scholarly journals Phosphodiesterase 2A and 3B variants are associated with primary aldosteronism

2021 ◽  
Vol 28 (1) ◽  
pp. 1-13
Author(s):  
Marcela Rassi-Cruz ◽  
Andrea G Maria ◽  
Fabio R Faucz ◽  
Edra London ◽  
Leticia A P Vilela ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Early Onset ◽  
Zona Glomerulosa ◽  
Unilateral Adrenalectomy ◽  
Transfected Cells ◽  
Functional Studies ◽  
Protein Levels ◽  
Whole Exome ◽  
Hyperplastic Tissue ◽  
Bilateral Adrenal Hyperplasia

Abstract Familial primary aldosteronism (PA) is rare and mostly diagnosed in early-onset hypertension (HT). However, ‘sporadic’ bilateral adrenal hyperplasia (BAH) is the most frequent cause of PA and remains without genetic etiology in most cases. Our aim was to investigate new genetic defects associated with BAH and PA. We performed whole-exome sequencing (paired blood and adrenal tissue) in six patients with PA caused by BAH that underwent unilateral adrenalectomy. Additionally, we conducted functional studies in adrenal hyperplastic tissue and transfected cells to confirm the pathogenicity of the identified genetic variants. Rare germline variants in phosphodiesterase 2A (PDE2A) and 3B (PDE3B) genes were identified in three patients. The PDE2A heterozygous variant (p.Ile629Val) was identified in a patient with BAH and early-onset HT at 13 years of age. Two PDE3B heterozygous variants (p.Arg217Gln and p.Gly392Val) were identified in patients with BAH and HT diagnosed at 18 and 33 years of age, respectively. A strong PDE2A staining was found in all cases of BAH in zona glomerulosa and/or micronodules (that were also positive for CYP11B2). PKA activity in frozen tissue was significantly higher in BAH from patients harboring PDE2A and PDE3B variants. PDE2A and PDE3B variants significantly reduced protein expression in mutant transfected cells compared to WT. Interestingly, PDE2A and PDE3B variants increased SGK1 and SCNN1G/ENaCg at mRNA or protein levels. In conclusion, PDE2A and PDE3B variants were associated with PA caused by BAH. These novel genetic findings expand the spectrum of genetic etiologies of PA.

scholarly journals Comprehensive Analysis of LIN28A in Chinese Patients With Early Onset Parkinson’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaojing Gu ◽  
Yanbing Hou ◽  
Yongping Chen ◽  
Ruwei Ou ◽  
Bei Cao ◽  
...  
Keyword(s):  
Early Onset ◽  
Chinese Patient ◽  
Chinese Patients ◽  
Loss Of Function ◽  
Developmental Defects ◽  
Functional Studies ◽  
Whole Exome ◽  
Increased Risk ◽  
Related Phenotype ◽  
Early Onset Parkinson’S Disease

A loss-of-function variant in Lin-28 Homolog A gene (LIN28A p. R192G, rs558060339) has been identified in two East Asian ancestry patients with early-onset PD (EOPD). Functional studies revealed that such a variant could lead to developmental defects and PD-related phenotype, and the phenotypes could be rescued after correction of the variant. The aim of the study was to screen the variants of LIN28A in Chinese patients with EOPD. A total of 682 EOPD patients were sequenced with whole exome sequencing and the coding and flanking region of LIN28A were analyzed. We identified a rare coding variant, p. P182L, of LIN28A in a Chinese patient with EOPD. Moreover, we also found a 3′-UTR polymorphism (rs4659441) to be associated with an increased risk for PD. However, our rare variant burden analysis did not support a role for LIN28A as a major causal gene for PD.

scholarly journals Analysis of Unilateral Adrenal Hyperplasia with Primary Aldosteronism from the Aspect of Messenger Ribonucleic Acid Expression for Steroidogenic Enzymes: A Comparative Study with Adrenal Cortices Adhering to Aldosterone-Producing Adenoma

Endocrinology ◽  
2006 ◽  
Vol 147 (2) ◽  
pp. 999-1006 ◽  
Author(s):  
Kazuto Shigematsu ◽  
Kioko Kawai ◽  
Junji Irie ◽  
Hideki Sakai ◽  
Osamu Nakashima ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Zona Glomerulosa ◽  
Adrenal Hyperplasia ◽  
Steroidogenic Enzymes ◽  
Unilateral Adrenalectomy ◽  
Messenger Ribonucleic Acid ◽  
Unilateral Adrenal Hyperplasia ◽  
Aldosterone Production ◽  
Long Term Follow Up ◽  
Aldosterone Producing Adenoma

Unilateral adrenal hyperplasia with primary aldosteronism is very rare and shows similar endocrine features to aldosterone-producing adenoma and bilateral adrenal hyperplasia. In this study, the mRNA expression of steroidogenic enzymes in unilateral adrenal hyperplasia was examined by in situ hybridization. We found subcapsular micronodules composed of spironolactone body-containing cells, which showed intense expression for 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase, 18-hydroxylase, and 21-hydroxylase but not 17α-hydroxylase, indicating aldosterone production. This expression pattern was the same as that in unilateral multiple adrenocortical micronodules, reported recently. Additionally, it was noted that a nodule with active aldosterone production was closely adjacent to one showing intense 17α-hydroxylase expression. In the adrenal cortices adhering to aldosterone-producing adenoma, the majority of hyperplastic zona glomerulosa and hyperplastic nodules demonstrated a decreased steroidogenic activity. However, minute nodules indicative of active aldosterone production were found at high frequency. These results suggest that the subcapsular micronodules observed might be the root of aldosterone-producing adenoma. Furthermore, we emphasize the need for long-term follow-up after unilateral adrenalectomy or enucleation of the adenoma because of the possibility that buds with autonomous aldosterone production may still be present in the contralateral or remaining adrenal tissue.

scholarly journals Role of Nox2 and p22phox in Persistent Postoperative Hypertension in Aldosterone-Producing Adenoma Patients after Adrenalectomy

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Xiaojing Geng ◽  
Li Yan ◽  
Jun Dong ◽  
Ying Liang ◽  
Yajuan Deng ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Secondary Hypertension ◽  
Zona Glomerulosa ◽  
Catalytic Core ◽  
Plasma Aldosterone Concentration ◽  
Unilateral Adrenalectomy ◽  
Protein Levels ◽  
Aldosterone Producing Adenoma

Adrenal aldosterone-producing adenoma (APA), producing the salt-retaining hormone aldosterone, commonly causes secondary hypertension, which often persists after unilateral adrenalectomy. Although persistent hypertension was correlated with residual hormone aldosterone, thein vivomechanism remains unclear. NADPH oxidase is the critical cause of aldosterone synthesisin vitro. Nox2 and p22phox comprise the NADPH oxidase catalytic core, serving to initiate a reactive oxygen species (ROS) cascade that may participate in the pathology. mRNAs of seven NADPH oxidase isoforms in APA were evaluated by RT-PCR and Q-PCR and their proteins by immunohistochemistry and Western blotting. NADPH oxidase activity was also detected. Nox2 and p22phox were especially abundant in APA. Particularly higher Nox2 and p22phox gene and protein levels were seen in APA than controls. Significant correlations betweenNox2mRNA andaldosterone synthase (CYP11B2)mRNA (R=0.66,P<0.01) and Nox2 protein and baseline plasma aldosterone concentration (PAC) (R=0.503,P<0.01) were detected in APA; however, none were found betweenp22phoxmRNA,CYP11B2mRNA,p22phoxprotein, and baseline PAC. Importantly, we found that Nox2 localized specifically in hyperplastic zona glomerulosa cells. In conclusion, our results highlight that Nox2 and p22phox may be directly involved in pathological aldosterone production and zona glomerulosa cell proliferation after APA resection.

scholarly journals Approaches to Gene Mutation Analysis Using Formalin-Fixed Paraffin-Embedded Adrenal Tumor Tissue From Patients With Primary Aldosteronism

2021 ◽  
Vol 12 ◽  
Author(s):  
Kazutaka Nanba ◽  
William E. Rainey ◽  
Aaron M. Udager
Keyword(s):  
Primary Aldosteronism ◽  
Zona Glomerulosa ◽  
Genetic Profiling ◽  
Tissue Sections ◽  
Whole Exome ◽  
Formalin Fixed Paraffin ◽  
Aldosterone Production ◽  
Formalin Fixed Paraffin Embedded ◽  
Ffpe Material ◽  
Formalin Fixed

Aldosterone production is physiologically under the control of circulating potassium and angiotensin II as well as adrenocorticotropic hormone and other secretagogues such as serotonin. The adrenal’s capacity to produce aldosterone relies heavily on the expression of a single enzyme, aldosterone synthase (CYP11B2). This enzyme carries out the final reactions in the synthesis of aldosterone and is expressed almost solely in the adrenal zona glomerulosa. From a disease standpoint, primary aldosteronism (PA) is the most common of all adrenal disorders. PA results from renin-independent adrenal expression of CYP11B2 and production of aldosterone. The major causes of PA are adrenal aldosterone-producing adenomas (APA) and adrenal idiopathic hyperaldosteronism. Our understanding of the genetic causes of APA has significantly improved through comprehensive genetic profiling with next-generation sequencing. Whole-exome sequencing has led to the discovery of mutations in six genes that cause renin-independent aldosterone production and thus PA. To facilitate broad-based prospective and retrospective studies of APA, recent technologic advancements have allowed the determination of tumor mutation status using formalin-fixed paraffin-embedded (FFPE) tissue sections. This approach has the advantages of providing ready access to archival samples and allowing CYP11B2 immunohistochemistry-guided capture of the exact tissue responsible for inappropriate aldosterone synthesis. Herein we review the methods and approaches that facilitate the use of adrenal FFPE material for DNA capture, sequencing, and mutation determination.

scholarly journals SUN-LB96 Basal Contralateral Aldosterone Suppression Is Rare in Lateralized Primary Aldosteronism and Can Be Useful in Predicting Surgical Outcome

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Marie-Josée Desrochers ◽  
Matthieu St-Jean ◽  
El Ghorayeb Nada ◽  
Isabelle Bourdeau ◽  
Benny So ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Surgical Outcome ◽  
Clinical Cure ◽  
Suppression Ratio ◽  
Postoperative Outcome ◽  
Roc Curves ◽  
Zona Glomerulosa ◽  
Unilateral Adrenalectomy ◽  
Biochemical Cure ◽  
Surgical Cure

Abstract Background: Adrenal venous sampling (AVS) is performed to distinguish between unilateral or bilateral source of aldosterone in primary aldosteronism (PA). Unilateral aldosteronomas should lead to suppression of renin and contralateral (CL) aldosterone secretion, assessed by the CL suppression ratio. We recently found that CL aldosterone suppression was relatively rare using the ratio of basal aldosterone concentration of the opposite adrenal vein/periphery (AOPP/AP) in contrast to the traditional cortisol-corrected aldosterone ratio ((A/C)OPP(A/C)P). Pathology studies showed frequent zona glomerulosa (ZG) hyperplasia adjacent to a dominant aldosteronoma, which could also indicate probable ZG hyperplasia in the CL adrenal. The ratio of basal CL suppression could be a usefull parameter to predict cure following unilateral adrenalectomy (UA), but controversy remains in the literature. Objectives: 1. To evaluate the prevalence of basal CL suppression using the AOPP/AP ratio as compared to the (A/C)OPP/(A/C)P ratio at previously established cut-offs. 2. To determine the best cut-off to predict clinical and biochemical surgical cure in two Canadian referral centers. 3. To compare the accuracy of the AOPP/AP ratio to the basal lateralization ratio (LR) and the post-ACTH LR in predicting the surgical outcome. Methods: 330 patients with PA and successful bilateral simultaneous basal and post-ACTH stimulated AVS (selectivity index &gt;2 basally and &gt;5 post-ACTH) were included; 124 patients found to be lateralized underwent UA. The follow-up data were evaluated for clinical and biochemical cure at 3 and 12 months using the PASO criteria. Results: Using AOPP/AP and (A/C)OPP/(A/C)P at the cut-off of 1, the prevalence of CL suppression is 6% and 45%, respectively. The median CL suppression ratio is 2.3 (1.3-5.1) in lateralized cases of PA using AOPP/AP. Using ROC curves, the AOPP/AP ratio is associated with clinical cure at 3 and 12 months and biochemical cure at 12 months. (A/C)OPP/(A/C)P is associated with biochemical cure only. The cut-offs for AOPP/AP offering the best sensitivity and specificity for clinical and biochemical cures at 12 months are 2.15 (Se 63% and Sp 71%) and 6.15 (Se 84% and Sp 77%), respectively. Basal LR and post-ACTH LR are associated with clinical cure but only the post-ACTH LR is associated with biochemical cure. Conclusions: Basal CL suppression defined by the AOPP/AP ratio is rare and incomplete compared to the traditional (A/C)OPP/(A/C)P ratio in lateralized cases of PA. This may reflect the frequent micronodular hyperplasia adjacent to dominant aldosteronomas and possibly in the CL adrenal. Basal CL aldosterone suppression may predict clinical postoperative outcome, but with modest accuracy.

scholarly journals Coding mutations inNUS1contribute to Parkinson’s disease

2018 ◽  
Vol 115 (45) ◽  
pp. 11567-11572 ◽  
Author(s):  
Ji-feng Guo ◽  
Lu Zhang ◽  
Kai Li ◽  
Jun-pu Mei ◽  
Jin Xue ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Onset ◽  
De Novo ◽  
Dopamine Level ◽  
De Novo Mutations ◽  
Functional Studies ◽  
Whole Exome ◽  
Independent Case ◽  
The Impact

Whole-exome sequencing has been successful in identifying genetic factors contributing to familial or sporadic Parkinson’s disease (PD). However, this approach has not been applied to explore the impact of de novo mutations on PD pathogenesis. Here, we sequenced the exomes of 39 early onset patients, their parents, and 20 unaffected siblings to investigate the effects of de novo mutations on PD. We identified 12 genes with de novo mutations (MAD1L1,NUP98,PPP2CB,PKMYT1,TRIM24,CEP131,CTTNBP2,NUS1,SMPD3,MGRN1,IFI35, andRUSC2), which could be functionally relevant to PD pathogenesis. Further analyses of two independent case-control cohorts (1,852 patients and 1,565 controls in one cohort and 3,237 patients and 2,858 controls in the other) revealed thatNUS1harbors significantly more rare nonsynonymous variants (P= 1.01E-5, odds ratio = 11.3) in PD patients than in controls. Functional studies inDrosophilademonstrated that the loss ofNUS1could reduce the climbing ability, dopamine level, and number of dopaminergic neurons in 30-day-old flies and could induce apoptosis in fly brain. Together, our data suggest that de novo mutations could contribute to early onset PD pathogenesis and identifyNUS1as a candidate gene for PD.

scholarly journals Temporospatial genomic profiling in glioblastoma identifies commonly altered core pathways underlying tumor progression

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Mylan R Blomquist ◽  
Shannon Fortin Ensign ◽  
Fulvio D’Angelo ◽  
Joanna J Phillips ◽  
Michele Ceccarelli ◽  
...  
Keyword(s):  
Standard Of Care ◽  
Resection Margins ◽  
Protein Activity ◽  
Transcriptional Signature ◽  
Functional Studies ◽  
Protein Levels ◽  
Aberrant Gene Expression ◽  
Whole Exome ◽  
Standard Of Care Treatment ◽  
Aberrant Gene

Abstract Background Tumor heterogeneity underlies resistance and disease progression in glioblastoma (GBM), and tumors most commonly recur adjacent to the surgical resection margins in contrast non-enhancing (NE) regions. To date, no targeted therapies have meaningfully altered overall patient survival in the up-front setting. The aim of this study was to characterize intratumoral heterogeneity in recurrent GBM using bulk samples from primary resection and recurrent samples taken from contrast-enhancing (EN) and contrast NE regions. Methods Whole exome and RNA sequencing were performed on matched bulk primary and multiple recurrent EN and NE tumor samples from 16 GBM patients who received standard of care treatment alone or in combination with investigational clinical trial regimens. Results Private mutations emerge across multi-region sampling in recurrent tumors. Genomic clonal analysis revealed increased enrichment in gene alterations regulating the G2M checkpoint, Kras signaling, Wnt signaling, and DNA repair in recurrent disease. Subsequent functional studies identified augmented PI3K/AKT transcriptional and protein activity throughout progression, validated by phospho-protein levels. Moreover, a mesenchymal transcriptional signature was observed in recurrent EN regions, which differed from the proneural signature in recurrent NE regions. Conclusions Subclonal populations observed within bulk resected primary GBMs transcriptionally evolve across tumor recurrence (EN and NE regions) and exhibit aberrant gene expression of common signaling pathways that persist despite standard or targeted therapy. Our findings provide evidence that there are both adaptive and clonally mediated dependencies of GBM on key pathways, such as the PI3K/AKT axis, for survival across recurrences.

scholarly journals SUN-195 Bilateral Aldosterone-Producing Adenomas: A New Subtype of Bilateral Primary Aldosteronism?

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Ana Alice Wolf Maciel ◽  
Thaís Castanheira de Freitas ◽  
Marcelo L Balancin ◽  
Felipe L Ledesma ◽  
Tatiana S Goldbaum ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Urinary Free Cortisol ◽  
Zona Glomerulosa ◽  
R Ratio ◽  
Basal Cortisol ◽  
Endocrine Hypertension ◽  
Free Cortisol ◽  
Biochemical Cure ◽  
Bilateral Adrenal Hyperplasia ◽  
The Right

Abstract Background: Primary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). PA subtypes include aldosterone-producing adenomas (APA) and bilateral adrenal hyperplasia. To date, few PA patients with bilateral adenomas have been reported, but only one case was well characterized by anatomopathological analysis and clinical outcome after adrenal sparing surgery (1). Clinical case: A 53-year-old woman was referred to investigate resistant HT and hypokalemia. (3.0 mEq/L). PA screening revealed aldosterone (A) of 37.9 ng/dL, renin (R) &lt; 1.6 (4.4-46.1 mUI/L), A/R ratio of 24.8. Confirmatory testing confirmed PA diagnosis: seated saline infusion test (A= 83.3 ng/dL) and intravenous furosemide test (R= 3.1 mUI/L; positive test &lt;13 mUI/L). Hypercortisolism investigation revealed a non-suppressible cortisol after an overnight 1 mg low-dose dexamethasone suppression [cortisol (C)= 2.9 μg/dL and dexamethasone= 701 (˃130 ng/dL)], and normal urinary free cortisol, midnight salivary cortisol, plasma DHEAS and ACTH levels. Computed tomography demonstrated bilateral adrenal nodules without adrenal thickening: 3.5 cm right nodule (pre-contrast density of 7UH density; absolute wash-out of 71%) and 2.5 cm left nodule (pre-contrast density of 8UH density; absolute wash-out of 78%). Sequential adrenal venous (AV) sampling (AVS) under continuous cosyntropin infusion showed a lateralization index of 3.4 (bilateral disease &lt;4). Then, the patient underwent right adrenalectomy and left nodulectomy. In the postoperative period, she presented normalization of K+ levels and complete HT remission. She remained under hydrocortisone replacement for 2 months. After 2 months, biochemical evaluation revealed normal basal cortisol levels (13.3 µg/dL) and biochemical cure of PA (A= 3.1 ng/dL and R= 15.3 mUI/L). Currently, she doesn’t have symptoms of adrenal insufficiency after discontinuation of hydrocortisone. Anatomopathological analysis showed bilateral adenomas (Weiss score of 0) in both sides without adjacent hyperplasia. CYP11B2 immunohistochemistry displayed a strong staining in 50% of cells in the right adenoma and in 30% of cells in the left adenoma. Few aldosterone-producing cell clusters (APCC) were identified in the right zona glomerulosa, which is a frequent finding in normal adrenals. Conclusion: We herein described a very rare case of PA caused by bilateral-producing adenomas, confirmed by AVS and CYP11B2 staining after adrenal sparing surgery.

scholarly journals The E3 ubiquitin ligase UBR5 interacts with TTC7A and may be associated with very early onset inflammatory bowel disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Neel Dhingani ◽  
Conghui Guo ◽  
Jie Pan ◽  
Qi Li ◽  
Neil Warner ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Early Onset ◽  
Intestinal Atresia ◽  
Compound Heterozygous ◽  
Functional Studies ◽  
Monogenic Disorders ◽  
Whole Exome ◽  
Inflammatory Bowel ◽  
Tetratricopeptide Repeat Domain

Abstract Very early onset inflammatory bowel disease (VEOIBD) denotes children with onset of IBD before six years of age. A number of monogenic disorders are associated with VEOIBD including tetratricopeptide repeat domain 7A (TTC7A) deficiency. TTC7A-deficiency is characterized by apoptotic colitis in milder cases with severe intestinal atresia and immunodeficiency in cases with complete loss of protein. We used whole exome sequencing in a VEOIBD patient presenting with colitis characterized by colonic apoptosis and no identified known VEOIBD variants, to identify compound heterozygous deleterious variants in the Ubiquitin protein ligase E3 component N-recognin 5 (UBR5) gene. Functional studies demonstrated that UBR5 co-immunoprecipitates with the TTC7A and the UBR5 variants had reduced interaction between UBR5 and TTC7A. Together this implicates UBR5 in regulating TTC7A signaling in VEOIBD patients with apoptotic colitis.

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