Primary aldosteronism, a common cause of severe hypertension1, features constitutive production of the adrenal steroid aldosterone. We analyzed a multiplex family with familial hyperaldosteronism type II (FH-II)2 and 80 additional probands with unsolved early-onset primary aldosteronism. Eight probands had novel heterozygous variants in CLCN2, including two de novo mutations and four independent occurrences of the identical p.Arg172Gln mutation; all relatives with early-onset primary aldosteronism carried the CLCN2 variant found in probands. CLCN2 encodes a voltage-gated chloride channel expressed in adrenal glomerulosa that opens at hyperpolarized membrane potentials. Channel opening depolarizes glomerulosa cells and induces expression of aldosterone synthase, the rate-limiting enzyme for aldosterone biosynthesis. Mutant channels cause gain of function, with higher open probabilities at the glomerulosa resting potential. These findings for the first time demonstrate a role of anion channels in glomerulosa membrane potential determination, aldosterone production and hypertension. They establish the cause of a substantial fraction of early-onset primary aldosteronism.

The CD45 family of transmembrane protein-tyrosine phosphatases plays a crucial role in the regulation of lymphocyte activation by coupling activation signals from antigen receptors to the signal transduction apparatus. Multiple CD45 isoforms, generated through regulated alternative mRNA splicing, differ only in the length and glycosylation of their extracellular domains. Differential distribution of these isoforms defines subsets of T cells having distinct functions and activation requirements. While the requirement for the intracellular protein-tyrosine phosphatase domains has been documented, the physiological role of the extracellular domains remains elusive. Here we report the generation of CD45-antisense transfected Jurkat T cell clones that lack CD45 or have been reconstituted to uniquely express either the smallest, CD45(0), or the largest, CD45(ABC), isoform. These cells exhibited marked isoform-dependent differences in IL-2 production and tyrosine phosphorylation of cellular proteins, including Vav after anti-CD3 stimulation. These results demonstrate that the distinct CD45 extracellular domains differentially regulate T cell receptor-mediated signaling pathways. Furthermore, these findings suggest that alterations in CD45 isoform expression by individual T cells during thymic ontogeny and after antigen exposure in the periphery directly affects the signaling pathways utilized. Activation of resting T lymphocytes through the T cell receptor (TCR)1 requires expression of the CD45 family of transmembrane protein-tyrosine phosphatases (PTPases) (1, 2). CD45 has been shown to regulate the basal activity of the Fyn and Lck protein-tyrosine kinases (PTKs) by dephosphorylation of their respective regulatory carboxyl-terminal tyrosine residues (3-7). However, it is not clear that these are CD45's sole functions. For example, new evidence suggests that CD45 can also dephosphorylate certain PTK substrates, such as the TCR chain (8) and the 32-kDa CD45-associated phosphoprotein, LPAP (9). Thus, the precise functions of the CD45 phosphatase in signal transduction are incompletely understood.While the requirement for the intracellular PTPase domains has been documented (10 -13), the function of the CD45 extracellular domain in lymphocyte signal transduction remains a major unresolved issue. In humans, five CD45 isoforms, ranging in size from 180 -220 kDa, are generated by the regulated alternative mRNA splicing of three exons, encoded by a single gene (14 -16). The alternatively spliced exons, commonly referred to as A, B, and C, are located near the 5Ј end of the gene and give rise to isoforms that differ only in their extracellular regions. Individual lymphocytes simultaneously express more than one CD45 isoform (17,18). However, the expression of certain isoforms is highly regulated, resulting in their differential expression on lymphocytes of different lineage (e.g. T versus B cells), as well as on distinct functional subsets of T cells (19 -22). Furthermore, individual T cells alter their isoform expression in ...

Idiopathic collapsing glomerulopathy (ICG) is a clinically and pathologically distinct variant of focal segmental glomerulosclerosis, characterized clinically by rapid progression of renal insufficiency, a male and African-American racial predominance, and pathologically by segmental glomerular collapse, visceral epithelial cell hypertrophy and hyperplasia, and the absence of endothelial tubuloreticular inclusions. Pathologically similar lesions have been reported in adult and pediatric patients with human immunodeficiency virus (HIV) infection and/or intravenous (IV) drug abuse. Most patients with ICG who have been reported in the literature are adults. Six children with ICG were retrospectively identified (two from East Carolina University, four from University of North Carolina-Chapel Hill). Clinical data and renal biopsy findings were reviewed for all patients. All six patients were male; five African-American and one Hispanic. Ages ranged from 2 to 17 years (mean 12 years). Steroid-resistant nephrotic syndrome was the presenting clinical finding. Average 24-h urine protein excretion was 6.3 g (range 3.2-15 g). Five patients were serologically negative for HIV infection (one patient not tested) and none had a history of IV drug abuse or known HIV risk factors. Progression to end-stage renal insufficiency in two patients within 1 year of biopsy required renal transplantation, and within 1 month of biopsy one patient required dialysis. We report a series of pediatric patients with ICG, an aggressive variant of focal segmental glomerulosclerosis. ICG in children is similar clinically and pathologically to this disease in adult patients.

Obesity is associated with the development of hypertension but it is still not clear why hypertension is not observed in all obese patients. Obesity is a risk factor for the development of obstructive sleep apnea syndrome (OSAS) in children. OSAS has been linked to the development of hypertension in adults and children. The purpose of this study was to test the hypothesis that OSAS is one of the reasons that some obese children are hypertensive and some are not. The overnight polysomnography records of 90 patients (aged 4.2-18.8 years) were reviewed. BMI(score) [body mass index (BMI)/95th percentile BMI for age, sex, and race] was used to express the degree of obesity. The severity of systolic hypertension and diastolic hypertension were expressed as SBP(score) (systolic BP/the 95th percentile systolic BP for age, sex, and height) and DBP(score) (diastolic BP/the 95th percentile diastolic BP for age, sex, and height), respectively. OSAS was defined as more than one episodes of apnea per hour (AI) or an O(2) saturation associated with obstructive apnea of less than 90%. There were 56 obese patients; 42 were hypertensive and 40 patients were diagnosed with OSAS. The incidence of hypertension (68% vs. 30%) and obesity (75% vs. 52%) was higher in OSAS patients than those without OSAS. Compared with the non-obese patients, obese patients had a higher incidence of hypertension or OSAS, a higher BMI(score), SBP(score), DBP(score), AI, hypopnea index (HI), and apnea-hypopnea index (AHI). In obese patients, both SBP(score) and DBP(score) correlated positively with BMI(score), arousal index, and HI. DBP(score) also correlated positively with AHI. Multiple regression analysis showed that HI and BMI(score) were significant independent predictors of SBP(score) or DBP(score). Obese and hypertensive patients had a higher HI, AHI, and incidence of OSAS (64% vs. 29%) than the obese and normotensive patients. In conclusion, HI had a significant correlation with the degree of hypertension in obese patients, which could not be attributed to the degree of obesity. These findings are consistent with the hypothesis that OSAS is one of the reasons why some obese children are hypertensive and some are not.

Rapid changes in serum sodium concentration can result in adverse neurological outcome. The gradual correction of hypernatremia in the setting of acute renal failure can be difficult to achieve. We describe an obese female teenager who presented with severe hypernatremia, hyperosmolar hyperglycemic nonketotic coma, acute renal failure, and rhabdomyolysis. Her hypernatremia and other serum chemistries were gradually corrected by repeatedly adjusting the dialysate electrolyte composition used during continuous venovenous hemodiafiltration. She had a full recovery of her renal function. She does not have clinical neurological sequelae from hypernatremia during a 1-year follow-up period.