Identification of a novel mutation in the gene for bone morphogenetic protein receptor II in an Israeli patient with familial primary pulmonary hypertension.
BACKGROUND
Primary pulmonary hypertension is a rare disorder, characterized by progressive pulmonary hypertension and right heart failure. It may be familial or sporadic. Mutations in bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor-beta receptor superfamily of receptors, underlie many cases of the disorder.


OBJECTIVE
To perform molecular analysis of a patient with familial PPH and provide her and her family with suitable genetic counseling.


METHODS
DNA was extracted from 10 ml whole blood, and the BMPR2 gene was screened for mutations. Individual exons were amplified by polymerase chain reaction and sequenced. Mutation confirmation and molecular characterization of additional family members was performed using restriction enzyme analysis followed by appropriate genetic counseling.


RESULTS
We identified a novel T to C missense mutation expected to result in substitution of arginine for a conserved cysteine in the ligand-binding domain of BMPR2. Screening of family members demonstrated the presence of the mutation in the father and a younger asymptomatic sister of the index patient.


CONCLUSIONS
Molecular diagnosis in PPH allows for identification of at-risk family members and raises the option of earlier diagnosis and possibly instituting earlier treatment in affected individuals. However, molecular screening of asymptomatic family members raises difficult ethical questions that can only be resolved by conducting large multicenter prospective studies in BMPR2 carriers.
Cahn
Avivit
A
Department of Human Genetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Meiner
Vardiella
V
Leitersdorf
Eran
E
Berkman
Neville
N
D000328:Adult; D001483:Base Sequence; D052006:Bone Morphogenetic Protein Receptors, Type II; D004252:DNA Mutational Analysis; D005260:Female; D005817:Genetic Counseling; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis / Q000235:genetics*; D007557:Israel; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D016133:Polymerase Chain Reaction / Q000379:methods; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
D017346:Protein Serine-Threonine Kinases; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II