RESUMO
Familial hyperkalemic hypertension (FHHt) is a Mendelian form of arterial hypertension that is partially explained by mutations in WNK1 and WNK4 that lead to increased activity of the Na(+)-Cl(-) cotransporter (NCC) in the distal nephron. Using combined linkage analysis and whole-exome sequencing in two families, we identified KLHL3 as a third gene responsible for FHHt. Direct sequencing of 43 other affected individuals revealed 11 additional missense mutations that were associated with heterogeneous phenotypes and diverse modes of inheritance. Polymorphisms at KLHL3 were not associated with blood pressure. The KLHL3 protein belongs to the BTB-BACK-kelch family of actin-binding proteins that recruit substrates for Cullin3-based ubiquitin ligase complexes. KLHL3 is coexpressed with NCC and downregulates NCC expression at the cell surface. Our study establishes a role for KLHL3 as a new member of the complex signaling pathway regulating ion homeostasis in the distal nephron and indirectly blood pressure.
Assuntos
Proteínas de Transporte/genética , Transporte de Íons/genética , Néfrons/metabolismo , Pseudo-Hipoaldosteronismo/genética , Simportadores de Cloreto de Sódio/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Sequência de Bases , Pressão Sanguínea/genética , Criança , Feminino , Humanos , Rim/metabolismo , Masculino , Proteínas dos Microfilamentos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Pseudo-Hipoaldosteronismo/metabolismo , Pseudo-Hipoaldosteronismo/fisiopatologia , Análise de Sequência de DNA , Transdução de Sinais , Simportadores de Cloreto de Sódio/genética , Adulto JovemRESUMO
PURPOSE: The purpose of this study was to describe the skeletal manifestations of primary hyperoxaluria type 1 (PH1), the most common of the primary hyperoxalurias. METHODS: We clinically and radiographically reviewed 12 consecutive patients diagnosed with PH1, aged between 2 and 17 years. All patients had evidence of some type of renal involvement, 4 of whom were at end-stage renal disease (ESRD) and were under dialysis. RESULTS: The main symptom was skeletal pain and was present only in the 4 severely involved patients and appeared during the second year of dialysis. The 2 most severely involved patients had evidence of pathological fractures. Radiological signs were present in patients with or without symptoms. These radiological signs were of two distinct types: those almost specific of oxalosis, such as dense and radiolucent metaphyseal bands and vertebral osteocondensations, which are found mainly in the severely involved individuals, and those less specific, such as signs of renal osteodystrophy, which are also found in less severely involved patients. Interestingly, our study revealed the presence of spondylolysis in 25% of cases. This latter finding is unique and has not previously been reported in the literature. CONCLUSIONS: The skeletal manifestations of PH1 include specific and less specific radiological signs, with some patients being asymptomatic, and others presenting with bone pain and pathological fractures, as well as spondylolysis.
RESUMO
Ureteric valves represent a very rare etiology of ureteral obstruction. We experienced an unusual case of bilateral distal ureteric valves that presented as bilateral primitive obstructed megaureters with anuria at the age of 40 days. To our knowledge, this is the second case of bilateral involvement of distal ureteric valves reported in the literature. Bilateral ureteral valves should be included in the differential diagnosis of bladder outlet obstruction, as well as bilateral primitive obstructed megaureters in children. Excision and ureteral reimplantation is curative.