Show simple item record

dc.contributor.authorJansen, S
dc.contributor.authorGeuer, S
dc.contributor.authorPfundt, R
dc.contributor.authorBrough, R
dc.contributor.authorGhongane, P
dc.contributor.authorHerkert, JC
dc.contributor.authorMarco, EJ
dc.contributor.authorWillemsen, MH
dc.contributor.authorKleefstra, T
dc.contributor.authorHannibal, M
dc.contributor.authorShieh, JT
dc.contributor.authorLynch, SA
dc.contributor.authorFlinter, F
dc.contributor.authorFitzPatrick, DR
dc.contributor.authorGardham, A
dc.contributor.authorBernhard, B
dc.contributor.authorRagge, N
dc.contributor.authorNewbury-Ecob, R
dc.contributor.authorBernier, R
dc.contributor.authorKvarnung, M
dc.contributor.authorMagnusson, EAH
dc.contributor.authorWessels, MW
dc.contributor.authorvan Slegtenhorst, MA
dc.contributor.authorMonaghan, KG
dc.contributor.authorde Vries, P
dc.contributor.authorVeltman, JA
dc.contributor.authorDeciphering Developmental Disorders Study
dc.contributor.authorLord, CJ
dc.contributor.authorVissers, LELM
dc.contributor.authorde Vries, BBA
dc.date.accessioned2017-05-03T13:50:57Z
dc.date.issued2017-04
dc.identifier.citationAmerican journal of human genetics, 2017, 100 (4), pp. 650 - 658
dc.identifier.issn0002-9297
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/627
dc.identifier.eissn1537-6605
dc.identifier.doi10.1016/j.ajhg.2017.02.005
dc.description.abstractIntellectual 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.
dc.formatPrint-Electronic
dc.format.extent650 - 658
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectDeciphering Developmental Disorders Study
dc.subjectHumans
dc.subjectCell Cycle
dc.subjectMutation
dc.subjectExons
dc.subjectAdolescent
dc.subjectChild
dc.subjectChild, Preschool
dc.subjectYoung Adult
dc.subjectIntellectual Disability
dc.subjectProtein Phosphatase 2C
dc.titleDe Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome.
dc.typeJournal Article
dcterms.dateAccepted2017-02-03
rioxxterms.versionofrecord10.1016/j.ajhg.2017.02.005
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2017-04
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfAmerican journal of human genetics
pubs.issue4
pubs.notesNo embargo
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.publication-statusPublished
pubs.volume100
pubs.embargo.termsNo embargo
icr.researchteamGene Functionen_US
dc.contributor.icrauthorLord, Christopheren


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record