18 research outputs found
Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis
Familial growth hormone deficiency provides an opportunity to identify new genetic causes of
short stature. Here we combine linkage analysis with whole-genome resequencing in patients
with growth hormone deficiency and maternally inherited gingival fibromatosis. We report
that patients from three unrelated families harbor either of two missense mutations,
c.347G>T p.(Arg116Leu) or c.1106C>T p.(Pro369Leu), in KCNQ1, a gene previously
implicated in the long QT interval syndrome. Kcnq1 is expressed in hypothalamic GHRH
neurons and pituitary somatotropes. Co-expressing KCNQ1 with the KCNE2 β-subunit shows
that both KCNQ1 mutants increase current levels in patch clamp analyses and are associated
with reduced pituitary hormone secretion from AtT-20 cells. In conclusion, our results reveal
a role for the KCNQ1 potassium channel in the regulation of human growth, and show that
growth hormone deficiency associated with maternally inherited gingival fibromatosis is an
allelic disorder with cardiac arrhythmia syndromes caused by KCNQ1 mutations
Combined gating and trafficking defect in Kv11.1 manifests as a malignant long QT syndrome phenotype in a large Danish p.F29L founder family
The role of CAV3 in long-QT syndrome:clinical and functional assessment of a caveolin-3/Kv11.1 double heterozygote versus caveolin-3 single heterozygote
Background—
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 QT
c
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.
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The role of CAV3 in long QT : clinical and functional assessment of a caveolin-3/Kc11.1 compound heterozygote
CITATION: Hedley, P. L. et al. 2013. The role of CAV3 in long QT : clinical and functional assessment of a caveolin-3/Kc11.1 compound heterozygote. Circulation: Cardiovascular Genetics, 6:452-461, doi:10.1161/CIRCGENETICS.113.000137.The original publication is available at https://www.ahajournals.orgBackground—
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.https://www.ahajournals.org/doi/10.1161/CIRCGENETICS.113.000137Publisher's versio
Antiarrhythmic effect of the Ca2+-activated K+ (SK) channel inhibitor ICA combined with either amiodarone or dofetilide in an isolated heart model of atrial fibrillation
Combined gating and trafficking defect in Kv11.1 manifests as a malignant long QT syndrome phenotype in a large Danish p.F29L founder family
Electrophysiological effects of small conductance Ca 2+ -activated K + channels in atrial myocytes
Atrial fibrillation (AF), a cardiac arrhythmia characterized by an abnormal heart rythm originated in the atria, is one of the most prevalent cardiac diseases. Although it may have diverse causes, genetic screening has shown that a percentage of pacients suffering of AF present a genetic variant related to disregulation of calcium-activated potassium (SK) channels. In this paper we review the main characteristics of these channels and use several mathematical models of human atrial cardiomyocytes to study their influence in the form of the atrial action potential. We show that an overexpression of SK channels results in decreased action potential duration and, under some circumstances, it may give rise to alternans, suggesting a pro-arrhythmic role of this current. This effect becomes more important at higher pacing rates. Nevertheless, we also find it to protect against spontaneous calcium release induced afterdepolarizations, acting in this case as an antiarrhythmic factor. © Springer Nature Switzerland AG 2019