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 J

Lapunzina, Pablo

Herberg, Friedrich W

Taylor, Susan S

Ruiz-Perez, Victor L

2020-10-14

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.

American Journal of Human Genetics 2020; online first: 14 October

American Journal of Human Genetics

https://ahro.austin.org.au/austinjspui/handle/1/25159

Ellis-van Creveld syndrome

GLI transcritpion factors

PKA

PRKACA

PRKACB

cAMP signaling

congenital heart defects

hedgehog signaling

mosaicism

postaxial polydactyly

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

Journal Article