Pulmonary Hypertension, Primary, 4

A number sign (#) is used with this entry because primary pulmonary hypertension-4 (PPH4) is caused by heterozygous mutation in the KCNK3 gene (603220) on chromosome 2p23.

Description

Primary pulmonary hypertension is a rare progressive disease characterized by increased pulmonary artery pressure in the absence of common causes of pulmonary hypertension, such as chronic heart, lung, or thromboembolic disease. There is often vascular remodeling. The clinical presentation can be nonspecific, and patients often receive a diagnosis late in their clinical course (summary by Ma et al., 2013).

For a general phenotypic description and a discussion of genetic heterogeneity of primary pulmonary hypertension, see PPH1 (178600).

Clinical Features

Ma et al. (2013) reported 3 unrelated families with primary pulmonary hypertension. Subsequently, 3 patients with sporadic disease were identified. The age at diagnosis ranged from 8 to 44 years, and both males and females were affected. Some patients developed cardiac arrhythmias. No patients responded to acute vasodilator challenge. Three patients eventually required lung transplantation and 3 patients died in their forties. Lung tissue from 1 patient showed medial hypertrophy of the pulmonary arteries, fibrointimal proliferation, and progressive generalized arterial dilatation with formation of complex plexiform lesions.

Inheritance

The transmission pattern of PPH4 in the families reported by Ma et al. (2013) was consistent with autosomal dominant inheritance and incomplete penetrance.

Molecular Genetics

In affected members of 3 unrelated families with autosomal dominant primary pulmonary hypertension-4, Ma et al. (2013) identified 3 different heterozygous missense mutations in the KCNK3 gene (603220.0001-603220.0003). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Two of 9 mutation carriers did not have evidence of the disease, indicating incomplete penetrance. Three additional heterozygous KCNK3 mutations (see, e.g., 603220.0004-603220.0005) were subsequently found in 3 unrelated patients with sporadic PPH. Overall, KCNK3 mutations were found in 3 (1.3%) of 230 patients with idiopathic disease and in 3 (3.2%) of 93 probands with familial disease. In vitro functional expression studies showed that all of the mutant channels had loss of function at physiologic pH compared to wildtype. In addition, 3 mutants tested showed reduced current density when coexpressed with the wildtype channel, consistent with a loss of function. Application of a phospholipase A2 inhibitor was able to ameliorate the reduction in potassium-channel current caused by some, but not all, of the mutant proteins. Ma et al. (2013) suggested that the mutations caused depolarization of the resting membrane potential, which could lead to pulmonary artery vasoconstriction.