scholarly journals Author response: Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism

2015 ◽  
Author(s):  
Ute I Scholl ◽  
Gabriel Stölting ◽  
Carol Nelson-Williams ◽  
Alfred A Vichot ◽  
Murim Choi ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Primary Aldosteronism ◽  
Early Onset ◽  
Author Response ◽  
Gain Of Function

scholarly journals Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Ute I Scholl ◽  
Gabriel Stölting ◽  
Carol Nelson-Williams ◽  
Alfred A Vichot ◽  
Murim Choi ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Primary Aldosteronism ◽  
Early Onset ◽  
De Novo ◽  
Incomplete Penetrance ◽  
De Novo Mutations ◽  
Channel Inactivation ◽  
Aldosterone Production ◽  
Genome Level ◽  
Insight Into

Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5%) shared the identical, previously unidentified, heterozygous CACNA1HM1549V mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (CaV3.2) expressed in adrenal glomerulosa. CACNA1HM1549V showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca2+, the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension.

scholarly journals Gain-of-function mutation in SCN5A causes ventricular arrhythmias and early onset atrial fibrillation

2017 ◽  
Vol 236 ◽  
pp. 187-193 ◽  
Author(s):  
Krystien V. Lieve ◽  
Arie O. Verkerk ◽  
Svitlana Podliesna ◽  
Christian van der Werf ◽  
Michael W. Tanck ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Early Onset ◽  
Ventricular Arrhythmias ◽  
Gain Of Function ◽  
Onset Atrial Fibrillation

scholarly journals Autosomal-dominant early-onset spastic paraparesis with brain calcification due to IFIH1 gain-of-function

2018 ◽  
Vol 39 (8) ◽  
pp. 1076-1080 ◽  
Author(s):  
Lyse Ruaud ◽  
Gillian I. Rice ◽  
Christelle Cabrol ◽  
Juliette Piard ◽  
Mathieu Rodero ◽  
...  
Keyword(s):  
Early Onset ◽  
Autosomal Dominant ◽  
Spastic Paraparesis ◽  
Gain Of Function ◽  
Brain Calcification

scholarly journals A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism

2018 ◽  
Vol 50 (3) ◽  
pp. 355-361 ◽  
Author(s):  
Fabio L. Fernandes-Rosa ◽  
Georgios Daniil ◽  
Ian J. Orozco ◽  
Corinna Göppner ◽  
Rami El Zein ◽  
...  
Keyword(s):  
Chloride Channel ◽  
Primary Aldosteronism ◽  
Gain Of Function ◽  
Channel Gene

Author response for "Molecular and histologic insights on early onset cardiomyopathy in Danon disease females"

2020 ◽  
Author(s):  
Luis Fernández ◽  
Laura Casamayor Polo ◽  
María Bravo García‐Morato ◽  
Ana Belén Enguita Valls ◽  
Elena Ruiz‐Bravo ◽  
...  
Keyword(s):  
Early Onset ◽  
Author Response ◽  
Danon Disease

Author response for "Is BRCA2 involved in early onset colorectal cancer risk?"

2019 ◽  
Author(s):  
Mathilde Gay‐Bellile ◽  
Maud Privat ◽  
Alexandra Martins ◽  
Sandrine M. Caputo ◽  
Céline Pebrel‐Richard ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Risk ◽  
Early Onset ◽  
Colorectal Cancer Risk ◽  
Author Response ◽  
Early Onset Colorectal Cancer

scholarly journals CACNA1HM1549V Mutant Calcium Channel Causes Autonomous Aldosterone Production in HAC15 Cells and Is Inhibited by Mibefradil

Endocrinology ◽  
2016 ◽  
Vol 157 (8) ◽  
pp. 3016-3022 ◽  
Author(s):  
Esther N. Reimer ◽  
Gudrun Walenda ◽  
Eric Seidel ◽  
Ute I. Scholl
Keyword(s):  
Calcium Channel ◽  
Primary Aldosteronism ◽  
Cancer Cell Line ◽  
Fold Increase ◽  
Extracellular Potassium ◽  
Channel Blockers ◽  
Adrenocortical Cancer ◽  
Transfected Cells ◽  
Channel Inactivation ◽  
Aldosterone Production

We recently demonstrated that a recurrent gain-of-function mutation in a T-type calcium channel, CACNA1HM1549V, causes a novel Mendelian disorder featuring early-onset primary aldosteronism and hypertension. This variant was found independently in five families. CACNA1HM1549V leads to impaired channel inactivation and activation at more hyperpolarized potentials, inferred to cause increased calcium entry. We here aimed to study the effect of this variant on aldosterone production. We heterologously expressed empty vector, CACNA1HWT and CACNA1HM1549V in the aldosterone-producing adrenocortical cancer cell line H295R and its subclone HAC15. Transfection rates, expression levels, and subcellular distribution of the channel were similar between CACNA1HWT and CACNA1HM1549V. We measured aldosterone production by an ELISA and CYP11B2 (aldosterone synthase) expression by real-time PCR. In unstimulated cells, transfection of CACNA1HWT led to a 2-fold increase in aldosterone levels compared with vector-transfected cells. Expression of CACNA1HM1549V caused a 7-fold increase in aldosterone levels. Treatment with angiotensin II or increased extracellular potassium levels further stimulated aldosterone production in both CACNA1HWT- and CACNA1HM1549V-transfected cells. Similar results were obtained for CYP11B2 expression. Inhibition of CACNA1H channels with the T-type calcium channel blocker Mibefradil completely abrogated the effects of CACNA1HWT and CACNA1HM1549V on CYP11B2 expression. These results directly link CACNA1HM1549V to increased aldosterone production. They suggest that calcium channel blockers may be beneficial in the treatment of a subset of patients with primary aldosteronism. Such blockers could target CACNA1H or both CACNA1H and the L-type calcium channel CACNA1D that is also expressed in the adrenal gland and mutated in patients with primary aldosteronism.

scholarly journals A novel KCND3 gain-of-function mutation associated with early-onset of persistent lone atrial fibrillation

2013 ◽  
Vol 98 (3) ◽  
pp. 488-495 ◽  
Author(s):  
Morten Salling Olesen ◽  
Lena Refsgaard ◽  
Anders Gaarsdal Holst ◽  
Anders Peter Larsen ◽  
Søren Grubb ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Early Onset ◽  
Gain Of Function ◽  
Lone Atrial Fibrillation
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