Genetics of pulmonary arterial hypertension

Abstract

Tremendous progress has been made in understanding the genetics of hereditable pulmonary arterial hypertension (HPAH) since its description in the 1950s. Germline mutations in the gene coding bone morphogenetic receptor type 2 ( BMPR2) are detectable in the majority of cases of HPAH, and in a small proportion of cases of idiopathic pulmonary arterial hypertension (IPAH). HPAH is an autosomal dominant disease characterized by reduced penetrance, variable expressivity, female predominance, and genetic anticipation. These characteristics suggest that endogenous and exogenous factors modify disease expression and areas of emphasis for future investigation. The variable clinical expression makes genetic counseling complex because the majority of carriers of a BMPR2 mutation will not be diagnosed with the disease. This issue will become increasingly important, as clinical testing for BMPR2 mutations is now available for the evaluation of patients and family members with HPAH and IPAH.

Figure 1

Pedigree of an extended kindred with heritable pulmonary arterial hypertension (HPAH) due to a BMPR2 mutation with reduced penetrance. This pedigree contains 16 total patients (11 females, 5 males) with HPAH, as well as 10 known heterozygotes (obligate carriers). Solid symbols represent individuals with disease. Circles represent women, squares represent men. Line through symbol represents death. Dot inside symbol represents obligate carrier of the BMPR2 mutation. Numbers below symbols represent age at death or current living age. Numbers inside symbols represent numbers of unaffected siblings of each gender. S inside symbol represents stillbirth. Diamond symbol represents sex unknown.

Figure 2

Age at diagnosis and death from pulmonary arterial hypertension in a French series of BMPR2 mutation carriers and noncarriers. Age at diagnosis (P < 0.001) and age at death (p = 0.003) are lower in BMPR2 mutation carriers, as compared with noncarriers. Adapted from Sztrymf et al. Reproduced with permission of American Journal of Respiratory and Critical Care Medicine.

Figure 3

Wild-type BMPR2 transcript levels, as measured by relative real-time polymerase chain reaction (PCR) analysis, in affected and unaffected BMPR2 mutation carriers. This study includes four distinct families with four different types of BMPR2 mutations predicted to have a haploinsufficient effect due to the activation of the nonsense-mediated decay pathway. Note the lower relative BMPR2 expression among affected carriers, as compared with unaffected carriers. Adapted from Hamid et al. Reproduced with permission of John Wiley & Sons, Inc.

Figure 4

A delicate balance between BMPR2 pathway and TGFβ pathway signaling modulates proproliferative and apop-totic forces. A BMPR2 mutation may perturb this balance, resulting in disease expression.