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No additional import charges at delivery! This item will be shipped through the Global Shipping Program and includes international tracking. Learn more - opens in a new window or tab. MetIle substitution was a de novo event identified in a sporadic PA patient and both p. SerLeu and p. Interestingly, the p.
Series: Human Molecular Genetics
ValGlu was identified in a patient affected by apparently sporadic APA who was cured by unilateral adrenalectomy These data indicate that CACNA1H might represent a susceptibility gene for PA development that could present with a wide range of clinical phenotypes PASNA primary aldosteronism with seizures and neurologic abnormalities, OMIM is a clinical syndrome characterized by primary aldosteronism and neurological symptoms. Electrophysiological in vitro studies showed that the mutations cause channel activation at less depolarized potentials and altered channel inactivation, with subsequent abnormal calcium signalling 8.
GlyAsp and p. IleMet have been reported 8. The index cases presented with early-onset severe hypertension, hypokalaemia and neurological manifestations, including seizures and cerebral palsy. In one of the two patients, blood pressure was successfully controlled by the calcium channel blocker amlodipine, raising the possibility that calcium channel blockers might represent a specific treatment for individuals affected by APAs carrying a CACNA1D somatic mutation. ValLeu was identified in a patient affected by autism and epilepsy with a phenotype partially overlapping with that observed in patients with PASNA syndrome The introduction of NGS technology allowed the identification of aldosterone-stimulating somatic mutations in a significant proportion of sporadic APAs 7.
While the molecular determinants of autonomous aldosterone overproduction have been at least partially unravelled, the molecular basis of bilateral hyperaldosteronism and adrenal cell proliferation in both APA and BAH are still poorly elucidated. It was postulated by Choi and coworkers 26 that the intracellular calcium influx induced by KCNJ5 mutations, other than driving aldosterone secretion, might promote cell proliferation.
However, subsequent studies demonstrated that the expression of mutant GIRK4 has a negative effect on HAC15 adrenocortical cells growth 28 suggesting that a second hit might be necessary for APA formation KCNJ5 sequencing in peripheral blood DNA from patients affected by sporadic bilateral hyperaldosteronism revealed three heterozygous missense germline mutations. The mutations p. Arg52His, p. GluLys and p.
GlyArg are not associated with FH-III and are not located in proximity of the selectivity filter of the channel Electrophysiological studies conducted in Xenopus oocytes showed that the expression of both the p. Arg52His and p. GluLys substitutions resulted in cell membrane depolarization, while the p. GlyArg mutation did not alter the resting potential ARMC5 gene maps on 16p11 and encodes the armadillo repeat containing 5, whose function is currently unknown, but is likely to act as a tumour-suppressor gene.
Somatic and germline mutations in ARMC5 are frequently found in macronodular adrenal hyperplasia and Cushing syndrome 40 and in a significant proportion of PA patients of African American descent However, another study failed to confirm this association in patients of European ancestry Following the seminal report by Choi and coworkers 26 , several centres from four continents investigated the prevalence of KCNJ5 somatic mutations in APAs.
Molecular Genetics & Gene Therapy of Cardiovascular Diseases - CRC Press Book
The prevalence appears to be consistently higher in East Asian populations compared to Western populations, and also in those centres where strict criteria for adrenal vein sampling interpretation were used Comprehensive clinical, biochemical and histopathological studies showed that the adenomas carrying KCNJ5 mutations are more prevalent in females than in males 46 and are associated with younger age at diagnosis and higher preoperative aldosterone levels These characteristics might at least partially account for the high amount of hybrid steroids detected in APA patients carrying KCNJ5 mutations 51 and, considering the high prevalence of KCNJ5 mutations in the East Asian patients, explain the potential diagnostic value of oxocortisol in subtype differentiation in this specific subpopulation In vitro pharmacological studies showed that mutated GIRK4 exhibited a different pharmacological profile compared to the wild type, in particular, the calcium channel blocker verapamil strongly inhibits the p.
LeuArg mutant channel, suggesting a potential therapeutic use of this drug Even more surprisingly, mutant GIRK4, but not the wild-type channel, is effectively inhibited by a series of molecules belonging to the macrolide class of antibiotics and by synthetic derivatives lacking the antibiotic activity In light of this recent finding, a murine model of PA due to a germline KNCJ5 mutation would be an extremely valuable tool for further pharmacological studies.
ATP1A1 somatic mutations account for 5. Since its original description 8 , 56 , a total of 31 different CACNA1D mutations have been reported 48 , accounting for 9. Your Name: optional. Your Email:. Colleague's Email:.
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Current Opinion in Nephrology and Hypertension9 3 , May Add Item s to:. An Existing Folder. A New Folder.