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Driver somatic mutations for aldosterone excess have been found in ≈90% of aldosterone-producing adenomas (APAs) using an aldosterone synthase (CYP11B2)-guided sequencing approach. In the present study, we identified a novel somatic CACNA1H mutation (c.T4289C, p.I1430T) in an APA without any currently known aldosterone-driver mutations using CYP11B2 immunohistochemistry-guided whole exome sequencing. The CACNA1H gene encodes a voltage-dependent T-type calcium channel alpha-1H subunit. Germline variants in this gene are known as a cause of familial hyperaldosteronism IV. Targeted next-generation sequencing detected identical CACNA1H variants in 2 additional APAs in a cohort of the University of Michigan, resulting in a prevalence of 4% (3/75) in APAs. We tested the functional effect of the variant on adrenal cell aldosterone production and CYP11B2 mRNA expression using the human adrenocortical HAC15 cell line with a doxycycline-inducible CACNA1HI1430T mutation. Doxycycline treatment increased CYP11B2 mRNA levels as well as aldosterone production, supporting a pathological role of the CACNA1H p.I1430T mutation on the development of primary aldosteronism. In conclusion, somatic CACNA1H mutation is a genetic cause of APAs. Although the prevalence of this mutation is low, this study will provide better understanding of molecular mechanism of inappropriate aldosterone production in APAs. [ABSTRACT FROM AUTHOR]

The neuropathies of the peripheral, central and autonomic nervous systems are known to be caused by hyperglycemia, a consequence of the deregulation of glucose in diabetes. Several in vivo models such as streptozotocin-induced diabetic rats, mice and Chinese hamsters have been used to study the pathogenesis of diabetic neuropathy because of their resemblance to human pathology. However, these in vivo models have met with strong ethical oppositions. Further, the system complexity has inherent limitations of inconvenience of analyzing ephemeral molecular events and crosstalk of signal transduction pathways. Alternative in vitro models have been selected and put to effective use in diabetic studies. We critically review the use of these in vitro models such as primary cultures of dorsal root ganglia, Schwann cells and neural tissue as well as neural cell lines which have proved to be excellent systems for detailed study. We also assess the use of embryo cultures for the study of hyperglycemic effects on development, especially of the nervous system. These systems function as useful models to scrutinize the molecular events underlying hyperglycemia-induced stress in neuronal systems and have been very effectively used for the same. This comprehensive overview of advantages and disadvantages of in vitro systems that are currently in use will be of interest especially for comparative assessment of results and for appropriate choice of models for experiments in diabetic neuropathy. [ABSTRACT FROM AUTHOR]