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.


METHODS
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.


CONCLUSIONS
Genetic changes in the BMPR2 gene may be overrepresented in patients with cardiac septal defects and exercise-induced pulmonary hypertension.
Pediatric Department, Vestfold Hospital Trust, Tønsberg, Norway. thomas.moller@siv.no
Thomas
T
Möller
Trond P
TP
Leren
Kristin L
KL
Eiklid
Henrik
H
Holmstrøm
Per Morten
PM
Fredriksen
Erik
E
Thaulow
D030301:Activin Receptors, Type II / Q000235:genetics; D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000235:genetics; D001483:Base Sequence / Q000235:genetics; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D000071063:Endoglin; D015444:Exercise; D005260:Female; D006344:Heart Septal Defects, Atrial / Q000000981:diagnostic imaging / Q000235:genetics*; D006345:Heart Septal Defects, Ventricular / Q000000981:diagnostic imaging / Q000209:etiology / Q000235:genetics*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000000981:diagnostic imaging / Q000209:etiology / Q000235:genetics*; D008297:Male; D009154:Mutation; D011956:Receptors, Cell Surface / Q000235:genetics; D018570:Risk Assessment; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics; D018608:Ultrasonography, Doppler; D016277:Ventricular Function, Left; D016278:Ventricular Function, Right; D055815:Young Adult
D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II