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. 2016 Dec;135(12):1399-1409.
doi: 10.1007/s00439-016-1731-1. Epub 2016 Sep 28.

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

Lijiang Ma  1 , Yavuz Bayram  2 , Heather M McLaughlin  3 , Megan T Cho  3 , Alyson Krokosky  4 , Clesson E Turner  4 , Kristin Lindstrom  5 , Caleb P Bupp  6 , Katey Mayberry  6 , Weiyi Mu  7 , Joann Bodurtha  7 , Veronique Weinstein  8 , Neda Zadeh  9 , Wendy Alcaraz  10 , Zöe Powis  10 , Yunru Shao  2 , Daryl A Scott  2   11 , Andrea M Lewis  2 , Janson J White  2 , Shalani N Jhangiani  2   12 , Elif Yilmaz Gulec  13 , Seema R Lalani  2 , James R Lupski  2   12   14   15 , Kyle Retterer  3 , Rhonda E Schnur  3 , Ingrid M Wentzensen  3 , Sherri Bale  3 , Wendy K Chung  16
Affiliations

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

Lijiang Ma et al. Hum Genet. 2016 Dec.

Abstract

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.

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Conflict of interest statement

Conflicts of Interest

The other authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Conservation of amino acids of PPP1CB and de novo variants identified in patients. A. Conservation of amino acid sequence of PPP1CB among human, dog, rat, pig, cow, mouse, chicken, xenopus, and zebrafish indicated. Variants identified in our patients are highlighted at amino acids 49, 183, 252 and 274.
Figure 1
Figure 1
Conservation of amino acids of PPP1CB and de novo variants identified in patients. A. Conservation of amino acid sequence of PPP1CB among human, dog, rat, pig, cow, mouse, chicken, xenopus, and zebrafish indicated. Variants identified in our patients are highlighted at amino acids 49, 183, 252 and 274.
Figure 2
Figure 2
Conservation of PPP1CB with isoforms of the catalytic subunit of PPP1C. Sequence alignment of PPP1CB with two other members of PPP1C-PPP1CA and PPP1CC show sequence conservation across the three proteins. Variants identified in this study are high-lighted in red.
Figure 3
Figure 3
PPP1CB protein modeling.
Figure 4
Figure 4
Facial features of individuals with the Pro49Arg (Patients 2 and 3) and Glu183Val PPP1CB (Patient 6) de novo variants.
See this image and copyright information in PMC

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