Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche Scientifique (UMRS) 970, Paris-Centre de Recherche Cardiovasculaire (PARCC), Paris, France.
Nat Genet. 2012 Mar 11;44(4):456-60, S1-3. doi: 10.1038/ng.2218.
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.
家族性高血钾型高血压（FHHt）是一种常染色体显性遗传性高血压，部分由 WNK1 和 WNK4 突变引起，导致远曲小管中 Na(+)-Cl(-)共转运蛋白（NCC）活性增加。通过对两个家族进行联合连锁分析和全外显子组测序，我们发现 KLHL3 是第三个导致 FHHt 的基因。对 43 名其他受影响个体的直接测序显示，存在 11 个额外的错义突变，这些突变与异质性表型和多种遗传方式相关。KLHL3 多态性与血压无关。KLHL3 蛋白属于肌动蛋白结合蛋白的 BTB-BACK-kelch 家族，可募集 Cullin3 基泛素连接酶复合物的底物。KLHL3 与 NCC 共表达，并在细胞表面下调 NCC 的表达。我们的研究确立了 KLHL3 作为调节远曲小管离子稳态的复杂信号通路的新成员，间接调节血压。
