INDEPTH geophysical and geological observations imply that a partially molten midcrustal layer exists beneath southern Tibet. This partially molten layer has been produced by crustal thickening and behaves as a fluid on the time scale of Himalayan deformation. It is confined on the south by the structurally imbricated Indian crust underlying the Tethyan and High Himalaya and is underlain, apparently, by a stiff Indian mantle lid. The results suggest that during Neogene time the underthrusting Indian crust has acted as a plunger, displacing the molten middle crust to the north while at the same time contributing to this layer by melting and ductile flow. Viewed broadly, the Neogene evolution of the Himalaya is essentially a record of the southward extrusion of the partially molten middle crust underlying southern Tibet.

Primary aldosteronism (PA) represents the most common cause of secondary hypertension, but little is known regarding its adrenal cellular origins. Recently, aldosterone-producing cell clusters (APCCs) with high expression of aldosterone synthase (CYP11B2) were found in both normal and PA adrenal tissue. PA-causing aldosteroneproducing adenomas (APAs) harbor mutations in genes encoding ion channels/pumps that alter intracellular calcium homeostasis and cause renin-independent aldosterone production through increased CYP11B2 expression. Herein, we hypothesized that APCCs have APArelated aldosterone-stimulating somatic gene mutations. APCCs were studied in 42 normal adrenals from kidney donors. To clarify APCC molecular characteristics, we used microarrays to compare the APCC transcriptome with conventional adrenocortical zones [zona glomerulosa (ZG), zona fasciculata, and zona reticularis]. The APCC transcriptome was most similar to ZG but with an enhanced capacity to produce aldosterone. To determine if APCCs harbored APA-related mutations, we performed targeted next generation sequencing of DNA from 23 APCCs and adjacent normal adrenal tissue isolated from both formalin-fixed, paraffin-embedded, and frozen tissues. Known aldosterone driver mutations were identified in 8 of 23 (35%) APCCs, including mutations in calcium channel, voltage-dependent, L-type, α1D-subunit (CACNA1D; 6 of 23 APCCs) and ATPase, Na + /K + transporting, α1-polypeptide (ATP1A1; 2 of 23 APCCs), which were not observed in the adjacent normal adrenal tissue. Overall, we show three major findings: (i) APCCs are common in normal adrenals, (ii) APCCs harbor somatic mutations known to cause excess aldosterone production, and (iii) the mutation spectrum of aldosteronedriving mutations is different in APCCs from that seen in APA. These results provide molecular support for APCC as a precursor of PA.primary aldosteronism | aldosterone | adrenal | somatic mutations | aldosterone-producing cell cluster P rimary aldosteronism (PA) accounts for 8% of hypertension and is the most common adrenal disease (1-4). PA patients can be classified into those with aldosterone-producing adenomas (APAs), idiopathic hyperaldosteronism, or familial hyperaldosteronism (FH), which is further divided into FH types 1-3 (FHI-FHIII) (5). In 1992, FHI was shown to result from a gene fusion of cytochrome P450, family 11, subfamily B, polypeptide 2 (CYP11B2: aldosterone synthase) and cytochrome P450, family 11, subfamily B, polypeptide 1 (CYP11B1; cortisol synthase) that resulted in zona fasciculata (ZF) expression of CYP11B2 and excess aldosterone production (6). For almost two decades after the original report, no other genetic abnormalities were identified in the other forms of PA.First reported in 2011, exome sequencing identified a series of germ-line and somatic mutations in genes that altered adrenal cell intracellular Ca 2+ in PA. The most common mutations are somatic mutations of the gene encoding the potassium inwardly rectifying channel, subfamily J, member 5 (KCNJ5)...

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