Journal Article

De novo missense variants in PPP1CB are associated with intellectual disability and congenital heart disease

Retterer, Kyle, Powis, Zöe, Weinstein, Veronique, Bodurtha, Joann, Ma, Lijiang, Jhangiani, Shalani N., McLaughlin, Heather M., Bupp, Caleb P., Gulec, Elif Yilmaz, Krokosky, Alyson, Turner, Clesson E., Schnur, Rhonda E., Bale, Sherri, Chung, Wendy K., Lalani, Seema R., Lupski, James R., Wentzensen, Ingrid M., Mayberry, Katey, Bayram, Yavuz, Shao, Yunru, Mu, Weiyi, Scott, Daryl A., Lindstrom, Kristin, Cho, Megan T., Alcaraz, Wendy, Zadeh, Neda, Lewis, Andrea M., White, Janson J.

2016

Overview

Intellectual disabilities are genetically heterogeneous and can be associated with congenital anomalies. Using whole-exome sequencing (WES), we identified five different de novo missense variants in the protein phosphatase-1 catalytic subunit beta ( PPP1CB ) gene in eight unrelated individuals who share an overlapping phenotype of dysmorphic features, macrocephaly, developmental delay or intellectual disability (ID), congenital heart disease, short stature, and skeletal and connective tissue abnormalities. Protein phosphatase-1 (PP1) is a serine/threonine-specific protein phosphatase involved in the dephosphorylation of a variety of proteins. The PPP1CB gene encodes a PP1 subunit that regulates the level of protein phosphorylation. All five altered amino acids we observed are highly conserved among the PP1 subunit family, and all are predicted to disrupt PP1 subunit binding and impair dephosphorylation. Our data suggest that our heterozygous de novo PPP1CB pathogenic variants are associated with syndromic intellectual disability.

• Publisher: Springer Berlin Heidelberg,Springer,Springer Nature B.V
• Subject: Adolescent / Adult / Amino acids / Biomedical and Life Sciences / Biomedicine / Cardiovascular disease / Child / Child, Preschool / Congenital diseases / Congenital heart defects / Connective tissue / Exome - genetics / Female / Gene Function / Genetic Association Studies / Genetic disorders / Genetic Predisposition to Disease / Genetics / Heart / Heart Defects, Congenital - genetics / Heart Defects, Congenital - physiopathology / Hospitals / Human Genetics / Humans / Intellectual disabilities / Intellectual Disability - genetics / Intellectual Disability - physiopathology / Kinases / Male / Medical schools / Medicine / Metabolic Diseases / Metabolism / Molecular Medicine / Mutation, Missense / Original Investigation / Pediatrics / Phosphatase / Phosphatases / Phosphorylation / Phosphorylation - genetics / Protein Phosphatase 1 - genetics / Proteins