Germline and Mosaic Variants in PRKACA and PRKACB Cause a Multiple Congenital Malformation Syndrome

• Published in: American journal of human genetics Vol. 107; no. 5; pp. 977 - 988
• Main Authors: Palencia-Campos, Adrian, Aoto, Phillip C., Machal, Erik M.F., Rivera-Barahona, Ana, Soto-Bielicka, Patricia, Bertinetti, Daniela, Baker, Blaine, Vu, Lily, Piceci-Sparascio, Francesca, Torrente, Isabella, Boudin, Eveline, Peeters, Silke, Van Hul, Wim, Huber, Celine, Bonneau, Dominique, Hildebrand, Michael S., Coleman, Matthew, Bahlo, Melanie, Bennett, Mark F., Schneider, Amy L., Scheffer, Ingrid E., Kibæk, Maria, Kristiansen, Britta S., Issa, Mahmoud Y., Mehrez, Mennat I., Ismail, Samira, Tenorio, Jair, Li, Gaoyang, Skålhegg, Bjørn Steen, Otaify, Ghada A., Temtamy, Samia, Aglan, Mona, Jønch, Aia E., De Luca, Alessandro, Mortier, Geert, Cormier-Daire, Valérie, Ziegler, Alban, Wallis, Mathew, Lapunzina, Pablo, Herberg, Friedrich W., Taylor, Susan S., Ruiz-Perez, Victor L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05-11-2020; Elsevier
• Subjects: Abnormalities, Multiple - diagnosis; Abnormalities, Multiple - genetics; Abnormalities, Multiple - pathology; Adolescent; Adult; Animals; Base Sequence; cAMP signaling; Cognitive Dysfunction - diagnosis; Cognitive Dysfunction - genetics; Cognitive Dysfunction - pathology; congenital heart defects; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits - chemistry; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits - deficiency; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits - genetics; Ellis-van Creveld syndrome; Female; Fingers - abnormalities; Fingers - pathology; Gene Expression Regulation, Developmental; Germ-Line Mutation; GLI transcritpion factors; Heart Septal Defects - diagnosis; Heart Septal Defects - genetics; Heart Septal Defects - pathology; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; hedgehog signaling; Holoenzymes - chemistry; Holoenzymes - deficiency; Holoenzymes - genetics; Humans; Infant, Newborn; Male; Mice; Models, Molecular; Mosaicism; NIH 3T3 Cells; Pedigree; PKA; Polydactyly - diagnosis; Polydactyly - genetics; Polydactyly - pathology; postaxial polydactyly; PRKACA; PRKACB; Protein Structure, Secondary; Toes - abnormalities; Toes - pathology; GLI transcritpion factors; cAMP signaling; Ellis-van Creveld syndrome; PKA; postaxial polydactyly; mosaicism; PRKACA; PRKACB; hedgehog signaling; congenital heart defects
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2020.09.005

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.