Germline and Mosaic Variants in PRKACA and PRKACB Cause a Multiple Congenital Malformation Syndrome
Palencia-Campos, A and Aoto, PC and Machal, EMF and Rivera-Barahona, A and Soto-Bielicka, P and Bertinetti, D and Baker, B and Vu, L and Piceci-Sparascio, F and Torrente, I and Boudin, E and Peeters, S and Van Hul, W and Huber, C and Bonneau, D and Hildebrand, MS and Coleman, M and Bahlo, M and Bennett, MF and Schneider, AL and Scheffer, IE and Kibaek, M and Kristiansen, BS and Issa, MY and Mehrez, MI and Ismail, S and Tenorio, J and Li, G and Skalhegg, BS and Otaify, GA and Temtamy, S and Aglan, M and Jonch, AE and De Luca, A and Mortier, G and Cormier-Daire, V and Ziegler, A and Wallis, M and Lapunzina, P and Herberg, FW and Taylor, SS and Ruiz-Perez, VL, Germline and Mosaic Variants in PRKACA and PRKACB Cause a Multiple Congenital Malformation Syndrome, American Journal of Human Genetics, 107, (5) pp. 977-988. ISSN 0002-9297 (2020) [Refereed Article]
PRKACA and PRKACB code for two catalytic subunits (Cα and Cβ) of cAMP-dependent protein kinase (PKA), a pleiotropic holoenzyme that regulates numerous fundamental biological processes such as metabolism, development, memory, and immune response. We report seven unrelated individuals presenting with a multiple congenital malformation syndrome in whom we identified heterozygous germline or mosaic missense variants in PRKACA or PRKACB. Three affected individuals were found with the same PRKACA variant, and the other four had different PRKACB mutations. In most cases, the mutations arose de novo, and two individuals had offspring with the same condition. Nearly all affected individuals and their affected offspring shared an atrioventricular septal defect or a common atrium along with postaxial polydactyly. Additional features included skeletal abnormalities and ectodermal defects of variable severity in five individuals, cognitive deficit in two individuals, and various unusual tumors in one individual. We investigated the structural and functional consequences of the variants identified in PRKACA and PRKACB through the use of several computational and experimental approaches, and we found that they lead to PKA holoenzymes which are more sensitive to activation by cAMP than are the wild-type proteins. Furthermore, expression of PRKACA or PRKACB variants detected in the affected individuals inhibited hedgehog signaling in NIH 3T3 fibroblasts, thereby providing an underlying mechanism for the developmental defects observed in these cases. Our findings highlight the importance of both Cα and Cβ subunits of PKA during human development.