Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. A rare Mendelian syndrome, pseudohypoaldosteronism type II (PHAII), featuring hypertension, hyperkalemia, and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption versus K+ and H+ excretion1. We used exome sequencing to identify mutations in Kelch-like 3 (KLHL3) or Cullin 3 (CUL3) in 41 PHAII kindreds. KLHL3 mutations are either recessive or dominant, while CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-Kelch proteins such as KLHL3 are components of Cullin/RING E3 ligase complexes (CRLs) that ubiquitinate substrates bound to Kelch propeller domains2–8. Dominant KLHL3 mutations are clustered in short segments within the Kelch propeller and BTB domains implicated in substrate9 and Cullin5 binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter (NCC) in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3/CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite combined complexities of locus heterogeneity, mixed models of transmission, and frequent de novo mutation, and establish a fundamental role for KLHL3/CUL3 in blood pressure, K+, and pH homeostasis.

Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5%) shared the identical, previously unidentified, heterozygous CACNA1HM1549V mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (CaV3.2) expressed in adrenal glomerulosa. CACNA1HM1549V showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca2+, the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension.DOI: http://dx.doi.org/10.7554/eLife.06315.001

Background and objectives: Low birth weight (LBW), resulting from intrauterine growth retardation (IUGR) or prematurity, is a risk factor for adult hypertension and chronic kidney disease. LBW is associated with reduced nephron endowment and increased glomerular volume; however, the development of secondary focal segmental glomerulosclerosis (FSGS) has not been reported previously.Design T he index case is a 15-yr-old Caucasian male who was found to have mild proteinuria during routine urinary screening. His birth was complicated by prematurity (23 wk gestational age) and a very low birth weight (1.40 kg). He had had numerous perinatal problems associated with prematurity including respiratory complications, intracranial hemorrhage, necrotizing enterocolitis, bowel obstruction, sepsis, and retinopathy of prematurity. There was no history of hematuria, urinary reflux, renal insufficiency, recent fevers, hearing loss, or familial renal disease. He was taking no medications. The patient was followed for several weeks and was found to have persistent, mild proteinuria not associated with exercise or posture (nonorthostatic).Physical examination revealed a height of 172 cm and a weight of 75 kg (body mass index ϭ 25.4 kg/m 2 ), BP of 127/79 mmHg (90th percentile), and no edema. Renal ultrasound revealed normal-appearing kidneys measuring 10.5 cm and 9.6 cm in length. Laboratory examination showed a hematocrit of 50% (normal ϭ 37% to 45%), white blood cell count 7.8 ϫ 10 9 /L (normal ϭ 4.5 to 13.5 ϫ 10 9 /L) with normal differential, platelet count 221 ϫ 10 9 /L (normal 150 to 450 ϫ 10 9 /L), blood urea nitrogen 15 mg/dl (5.8 mmol/L) (normal ϭ 7 to 18 mg/dl [2.5 to 6.4 mmol/L]), creatinine clearance 100 cc/min, serum creatinine 0.9 mg/dl (75.6 mol/L), total serum protein 7.3 g/dl (73 g/L) (normal 6 to 8.2 g/dl [60 to 82 g/L]), and serum albumin 4.4 g/dl (44 g/L) (normal 3.4 to 5.0 g/dl [34 to 50 g/L]). Serum electrolytes, including sodium, potassium, bicarbonate, chloride, and calcium, were normal. The following serologies were negative: anti-nuclear antibody, anti-double-stranded DNA antibody, hepatitis B surface antigen, and hepatitis C antibody. Serum complement levels, including C3 and C4, were within normal range. Urinalysis revealed a specific gravity of 1.030, pH 5, and protein Ͼ 300 mg/dl, with negative glucose, heme and leukocyte esterase. The 24-h urinary protein was 1.34 g. Microscopic examination of the urine revealed zero to five white blood cells per high-power field, no red blood cells, and no hyaline or granular casts. A renal biopsy was performed to determine the cause of persistent subnephrotic proteinuria.Light microscopic examination showed one core of tissue consisting of renal cortex and a small portion of outer medulla. There were 8 glomeruli, none of which were globally sclerotic. The glomeruli appeared hypertrophied but normocellular, with patent capillaries and glomerular basement membranes of normal thickness. No immune-type fuchsinophilic deposits were identified with the trichrome stain. T...