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 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 De Novo Mutations in EIF2B1 Affecting eIF2 Signaling Cause Neonatal/Early-Onset Diabetes and Transient Hepatic Dysfunction

Diabetes ◽  
2019 ◽  
Vol 69 (3) ◽  
pp. 477-483 ◽  
Author(s):  
Elisa De Franco ◽  
Richard Caswell ◽  
Matthew B. Johnson ◽  
Matthew N. Wakeling ◽  
Amnon Zung ◽  
...  
Keyword(s):  
Early Onset ◽  
Hepatic Dysfunction ◽  
De Novo ◽  
De Novo Mutations ◽  
Onset Diabetes

De novo mutations in ATP1A2 and CACNA1A are frequent in early-onset sporadic hemiplegic migraine

Neurology ◽  
2010 ◽  
Vol 75 (11) ◽  
pp. 967-972 ◽  
Author(s):  
F. Riant ◽  
A. Ducros ◽  
C. Ploton ◽  
C. Barbance ◽  
C. Depienne ◽  
...  
Keyword(s):  
Early Onset ◽  
De Novo ◽  
De Novo Mutations ◽  
Hemiplegic Migraine

scholarly journals De Novo Mutations (GAG Deletion) in the DYT1 Gene in Two Non-Jewish Patients with Early-onset Dystonia

1998 ◽  
Vol 7 (7) ◽  
pp. 1133-1136 ◽  
Author(s):  
C. Klein ◽  
M. F. Brin ◽  
D. de Leon ◽  
S. A. Limborska ◽  
I. A. Ivanova-Smolenskaya ◽  
...  
Keyword(s):  
Early Onset ◽  
De Novo ◽  
De Novo Mutations ◽  
Dyt1 Gene

scholarly journals Quantifying concordant genetic effects of de novo mutations on multiple disorders

2021 ◽  
Author(s):  
Hanmin Guo ◽  
Lin Hou ◽  
Yu Shi ◽  
Sheng Chih Jin ◽  
Xue Zeng ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
De Novo ◽  
Statistical Significance ◽  
Genetic Effects ◽  
Incomplete Penetrance ◽  
De Novo Mutations ◽  
Risk Genes ◽  
Fetal Tissues ◽  
Statistical Framework ◽  
Shared Genetic

AbstractExome sequencing on tens of thousands of parent-proband trios has identified numerous deleterious de novo mutations (DNMs) and implicated risk genes for many disorders. Recent studies have suggested shared genes and pathways are enriched for DNMs across multiple disorders. However, existing analytic strategies only focus on genes that reach statistical significance for multiple disorders and require large trio samples in each study. As a result, these methods are not able to characterize the full landscape of genetic sharing due to polygenicity and incomplete penetrance. In this work, we introduce EncoreDNM, a novel statistical framework to quantify shared genetic effects between two disorders characterized by concordant enrichment of DNMs in the exome. EncoreDNM makes use of exome-wide, summary-level DNM data, including genes that do not reach statistical significance in single-disorder analysis, to evaluate the overall and annotation-partitioned genetic sharing between two disorders. Applying EncoreDNM to DNM data of nine disorders, we identified abundant pairwise enrichment correlations, especially in genes intolerant to pathogenic mutations and genes highly expressed in fetal tissues. These results suggest that EncoreDNM improves current analytic approaches and may have broad applications in DNM studies.

A de novo deletional germline mutation in the MLH1 gene resulting in early onset colorectal cancer in a woman with a negative family history: A case report

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21067-21067
Author(s):  
D. Zakalik ◽  
N. S. Goldstein ◽  
W. L. Ducaine
Keyword(s):  
Colorectal Cancer ◽  
Family History ◽  
Early Onset ◽  
De Novo ◽  
Germline Mutations ◽  
De Novo Mutations ◽  
Mlh1 Gene ◽  
Negative Family History ◽  
Mmr Genes ◽  
Early Onset Colorectal Cancer

21067 Background: Hereditary non-polyposis colorectal cancer (HNPCC) is a genetic disorder that results in an increased risk of early onset colorectal cancer (CRC). HNPCC is caused by germline mutations in DNA mismatch repair (MMR) genes, including MLH1 and MSH2, and is transmitted in an autosomal dominant manner. De novo germline mutations in MMR genes are exceedingly rare. We now describe a case of a de novo germline mutation in MLH1 associated with early onset CRC in a young woman with a negative family history. Methods: We present a case of a 31-year-old Caucasian female who presented with abdominal pain. Colonoscopy revealed a moderately differentiated adenocarcinoma with focal mucin production involving the sigmoid colon, with a final staging of T4N0M0. Genetic testing was offered because of her young age at diagnosis, having fulfilled the Bethesda guidelines. Microsatellite instability (MSI) testing using a panel of six microsatellite loci was performed on the tumor sample from the affected patient. Immunohistochemistry (IHC) testing for MLH1 and MSH2 was performed. Following counseling and with informed consent, DNA was isolated and sequenced using bi-directional PCR of the MLH1 gene. All exons of MLH1 and MSH2 were analyzed by standard Southern blot methods. Paternity was established using eight genetic loci. Results: The patient's tumor revealed high MSI and complete absence of MLH1 immunoreactivity. MSH2 IHC staining was normal. A large deletional mutation involving exons 5–12 of MLH1 was identified by Southern blot analysis. The patient's parents and siblings were tested and found to have wild type MLH1. Paternity was confirmed with greater than 99.9% certainty. Conclusions: De novo mutations in MMR genes are a rare cause of HNPCC. We report the first case of a large de novo deletion in the MLH1 gene accounting for early onset CRC. Such de novo mutations, albeit rare, must be considered in patients who present with early onset CRC and a negative family history. These results support the use of the Bethesda guidelines to identify individuals who may carry mutations in the MMR genes. No significant financial relationships to disclose.

De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy

2017 ◽  
Vol 54 (8) ◽  
pp. 550-557 ◽  
Author(s):  
Stéphanie Guey ◽  
Lou Grangeon ◽  
Francis Brunelle ◽  
Françoise Bergametti ◽  
Jeanne Amiel ◽  
...  
Keyword(s):  
Early Onset ◽  
De Novo ◽  
De Novo Mutations ◽  
Moyamoya Angiopathy

De Novo Mutations inSLC35A2Encoding a UDP-Galactose Transporter Cause Early-Onset Epileptic Encephalopathy

2013 ◽  
Vol 34 (12) ◽  
pp. 1708-1714 ◽  
Author(s):  
Hirofumi Kodera ◽  
Kazuyuki Nakamura ◽  
Hitoshi Osaka ◽  
Yoshihiro Maegaki ◽  
Kazuhiro Haginoya ◽  
...  
Keyword(s):  
Early Onset ◽  
De Novo ◽  
Epileptic Encephalopathy ◽  
De Novo Mutations

scholarly journals De Novo Mutations in YWHAG Cause Early-Onset Epilepsy

2017 ◽  
Vol 101 (2) ◽  
pp. 300-310 ◽  
Author(s):  
Ilaria Guella ◽  
Marna B. McKenzie ◽  
Daniel M. Evans ◽  
Sarah E. Buerki ◽  
Eric B. Toyota ◽  
...  
Keyword(s):  
Early Onset ◽  
De Novo ◽  
De Novo Mutations

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
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