Genetics and mediators in pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is an uncommon disorder of the pulmonary vasculature characterized by remodeling of the smallest pulmonary arteries, leading to a progressive increase in pulmonary vascular resistance. Various forms of PAH exist, including familial (FPAH) and idiopathic (IPAH) forms and associated conditions. FPAH transmits as an autosomal dominant trait that exhibits genetic anticipation but also markedly reduced penetrance (20%). The primary genetic defect of FPAH, identifiable in more than 70% of cases of FPAH, is a mutation in the gene encoding bone morphogenetic protein receptor type 2 (BMPR2), a member of the transforming growth factor beta superfamily. The true prevalence of BMPR2 mutations in IPAH is unknown, with reports ranging from 10% to 40% of patients. The cause of the variable phenotypic expression of PAH among carriers of mutated BMPR2 genes and patients is unclear, and likely related to environmental and genetic modifiers of disease not yet fully elucidated. Although BMPR2-related pathways seem to be pivotal, many other mediator pathways participate in the pathogenesis of different forms of PAH and are being actively investigated, both independently and in combination. As understanding of the molecular basis of this devastating disease improves, opportunities for earlier diagnosis, additional therapeutic regimens, and perhaps disease prevention will emerge.

Fig. 1

Pedigree of an extended kindred with familial pulmonary arterial hypertension (FPAH). This pedigree now links six families that were previously labeled as independent, and 23 total patients who had FPAH. Solid symbols represent individuals who have 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.

Fig. 2

Distribution of mutations across the BMPR2 gene. (A) Line graph illustrating the distribution and frequency of recurrent mutations. The x-axis represents the position of mutations relative to the BMPR2 cDNA below, and the y-axis defines the number of unrelated probands observed to harbor each mutation. The contiguous black and dotted line identifies the two amino acid substitutions recurrent at position 491. (B) Proportional representation of the BMPR2 cDNA, with exons 1–13 indicated. The boxed regions delineate the extracellular (ECD), transmembrane (TM), kinase (KD), and cytoplasmic (CD) domains of the receptor depicted below. Large gene rearrangements (deletions and duplications) identified in PAH cases are arrayed below the cDNA. (C) Table summarizing the total number of PAH-causing mutations observed in each functional domain and nondomain encoding sequence. (From Machado RD, Aldred MA, James V, et al. Mutations of the TGF-β type II receptor BMPR2 in pulmonary arterial hypertension. Human Mutation 2006; 27(2):121–32; with permission).