RESUMO
Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin 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 in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis.
Assuntos
Proteínas de Transporte/genética , Proteínas Culina/genética , Hipertensão/genética , Mutação/genética , Pseudo-Hipoaldosteronismo/genética , Desequilíbrio Hidroeletrolítico/genética , Proteínas Adaptadoras de Transdução de Sinal , Sequência de Aminoácidos , Animais , Sequência de Bases , Pressão Sanguínea/genética , Proteínas de Transporte/química , Estudos de Coortes , Proteínas Culina/química , Eletrólitos , Éxons/genética , Feminino , Perfilação da Expressão Gênica , Genes Dominantes/genética , Genes Recessivos/genética , Genótipo , Homeostase/genética , Humanos , Concentração de Íons de Hidrogênio , Hipertensão/complicações , Hipertensão/fisiopatologia , Masculino , Camundongos , Proteínas dos Microfilamentos , Modelos Moleculares , Dados de Sequência Molecular , Fenótipo , Potássio/metabolismo , Pseudo-Hipoaldosteronismo/complicações , Pseudo-Hipoaldosteronismo/fisiopatologia , Cloreto de Sódio/metabolismo , Desequilíbrio Hidroeletrolítico/complicações , Desequilíbrio Hidroeletrolítico/fisiopatologiaRESUMO
The case of a 14 year old boy with subarachnoid hemorrhage and atresia of the aorta without patent ductus arteriosus or intracardiac shunt is described. This case calls attention to the possibility of aortic obstruction in adolescents or young adults with hypertensive stroke. The clinical symptoms, radiographic findings, and surgical repair of isolated aortic interruption, including atresia, are discussed.
Assuntos
Coartação Aórtica/diagnóstico , Adolescente , Aorta Torácica/anormalidades , Aorta Torácica/cirurgia , Coartação Aórtica/complicações , Coartação Aórtica/cirurgia , Angiografia Cerebral , Diagnóstico Diferencial , Humanos , Hipertensão/etiologia , Masculino , Acidente Vascular Cerebral/etiologia , Hemorragia Subaracnóidea/etiologia , VentriculostomiaRESUMO
A 3-month-old infant presented to the pediatric emergency department with respiratory distress and tetany after ingestion of a phosphate-containing oral laxative. The initial phosphorus level was 38.3 mg/dL. With aggressive fluid resuscitation and intravenous calcium administration, the infant completely recovered. Although the risks of phosphate-containing enemas are well described, life-threatening hyperphosphatemia can also result from administration of phosphate-containing oral laxatives. Aggressive fluid hydration is the mainstay of treatment. Intravenous calcium administration may be necessary to avoid hemodynamic collapse despite the theoretical possibility of metastatic calcifications. Physicians should be alerted to the possibility of phosphate toxicity and hypocalcemic tetany in young children when treated with over-the-counter laxatives. Caregivers should be advised not to administer over-the-counter laxatives to infants without physician supervision.