay que remarcar que el fenotipo predominante en esta última variante es MCD, y un gran número de las muertes cardiovasculares se deben a fallo cardíaco o trasplante (52) .…”

Section: ) Valor Pronósticounclassified

Aportes de la genética al estudio y manejo clínico de las miocardiopatías

Ortíz-Genga

Ochoa

Monserrat³

2018

Rev.Urug.Cardiol.

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Cardiomyopathies are heterogeneous diseases associated with sudden death in the young. The diagnosis and associated prognosis is sometimes difficult to establish. The genetic study could be an important tool for the clinical work-up of patients and families with these diseases. Cardiomyopathies are usually monogenic diseases, with incomplete penetrance and variable clinical expressivity. Several genes are associated with the same phenotype, and a particular gene could be related with different diseases. All the genes related with a particular phenotype could be study with the available sequencing technology at a reasonable price and turnaround time for the results. The yield of genetic tests depends on the type of cardiomyopathy and is specifically driven by the clinical pre-test probability of each case. The interpretation of genetic studies is complex and the main challenge for the correct clinical application of the results. Interpretation depends on several variables and should be performed by multidisciplinary teams with clinical and genetic expertise on cardiomyopathies. A positive genetic study could contribute with important diagnostic and prognostic information for the patient and the family. This information could be useful for lifestyle modifications, specific treatment selection and, in some cases, to decide the correct moment for primary prevention device's implantation. Cascade family screening after a positive genetic diagnosis is a cost-effective strategy for health-care systems.

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Recurrent and founder mutations in the Netherlands: mutation p.K217del in troponin T2, causing dilated cardiomyopathy*

Cited by 3 publications

References 26 publications

Genotype‐specific pathogenic effects in human dilated cardiomyopathy

Genotype‐specific pathogenic effects in human dilated cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy/Dysplasia (ARVC/D)

Aportes de la genética al estudio y manejo clínico de las miocardiopatías

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