Browsing by Author "Kanters, Jorgen K."
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- ItemMutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2(BioMed Central, 2014-03) Christiansen, Michael; Hedley, Paula L.; Theilade, Juliane; Stoevring, Birgitte; Leren, Trond P.; Eschen, Ole; Sørensen, Karina M.; Tybjærg-Hansen, Anne; Ousager, Lilian B.; Pedersen, Lisbeth N.; Frikke-Schmidt, Ruth; Aidt, Frederik H.; Hansen, Michael G.; Hansen, Jim; Bloch Thomsen, Poul E.; Toft, Egon; Henriksen, Finn L.; Bundgaard, Henning; Jensen, Henrik K.; Kanters, Jorgen K.Background: Long QT syndrome (LQTS) is a cardiac ion channelopathy which presents clinically with palpitations, syncope or sudden death. More than 700 LQTS-causing mutations have been identified in 13 genes, all of which encode proteins involved in the execution of the cardiac action potential. The most frequently affected genes, covering > 90% of cases, are KCNQ1, KCNH2 and SCN5A. Methods: We describe 64 different mutations in 70 unrelated Danish families using a routine five-gene screen, comprising KCNQ1, KCNH2 and SCN5A as well as KCNE1 and KCNE2. Results: Twenty-two mutations were found in KCNQ1, 28 in KCNH2, 9 in SCN5A, 3 in KCNE1 and 2 in KCNE2. Twenty-six of these have only been described in the Danish population and 18 are novel. One double heterozygote (1.4% of families) was found. A founder mutation, p.F29L in KCNH2, was identified in 5 “unrelated” families. Disease association, in 31.2% of cases, was based on the type of mutation identified (nonsense, insertion/deletion, frameshift or splice-site). Functional data was available for 22.7% of the missense mutations. None of the mutations were found in 364 Danish alleles and only three, all functionally characterised, were recorded in the Exome Variation Server, albeit at a frequency of < 1:1000. Conclusion: The genetic etiology of LQTS in Denmark is similar to that found in other populations. A large founder family with p.F29L in KCNH2 was identified. In 48.4% of the mutations disease causation was based on mutation type or functional analysis.
- ItemThe role of CAV3 in long QT : clinical and functional assessment of a caveolin-3/Kc11.1 compound heterozygote(American Heart Association, 2013) Hedley, Paula L.; Kanters, Jorgen K.; Dembic, Maja; Jesperson, Thomas; Skibsbye, Lasse; Aidt, Frederik H.; Eschen, Ole; Graff, Claus; Behr, Elijah R.; Schlamowitz, Sarah; Corfield, Valerie A.; McKenna, Willim J.; Christiansen, MichaelBackground— Mutations in CAV3, coding for caveolin-3, the major constituent scaffolding protein of cardiac caveolae, have been associated with skeletal muscle disease, cardiomyopathy, and most recently long–QT syndrome (LQTS) and sudden infant death syndrome. We examined the occurrence of CAV3 mutations in a large cohort of patients with LQTS. Methods and Results— Probands with LQTS (n=167) were screened for mutations in CAV3 using direct DNA sequencing. A single proband (0.6%) was found to be a heterozygous carrier of a previously described missense mutation, caveolin-3:p.T78M. The proband was also a heterozygous carrier of the trafficking-deficient Kv11.1:p.I400N mutation. The caveolin-3:p.T78M mutation was found isolated in 3 family members, none of whom had a prolonged QTc interval. Coimmunoprecipitations of caveolin-3 and the voltage-gated potassium channel subunit (Kv11.1) were performed, and the electrophysiological classification of the Kv11.1 mutant was carried out by patch-clamp technique in human embryonic kidney 293 cells. Furthermore, the T-wave morphology was assessed in mutation carriers, double mutation carriers, and nonmutation carriers by applying a morphology combination score. The morphology combination score was normal for isolated caveolin-3:p.T78M carriers and of LQT2 type in double heterozygotes. Conclusions— Mutations in CAV3 are rare in LQTS. Furthermore, caveolin-3:p.T78M did not exhibit a LQTS phenotype. Because no association has ever been found between LQTS and isolated CAV3 mutations, we suggest that LQTS9 is considered a provisional entity.