A novel BMPR2 gene mutation associated with exercise-induced pulmonary hypertension in septal defects.

OBJECTIVE: Our study aimed to investigate the relationship between exercise-induced pulmonary arterial hypertension and genetic changes related to the transforming growth factor-β (TGF-β) signalling pathway in patients with cardiac septal defects.

DESIGN: In a population-based group of 44 patients (age 13-25 years) with either isolated ventricular septal defect (n=27) or isolated atrial septal defect (n=17), right ventricular systolic pressure response to submaximal exercise was studied by echocardiography and classified as normal (≤45 mmHg), borderline (45-50 mmHg) or abnormal (>50 mmHg). Three genes related to TGF-β, bone morphogenetic protein receptor type 2 (BMPR2), activin receptor-like kinase 1 (ALK1) and endoglin (ENG), were analyzed by DNA sequencing (only BMPR2) and multiplex ligand-dependent probe amplification (BMPR2, ALK1 and ENG).

RESULTS: Pressure response was borderline in five and abnormal in nine patients. Five patients showed mutations in exon 12 of the bone morphogenetic protein receptor type 2 gene. The previously described polymorphism S775N (c. 2324, G > A) was found in three patients with normal pressure response. The mutation Y589C (c. 1766, A > G), which has not been described previously, was found in two of 14 patients with borderline/abnormal pressure response.

CONCLUSION: Genetic changes in the BMPR2 gene may be overrepresented in patients with cardiac septal defects and exercise-induced pulmonary hypertension.