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The classic way to describe a disease is to begin with nomenclature, definitions, and classifications. A fortunate coincidence gives us the opportunity today to start from the very early stages of pathophysiologic processes, a gene mutation. In fact, in a recently published paper1 the gene involved in familial primary pulmonary hypertension (PPH) has been described and the finding has been confirmed by a second independent group.2
Familial PPH has an incidence of at least 6% among all cases of PPH; it is an autosomal dominant disorder with reduced penetrance and genetic anticipation, and has been mapped to a locus designatedPPH1 on chromosome 2q33. The mutations interest the gene BMPR2, encoding a transforming growth factor β (TGF-β) type II receptor (BMPR-II) that is located in the cell membrane.3 TGF-β is representative of a large family of small polypeptides that have many different effects on growth and development. In fact, depending on the cell type, the TGF-β pathway influences many different processes such as growth, mobility, angiogenesis, immunosuppression, and apoptosis. Interestingly, mutations in the BMPR-II gene have also been found in more than 20% of human colorectal cancers. A link between PPH and tumorigenesis has been suspected in the past,4 based on exuberant proliferative vascular changes of pulmonary arteries and on monoclonal endothelial cell proliferation of plexiform lesions.5 BMPR2 germline mutations have been detected in 55% of cases of familial PPH and also in 26% of sporadic cases of PPH, raising the possibility that familial cases are more frequent than expected.6 Until now 46 different mutations of BMPR2 have been identified in PPH patients, and most of them produce a loss of function for the BMPR-II receptor.7 Thus, haploinsufficiency seems to be the molecular mechanism that initiates PPH. On the other hand, the high …