case_images: PMC10782117_01
case_images: Molecular details of BMPR2 mutation and pedigree chart. Panel (a) Electropherogram of the normal wild type (above) and the c.346T>C mutation in the BMPR2 gene (below) resulting in the substitution of cysteine by arginine at the position 116. Panel (b) Details of the pathogenic BMPR2 variant (rs1574464160) identified in the patient. Panel (c) Pedigree chart of the family. Panel (d) Structure of the extracellular domain of the BMPR2 wild type (PDB ID: 2HLQ; pink cartoon); mutated (cyan cartoon); and the superimposed image of wild type and mutated gene in order from left to right. Changes in the secondary structural elements are indicated by black arrows. Panel (e) MEP surface map of mutated BMPR2 gene (left) and wild type gene (right) showing change in electrostatic potential from negative to positive, marked by black boxes. Arg, arginine; BMPR2, bone morphogenetic protein receptor 2; CADD score, combined annotation dependent depletion score; Cys, cysteine; GnomAD, genome aggregation consortium used ensemble transcript and reference sequence for the BMPR2 gene: ENST00000374580.8, NM_001204; MEP, molecular electrostatic potential; REVEL, rare exome variant ensemble learner.
case_images: PUL2-14-e12335-g001.jpg
case_images: PMC10782117_01_PUL2-14-e12335-g001.jpg
case_images: pul212335-fig-0001
case_images: The mother and elder sister had deceased from severe progressive idiopathic PAH (IPAH) before genetic study was available (Figure 1, panel c). The mutation is a heterozygous missense mutation c.346T>C (thymine replaced by cytosine) in the exon 3 of the BMPR2 gene which encodes for the ligand binding domain (Figure 1, panel a). The pathologic significance of the mutation was confirmed by detailed analysis (Figure 1, panel b) along with the presence of highly conserved cysteine at position 116 across multiple species including humans. The changes in the secondary structural elements of the mutant were decrease in the beta sheets (beta-3, beta-4, and beta-6) and the loop conformation of beta-4 sheet when compared to wild type (Figure 1, panel d). In addition, the molecular electrostatic potential surface mapping showed a change in charge distribution from negative (cysteine) to positive (arginine) on the mutated structure (Figure 1, panel e).