Channelopathy Genes in Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. The underlying pathogenetic mechanisms are heterogeneous and current therapies aim to decrease pulmonary vascular resistance but no curative treatments are available. Causal genetic variants can be identified in ~13% of adults and 43% of children with PAH. Knowledge of genetic diagnoses can inform clinical management of PAH, including multimodal medical treatment, surgical intervention and transplantation decisions, and screening for associated conditions, as well as risk stratification for family members. Roles for rare variants in three channelopathy genes-ABCC8, ATP13A3, and KCNK3-have been validated in multiple PAH cohorts, and in aggregate explain ~2.7% of PAH cases. Complete or partial loss of function has been demonstrated for PAH-associated variants in ABCC8 and KCNK3. Channels can be excellent targets for drugs, and knowledge of mechanisms for channel mutations may provide an opportunity for the development of PAH biomarkers and novel therapeutics for patients with hereditary PAH but also potentially more broadly for all patients with PAH.

Keywords: channelopathy; genetics; lung disease; pulmonary arterial hypertension.

Figure 1

ABCC8 two-dimensional protein schematic. Variants identified in adult-onset PAH cases are shown above the protein schematic; variants identified in children are shown below. Variant type is color-coded. The number of PAH carriers identified with a particular variant is shown along the y-axis. Note that splice variants are not included and variant density may impede visualization of closely-located variants. Conserved protein domains are indicated by colored rectangles. ABC_membrane, ABC transporter transmembrane region; ABC_tran, ABC transporter. Map generated using MutationMapper at cBioPortal.org, accessed on 2 January 2022.

Figure 2

ATP13A3 two-dimensional protein schematic. Variants identified in adult-onset PAH cases are shown above the protein schematic; variants identified in children are shown below. Variant type is color-coded. The number of PAH carriers identified with a particular variant is shown along the y-axis. Conserved protein domains are indicated by colored rectangles. E1-E2_ATPase, cation transporter ATPase; HAD, haloacid dehalogenase-like hydrolase. Map generated using MutationMapper at cBioPortal.org, accessed on 2 January 2022.

Figure 3

KCNK3 two-dimensional protein schematic. Variants identified in adult-onset PAH cases are shown above the protein schematic; variants identified in children are shown below. All variants are missense. The number of PAH carriers identified with a particular variant is shown along the y-axis. Conserved protein domains are indicated by colored rectangles. Ion_trans_2, ion channel. Map generated using MutationMapper at cBioPortal.org, accessed on 2 January 2022.