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

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

doi:10.1007/s00439-016-1731-1

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

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1399-1409
Number of pages	11
Journal	Human genetics
Volume	135
Issue number	12
DOIs	https://doi.org/10.1007/s00439-016-1731-1
State	Published - Dec 1 2016

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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Ma, L., Bayram, Y., McLaughlin, H. M., Cho, M. T., Krokosky, A., Turner, C. E., Lindstrom, K., Bupp, C. P., Mayberry, K., Mu, W., Bodurtha, J., Weinstein, V., Zadeh, N., Alcaraz, W., Powis, Z., Shao, Y., Scott, D. A., Lewis, A. M., White, J. J., ... Chung, W. K. (2016). De novo missense variants in PPP1CB are associated with intellectual disability and congenital heart disease. Human genetics, 135(12), 1399-1409. https://doi.org/10.1007/s00439-016-1731-1

Ma, L, Bayram, Y, McLaughlin, HM, Cho, MT, Krokosky, A, Turner, CE, Lindstrom, K, Bupp, CP, Mayberry, K, Mu, W , Bodurtha, J, Weinstein, V, Zadeh, N, Alcaraz, W, Powis, Z, Shao, Y, Scott, DA, Lewis, AM, White, JJ, Jhangiani, SN, Gulec, EY, Lalani, SR, Lupski, JR, Retterer, K, Schnur, RE, Wentzensen, IM, Bale, S & Chung, WK 2016, 'De novo missense variants in PPP1CB are associated with intellectual disability and congenital heart disease', Human genetics, vol. 135, no. 12, pp. 1399-1409. https://doi.org/10.1007/s00439-016-1731-1

@article{f6c59119a17144c29c49fee4a8c4ec92,

title = "De novo missense variants in PPP1CB are associated with intellectual disability and congenital heart disease",

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.",

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

note = "Funding Information: We thank the patients and their families for their generous participation. This work was supported in part by a grant from the Simons Foundation and from the NIH (GM030518), NINDS (NS058529), and NHGRI/NHLBI (HG006542). Publisher Copyright: {\textcopyright} 2016, Springer-Verlag Berlin Heidelberg.",

year = "2016",

month = dec,

day = "1",

doi = "10.1007/s00439-016-1731-1",

language = "English (US)",

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T1 - De novo missense variants in PPP1CB are associated with intellectual disability and congenital heart disease

AU - Ma, Lijiang

AU - Bayram, Yavuz

AU - McLaughlin, Heather M.

AU - Cho, Megan T.

AU - Krokosky, Alyson

AU - Turner, Clesson E.

AU - Lindstrom, Kristin

AU - Bupp, Caleb P.

AU - Mayberry, Katey

AU - Mu, Weiyi

AU - Bodurtha, Joann

AU - Weinstein, Veronique

AU - Zadeh, Neda

AU - Alcaraz, Wendy

AU - Powis, Zöe

AU - Shao, Yunru

AU - Scott, Daryl A.

AU - Lewis, Andrea M.

AU - White, Janson J.

AU - Jhangiani, Shalani N.

AU - Gulec, Elif Yilmaz

AU - Lalani, Seema R.

AU - Lupski, James R.

AU - Retterer, Kyle

AU - Schnur, Rhonda E.

AU - Wentzensen, Ingrid M.

AU - Bale, Sherri

AU - Chung, Wendy K.

N1 - Funding Information: We thank the patients and their families for their generous participation. This work was supported in part by a grant from the Simons Foundation and from the NIH (GM030518), NINDS (NS058529), and NHGRI/NHLBI (HG006542). Publisher Copyright: © 2016, Springer-Verlag Berlin Heidelberg.

PY - 2016/12/1

Y1 - 2016/12/1

N2 - 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.

AB - 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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U2 - 10.1007/s00439-016-1731-1

DO - 10.1007/s00439-016-1731-1

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EP - 1409

JO - Human genetics

JF - Human genetics

IS - 12

ER -

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

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