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De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome.

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Date
2017-04
ICR Author
Lord, Christopher
Author
Jansen, S
Geuer, S
Pfundt, R
Brough, R
Ghongane, P
Herkert, JC
Marco, EJ
Willemsen, MH
Kleefstra, T
Hannibal, M
Shieh, JT
Lynch, SA
Flinter, F
FitzPatrick, DR
Gardham, A
Bernhard, B
Ragge, N
Newbury-Ecob, R
Bernier, R
Kvarnung, M
Magnusson, EAH
Wessels, MW
van Slegtenhorst, MA
Monaghan, KG
de Vries, P
Veltman, JA
Deciphering Developmental Disorders Study
Lord, CJ
Vissers, LELM
de Vries, BBA
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Type
Journal Article
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Abstract
Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in ∼35%-40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis. We identified 14 individuals with mild to severe ID and/or developmental delay and de novo truncating PPM1D mutations. Additionally, deep phenotyping revealed overlapping behavioral problems (ASD, ADHD, and anxiety disorders), hypotonia, broad-based gait, facial dysmorphisms, and periods of fever and vomiting. PPM1D is expressed during fetal brain development and in the adult brain. All mutations were located in the last or penultimate exon, suggesting escape from nonsense-mediated mRNA decay. Both PPM1D expression analysis and cDNA sequencing in EBV LCLs of individuals support the presence of a stable truncated transcript, consistent with this hypothesis. Exposure of cells derived from individuals with PPM1D truncating mutations to ionizing radiation resulted in normal p53 activation, suggesting that p53 signaling is unaffected. However, a cell-growth disadvantage was observed, suggesting a possible effect on the stress-response pathway. Thus, we show that de novo truncating PPM1D mutations in the last and penultimate exons cause syndromic ID, which provides additional insight into the role of cell-cycle checkpoint genes in neurodevelopmental disorders.
URI
https://repository.icr.ac.uk/handle/internal/627
DOI
https://doi.org/10.1016/j.ajhg.2017.02.005
Collections
  • Breast Cancer Research
  • Molecular Pathology
Subject
Deciphering Developmental Disorders Study
Humans
Cell Cycle
Mutation
Exons
Adolescent
Child
Child, Preschool
Young Adult
Intellectual Disability
Protein Phosphatase 2C
Research team
Gene Function
Language
eng
Date accepted
2017-02-03
License start date
2017-04
Citation
American journal of human genetics, 2017, 100 (4), pp. 650 - 658

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