Pulmonary Hypertension, Primary, 2

A number sign (#) is used with this entry because of evidence that primary pulmonary hypertension-2 (PPH2) is caused by heterozygous mutation in the SMAD9 gene (603295) on chromosome 13q13.

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

Shintani et al. (2009) reported a boy who was diagnosed with pulmonary hypertension at age 8 years. Two sibs of the proband had died of pulmonary disease at ages 13 years and less than 2 years.

In a patient with primary pulmonary hypertension-2, Shintani et al. (2009) identified a heterozygous truncating mutation in the SMAD9 gene (603295.0001). In vitro functional expression assays showed that the mutant SMAD9 protein could not be phosphorylated, did not interact with SMAD4 (600993), and was inefficient in activating the BMP responsive promoter-reporter, resulting in downregulation of downstream TGFB/BMP signaling. Family history revealed that the unaffected father also carried the mutation, indicating reduced penetrance.

In a 7-year-old Japanese girl with PPH2, Nasim et al. (2011) identified a heterozygous missense mutation in the SMAD9 gene (K43E; 603295.0002). The patient underwent lung transplantation.

In a woman with PPH2, Drake et al. (2011) identified a heterozygous truncating mutation in the SMAD9 gene (R294X; 603295.0003). No additional clinical features were reported. Pulmonary artery endothelial cells derived from this patient showed no significant induction of miR21 (611020) when treated with BMP9 (605120). Mutant cells showed increased proliferation compared to controls, and overexpression of miR21 induced growth suppression. Overexpression of SMAD9 in SMAD9-mutant cells normalized the proliferation rate and normalized miR levels. Canonical BMP signaling remained relatively intact in SMAD9-mutant cells, with less than a 50% reduction in fold-change of downstream target genes. The findings suggested that aberrant miR processing may play an important role in the pathogenesis of PPH.

Huang et al. (2009) found that loss of Smad8 function in adult mice resulted in characteristic changes in distal pulmonary arteries including medial thickening and smooth muscle hyperplasia as observed in patients with PPH. Smad8-mutant pulmonary vasculature had upregulated activin (see 147290)/Tgf-beta (190180) signaling and pathologic remodeling with aberrant Prx1 (PRRX1; 167420) and tenascin C (TNC; 187380) expression. A subset of Smad8 mutants had pulmonary adenomas, possibly uncovering a function for Smad8 in normal growth control. Huang et al. (2009) hypothesized that Smad8 may play a role in both pulmonary hypertension and lung tumorigenesis.