Yiran Jiang

Activating Hotspot L205R Mutation in PRKACA and Adrenal Cushing's Syndrome

Adrenal Cushing’s syndrome is caused by excess production of glucocorticoid from adrenocortical tumors and hyperplasias, which leads to metabolic disorders. We performed whole-exome sequencing of 49 blood-tumor pairs and RNA sequencing of 44 tumors from cortisol-producing adrenocortical adenomas (ACAs), adrenocorticotropic hormone–independent macronodular adrenocortical hyperplasias (AIMAHs), and adrenocortical oncocytomas (ADOs). We identified a hotspot in the PRKACA gene with a L205R mutation in 69.2% (27 out of 39) of ACAs and validated in 65.5% of a total of 87 ACAs. Our data revealed that the activating L205R mutation, which locates in the P+1 loop of the protein kinase A (PKA) catalytic subunit, promoted PKA substrate phosphorylation and target gene expression. Moreover, we discovered the recurrently mutated gene DOT1L in AIMAHs and CLASP2 in ADOs. Collectively, these data highlight potentially functional mutated genes in adrenal Cushing’s syndrome. Adrenal Cushing’s syndrome involves recurrent mutations in a key signal transduction pathway [Also see Perspective by Kirschner] Candidate Cushings culprit identified Cushings syndrome is a rare condition resulting from the excess production of cortisol. About 15% of Cushings syndrome cases are associated with an adrenocortical tumor. However, the genetic etiology of these adrenocortical tumors is ill defined (see the Perspective by Kirschner). Cao et al. and Sato et al. both performed whole-exome sequencing of tumors from individuals with adrenal Cushings syndrome and compared it with the patients own matched non-tumor DNA and identified recurrent mutations in the protein kinase A catalytic subunit alpha (PRKACA) gene, as well as less frequent mutations in other putative pathological genes. The most common recurrent mutation activated the kinase, which may suggest a potential therapeutic target. Science, this issue p. 913, p. 917; see also p. 804

An atlas of DNA methylomes in porcine adipose and muscle tissues

It is evident that epigenetic factors, especially DNA methylation, have essential roles in obesity development. Here, using pig as a model, we investigate the systematic association between DNA methylation and obesity. We sample eight variant adipose and two distinct skeletal muscle tissues from three pig breeds living within comparable environments but displaying distinct fat level. We generate 1,381 Gb of sequence data from 180 methylated DNA immunoprecipitation libraries, and provide a genome-wide DNA methylation map as well as a gene expression map for adipose and muscle studies. The analysis shows global similarity and difference among breeds, sexes and anatomic locations, and identifies the differentially methylated regions. The differentially methylated regions in promoters are highly associated with obesity development via expression repression of both known obesity-related genes and novel genes. This comprehensive map provides a solid basis for exploring epigenetic mechanisms of adipose deposition and muscle growth.

Prevalence of and risk factors for primary aldosteronism among patients with resistant hypertension in China.

Objectives: It is estimated that there are more than 16 million adults with drug-resistant hypertension in China. Nevertheless, the prevalence of and risk factors for primary aldosteronism, a highly curable condition among adults with drug-resistant hypertension, has not been fully investigated. Methods: Between January 2010 and October 2011, a multicenter epidemiologic study was conducted among 1656 patients with resistant hypertension in 11 provinces of China. Serum aldosterone and plasma renin activity were measured in every participant and aldosterone-to-renin ratio (ARR) was calculated. Patients with ARR more than 20 underwent an intravenous (i.v.) sodium infusion test, and diagnosis of primary aldosteronism was established by the presence of unsuppressed postinfusion aldosterone (>8 ng/dl). Patients with biochemically proved primary aldosteronism then underwent adrenal computed tomography (CT) scanning and adrenal vein sampling (AVS) for subtype classification. Results: Among the 1656 patients, 494 (29.8%) had ARR greater than 20 and underwent i.v. sodium infusion. Of these 494, 118 were diagnosed as primary aldosteronism, yielding a prevalence of 7.1% (95% confidential interval 5.9–8.3%). Seventy of the 118 patients were categorized into unilateral (39) and bilateral (31) by AVS. Generalized additive regression analysis revealed that among all the factors investigated (age of hypertension onset, BMI, family history of hypertension, cigarette smoking, alcohol consumption, diabetes, serum potassium, hyperlipidemia, and creatinine), only age of hypertension onset and serum potassium were independently associated with the presence of primary aldosteronism. Conclusion: The prevalence of primary aldosteronism among Chinese patients with resistant hypertension is relatively lower than that reported previously for other ethnic populations. The screening for primary aldosteronism should be focused on those with early onset hypertension and/or hypokalemia.

Diagnostic Value of ACTH Stimulation Test in Determining the Subtypes of Primary Aldosteronism

BACKGROUND Adrenal venous sampling is recommended as the golden standard for subtyping primary aldosteronism (PA). However, it is invasive and inconvenient, and seeking a better way to make differential diagnosis of PA is necessary. OBJECTIVE The objective of the study was to evaluate the diagnostic value of ACTH stimulation test under 1 mg dexamethasone suppression test (DST) in determining the subtypes of PA. METHODS Ninety-five patients with PA confirmed by saline infusion test were included in this study. According to adrenal venous sampling and histopathology, 39 patients were diagnosed as bilateral adrenal hyperplasia (BAH), 37 as aldosterone-producing adenoma (APA), and 19 as unilateral adrenal hyperplasia (UAH). An ACTH stimulation test under 1 mg DST was performed in all patients. Plasma aldosterone and cortisol levels were measured every 30 minutes until 120 minutes after the iv injection of 50 IU ACTH. RESULTS During the ACTH stimulation test, aldosterone levels in APA and UAH were similar (P > .05) but higher than those in BAH (P < .001). Furthermore, stimulated aldosterone levels of unilateral PA (APA and UAH) were significantly higher than bilateral PA (BAH) (P < .001). Receiver-operated characteristics curve analyses showed the aldosterone after ACTH stimulation was effective for distinguishing between unilateral PA and bilateral PA. The diagnostic accuracy was highest at 120 minutes after ACTH stimulation, and the optimal cutoff value of the aldosterone was 77.90 ng/dL, with a sensitivity of 76.8%, a specificity of 87.2%, a positive predictive value of 89.6%, and a negative predictive value of 72.3%. CONCLUSIONS The ACTH stimulation test under 1 mg DST is useful to determine the subtypes of PA, especially in unilateral and bilateral PA, and may guide further treatment in PA patients.

Low serum potassium level is associated with nonalcoholic fatty liver disease and its related metabolic disorders

Subjects with nonalcoholic fatty liver disease (NAFLD) have a high risk of developing type 2 diabetes and cardiovascular diseases. Low serum potassium concentration or low dietary potassium intake can result in metabolic disorders.

Downregulation of miR-375 in aldosterone-producing adenomas promotes tumour cell growth via MTDH.

Previous studies have investigated the genetic and molecular basis of primary aldosteronism (PA), a common cause of human hypertension, but the effects of microRNAs (miRNAs) on the adrenocortical cell proliferation and aldosterone production are largely obscure. Here, we characterized miRNA expression patterns in the subtypes of PA to gain a better understanding of its pathogenesis.

Relationship between pituitary stalk (PS) visibility and the severity of hormone deficiencies: PS interruption syndrome revisited

Pituitary stalk interruption syndrome (PSIS) is a rare cause of combined pituitary hormone deficiency characterized by a triad shown in pituitary imaging, yet it has never been evaluated due to the visibility of pituitary stalk (PS) in imaging findings.

Gene expression profiles of phaeochromocytomas with ERBB2 overexpression reveal a new molecular mechanism tumourigenicity

Phaeochromocytomas (PHEO) and functional paragangliomas (PGLs) are catecholamine‐secreting neuroendocrine tumours. Although most PHEO/PGLs are benign, 10–35% present as (or develop into) malignant tumours with a poor prognosis. Overexpression of ERBB2 (v‐erb‐b2 erythroblastic leukaemia viral oncogene homologue 2) has been reported to be associated with malignant PHEO. We used gene expression profiling of PHEO/PGLs to gain a better understanding of the tumourigenic pathways associated with ERBB2.

Steroidogenic Acute Regulatory Protein Overexpression Correlates with Protein Kinase A Activation in Adrenocortical Adenoma

The association of pathological features of cortisol-producing adrenocortical adenomas (ACAs) with somatic driver mutations and their molecular classification remain unclear. In this study, we explored the association between steroidogenic acute regulatory protein (StAR) expression and the driver mutations activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling to identify the pathological markers of ACAs. Immunohistochemical staining for StAR and mutations in the protein kinase cAMP-activated catalytic subunit alpha (PRKACA), protein kinase cAMP-dependent type I regulatory subunit alpha (PRKAR1A) and guanine nucleotide binding protein, alpha stimulating (GNAS) genes were examined in 97 ACAs. The association of StAR expression with the clinical and mutational features of the ACAs was analyzed. ACAs with mutations in PRKACA, GNAS, and PRKAR1A showed strong immunopositive staining for StAR. The concordance between high StAR expression and mutations activating cAMP/PKA signaling in the ACAs was 99.0%. ACAs with high expression of StAR had significantly smaller tumor volume (P < 0.001) and higher urinary cortisol per tumor volume (P = 0.032) than those with low expression of StAR. Our findings suggest that immunohistochemical staining for StAR is a reliable pathological approach for the diagnosis and classification of ACAs with cAMP/PKA signaling-activating mutations.

Factors affecting parathyroid hormone levels in different types of primary aldosteronism

Recent studies have found that mild secondary hyperparathyroidism might be another clinical feature of patients with primary aldosteronims (PA), but whether serum parathyroid hormone level (PTH) is correlated with subtypes of PA and what contributes to the elevated PTH level remains unclear.