Somatic Mutations in Are Associated With Aldosterone-Producing Adenomas.

Background: Primary aldosteronism is a common but underdiagnosed cause of endocrine hypertension that contributes to global cardiovascular morbidity and mortality. It is characterized by renin-independent hyperaldosteronism that originates from adrenal lesions-the majority of which are found to harbor aldosterone-driver somatic mutations in genes encoding ion-transporting proteins. These mutations disrupt intracellular calcium homeostasis, facilitating a pathological increase in aldosterone synthase expression and aldosterone production.

Expression and function of Connexin 43 and Connexin 37 in the murine zona glomerulosa.

The zona glomerulosa (ZG) synthesizes the mineralocorticoid aldosterone. The primary role of aldosterone is the maintenance of volume and electrolyte homeostasis. Aldosterone synthesis is primarily regulated via tightly controlled oscillations in intracellular calcium levels in response to stimulation.

Familial hyperaldosteronism: an European Reference Network on Rare Endocrine Conditions clinical practice guideline.

We describe herein the European Reference Network on Rare Endocrine Conditions clinical practice guideline on diagnosis and management of familial forms of hyperaldosteronism. The guideline panel consisted of 10 experts in primary aldosteronism, endocrine hypertension, paediatric endocrinology, and cardiology as well as a methodologist. A systematic literature search was conducted, and because of the rarity of the condition, most recommendations were based on expert opinion and small patient series.

T- and L-Type Calcium Channels Maintain Calcium Oscillations in the Murine Zona Glomerulosa.

Background: The zona glomerulosa of the adrenal gland is responsible for the synthesis and release of the mineralocorticoid aldosterone. This steroid hormone regulates salt reabsorption in the kidney and blood pressure. The most important stimuli of aldosterone synthesis are the serum concentrations of angiotensin II and potassium.

Isradipine therapy in Cacna1dIle772Met/+ mice ameliorates primary aldosteronism and neurologic abnormalities.

Somatic gain-of-function mutations in the L-type calcium channel CaV1.3 (CACNA1D gene) cause adrenal aldosterone-producing adenomas and micronodules. De novo germline mutations are found in a syndrome of primary aldosteronism, seizures, and neurologic abnormalities (PASNA) as well as in autism spectrum disorder.

Adrenal Anion Channels: New Roles in Zona Glomerulosa Physiology and in the Pathophysiology of Primary Aldosteronism.

The mineralocorticoid aldosterone is produced in the zona glomerulosa of the adrenal cortex. Its synthesis is regulated by the serum concentrations of the peptide hormone angiotensin II and potassium. The primary role of aldosterone is to control blood volume and electrolytes.

Ca3.2 (CACNA1H) in Primary Aldosteronism.

Aldosterone is a steroid hormone produced in the zona glomerulosa (ZG) of the adrenal cortex. The most prominent function of aldosterone is the control of electrolyte homeostasis and blood pressure via the kidneys. The primary factors regulating aldosterone synthesis are the serum concentrations of angiotensin II and potassium.

Generation of sheep with defined FecB and TBXT mutations and porcine blastocysts with KCNJ5 mutation using prime editing.

Background: Rewriting the genomes of living organisms has been a long-standing aim in the biological sciences. The revelation of the CRISPR/Cas9 technology has revolutionized the entire biological field. Since its emergence, this technology has been widely applied to induce gene knockouts, insertions, deletions, and base substitutions.

Integration of artificial intelligence and plasma steroidomics with laboratory information management systems: application to primary aldosteronism.

Objectives: Mass spectrometry-based steroidomics combined with machine learning (ML) provides a potentially powerful approach in endocrine diagnostics, but is hampered by limitations in the conveyance of results and interpretations to clinicians. We address this shortcoming by integration of the two technologies with a laboratory information management systems (LIMS) model.

Methods: The approach involves integration of ML algorithm-derived models with commercially available mathematical programming software and a web-based LIMS prototype.

Genetics of Primary Aldosteronism.

Primary aldosteronism is considered the commonest cause of secondary hypertension. In affected individuals, aldosterone is produced in an at least partially autonomous fashion in adrenal lesions (adenomas, [micro]nodules or diffuse hyperplasia). Over the past decade, next-generation sequencing studies have led to the insight that primary aldosteronism is largely a genetic disorder.

A Novel Homozygous KLHL3 Mutation as a Cause of Autosomal Recessive Pseudohypoaldosteronism Type II Diagnosed Late in Life.

Introduction: Pseudohypoaldosteronism type II (PHA II) is a Mendelian disorder, featuring hyperkalemic acidosis and low plasma renin levels, typically associated with hypertension. Mutations in WNK1, WNK4, CUL3, and KLHL3 cause PHA II, with dominant mutations in WNK1, WNK4, and CUL3 and either dominant or recessive mutations in KLHL3. Fourteen families with recessive KLHL3 mutations have been reported, with diagnosis at the age of 3 months to 56 years, typically in individuals with normal kidney function.

Salt-Sensitive Hypertension in GR Rats Is Accompanied with Dysregulation in Adrenal Soluble Epoxide Hydrolase and Polyunsaturated Fatty Acid Pathways.

Mutations within the glucocorticoid receptor (GR) gene locus lead to glucocorticoid resistance which is characterized by several clinical symptoms such as adrenal gland hyperplasia and salt-sensitive hypertension, although the underlying mechanisms are still unknown. We studied GR haploinsufficient (GR) Sprague Dawley rats which, on a standard diet, showed significantly increased plasma aldosterone and corticosterone levels and an adrenocortex hyperplasia accompanied by a normal systolic blood pressure. Following a high salt diet, these rats developed salt-sensitive hypertension and maintained elevated enzyme-soluble epoxide hydrolase (sEH) in adrenal glands, while sEH was significantly decreased in wild-type rats.

Diagnosis and treatment of primary aldosteronism.

Primary aldosteronism is a common cause of secondary hypertension associated with excess cardiovascular morbidities. Primary aldosteronism is underdiagnosed because it does not have a specific, easily identifiable feature and clinicians can be poorly aware of the disease. The diagnostic investigation is a multistep process of screening, confirmatory testing, and subtype differentiation of unilateral from bilateral forms for therapeutic management.

Enhanced Ca signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model ( ).

Gain-of-function mutations in the gene (encoding the T-type calcium channel Ca3.2) cause autosomal-dominant familial hyperaldosteronism type IV (FH-IV) and early-onset hypertension in humans. We used CRISPR/Cas9 to generate knockin mice as a model of the most common FH-IV mutation, along with corresponding knockout mice ( ).

Kidney physiology and susceptibility to acute kidney injury: implications for renoprotection.

Kidney damage varies according to the primary insult. Different aetiologies of acute kidney injury (AKI), including kidney ischaemia, exposure to nephrotoxins, dehydration or sepsis, are associated with characteristic patterns of damage and changes in gene expression, which can provide insight into the mechanisms that lead to persistent structural and functional damage. Early morphological alterations are driven by a delicate balance between energy demand and oxygen supply, which varies considerably in different regions of the kidney.

Predicting functional effects of missense variants in voltage-gated sodium and calcium channels.

Malfunctions of voltage-gated sodium and calcium channels (encoded by and family genes, respectively) have been associated with severe neurologic, psychiatric, cardiac, and other diseases. Altered channel activity is frequently grouped into gain or loss of ion channel function (GOF or LOF, respectively) that often corresponds not only to clinical disease manifestations but also to differences in drug response. Experimental studies of channel function are therefore important, but laborious and usually focus only on a few variants at a time.

Subcellular localization of fibroblast growth factor receptor type 2 and correlation with CTNNB1 genotype in adrenocortical carcinoma.

Objective: Fibroblast growth factor receptor (FGFR) 2 regulates the development of the adrenal gland in mice. In addition, FGFR2-mediated signalling has been shown to prevent apoptosis and to enhance proliferation in adrenocortical precursor cells. The activation of the Wingless/Int-1 (WNT)/beta catenin pathway as a key mechanism of adrenocortical tumourigenesis has been linked to FGFR2 signalling in other cell types.

Generation and characterization of a mitotane-resistant adrenocortical cell line.

Mitotane is the only drug approved for the therapy of adrenocortical carcinoma (ACC). Its clinical use is limited by the occurrence of relapse during therapy. To investigate the underlying mechanisms in vitro, we here generated mitotane-resistant cell lines.

Paroxysmal tonic upgaze: A heterogeneous clinical condition responsive to carbonic anhydrase inhibition.

Background: Paroxysmal tonic upgaze (PTU), defined as an involuntary upward movement of the eyes, has been considered as a benign phenomenon but may also be associated with ataxia and developmental delay.

Methods: We report eight children with PTU; six of them also exhibiting symptoms of ataxia and/or developmental delay. Treatment with carbonic anhydrase inhibition was offered to children with persisting and/or severe forms.

Genetic causes of primary aldosteronism.

Primary aldosteronism is characterized by at least partially autonomous production of the adrenal steroid hormone aldosterone and is the most common cause of secondary hypertension. The most frequent subforms are idiopathic hyperaldosteronism and aldosterone-producing adenoma. Rare causes include unilateral hyperplasia, adrenocortical carcinoma and Mendelian forms (familial hyperaldosteronism).

CLCN2 clicks with aldosterone-producing adenomas, too!

Germline mutations in the chloride channel gene CLCN2 have been described as cause of familial hyperaldosteronism type II. In this issue, Dutta and colleagues in a groundbreaking study identify a somatic (tumor-specific) CLCN2 mutation in an aldosterone-producing adenoma, expanding the disease spectrum associated with CLCN2 mutations.

Pathogenesis of Familial Hyperaldosteronism Type II: New Concepts Involving Anion Channels.

Purpose Of Review: The application of advanced genetic techniques has recently begun to unravel the genetic basis for familial primary aldosteronism type 2 (FH-II).

Recent Findings: Whole-exome sequencing in a large family with FH-II revealed a shared rare damaging heterozygous variant in CLCN2 (chr.3: g.

Mutations in Pituitary Cushing Adenomas-Targeted Analysis by Next-Generation Sequencing.

Gain-of-function somatic mutations in the ubiquitin specific protease 8 () gene have recently been reported as a cause of pituitary adenomas in Cushing disease. Molecular diagnostic testing of tumor tissue may aid in the diagnosis of specimens obtained through therapeutic transsphenoidal surgery; however, for small tumors, availability of fresh tissue is limited, and contamination with normal tissue is frequent. We performed molecular testing of DNA isolated from single formalin-fixed and paraffin-embedded (FFPE) tissue sections of 42 pituitary adenomas from patients with Cushing disease (27 female patients and 15 male patients; mean age at surgery, 42.