Rare mutations in renal sodium and potassium transporter genes exhibit impaired transport function

Abstract

Purpose of review: Recent efforts to explore the genetic underpinnings of hypertension revealed rare mutations in kidney salt transport genes contribute to blood pressure (BP) variation and hypertension susceptibility in the general population. The current review focuses on these latest findings, highlighting a discussion about the rare mutations and how they affect the transport function.

Recent findings: Rare mutations that confer a low BP trait and resistance to hypertension have recently been extensively studied. Physiological and biochemical analyses of the affected renal salt transport molecules [NKCC2 (SLC12A1), ROMK (KCNJ1), and NCC (SLC12A3)] revealed that most of the mutations do, in fact, cause a loss of transport function. The mutations disrupt the transport by many different mechanisms, including altering biosynthetic processing, trafficking, ion transport, and regulation.

Summary: New insights into the genetic basis of hypertension have recently emerged, supporting a major role of rare, rather than common, gene variants. Many different rare mutations have been found to affect the functions of different salt transporter genes by different mechanisms, yet all confer the same BP phenotype. These studies reinforce the critical roles of the kidney, and renal salt transport in BP regulation and hypertension.

Figure 1

Rare Hypertension Resistance Variants were identified in NKCC2 and ROMK, which are essential for salt reabsorption in the thick ascending limb, and NCC, the thiazide sensitive transporter that is responsible for salt reabsorption in the distal convoluted tubule. Homozygous mutations in NKCC2 and ROMK cause Bartter's syndrome. Homozygous mutations in NCC cause Gitelman's syndrome. Carriers of these mutations are protected from hypertension.

Figure 2

Atomic Resolution model of ROMK. Two of four subunits are shown for clarity. HR Variants are located in the cytoplasmic domain. Inset on right shows HR variants that affect PIP2-dependent gating reside in the PIP2 binding site.

Figure 3

Location of HR Variants in NKCC2 (A) and NCC (B).