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De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome
- Source :
- American Journal of Human Genetics, 100, 4, pp. 650-658, American Journal of Human Genetics, 100(4), 650-658. Cell Press, American Journal of Human Genetics, 100, 650-658, American Journal of Human Genetics, 100(4), 650-658. CELL PRESS, Jansen, S, Geuer, S, Pfundt, R, Brough, R, Ghongane, P, Herkert, J C, Marco, E J, Willemsen, M H, Kleefstra, T, Hannibal, M, Shieh, J T, Lynch, S A, Flinter, F, FitzPatrick, D R, Gardham, A, Bernhard, B, Ragge, N, Newbury-Ecob, R, Bernier, R, Kvarnung, M, Magnusson, E A H, Wessels, M W, van Slegtenhorst, M A, Monaghan, K G, de Vries, P, Veltman, J A, Lord, C J & Vissers, L E L M & de Vries, B B A 2017, ' De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome ', American Journal of Human Genetics, vol. 100, no. 4, pp. 650-658 . https://doi.org/10.1016/j.ajhg.2017.02.005
- Publication Year :
- 2017
-
Abstract
- Contains fulltext : 174535.pdf (Publisher’s version ) (Closed access) Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in approximately 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.
- Subjects :
- 0301 basic medicine
BLOOD
Adolescent
WIP1
Biology
Bioinformatics
medicine.disease_cause
DISEASE
Frameshift mutation
03 medical and health sciences
Exon
Young Adult
Report
Intellectual Disability
Intellectual disability
SCHIZOPHRENIA
Journal Article
Genetics
medicine
Humans
AUTISM
Child
Gene
Genetics (clinical)
Mutation
SPECTRUM
Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7]
FRAMESHIFT
Cell Cycle
DOMINANT ROBINOW SYNDROME
Exons
medicine.disease
CANCER
GENE
Hypotonia
Protein Phosphatase 2C
030104 developmental biology
Schizophrenia
Child, Preschool
Autism
medicine.symptom
Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Subjects
Details
- Language :
- English
- ISSN :
- 00029297
- Database :
- OpenAIRE
- Journal :
- American Journal of Human Genetics, 100, 4, pp. 650-658, American Journal of Human Genetics, 100(4), 650-658. Cell Press, American Journal of Human Genetics, 100, 650-658, American Journal of Human Genetics, 100(4), 650-658. CELL PRESS, Jansen, S, Geuer, S, Pfundt, R, Brough, R, Ghongane, P, Herkert, J C, Marco, E J, Willemsen, M H, Kleefstra, T, Hannibal, M, Shieh, J T, Lynch, S A, Flinter, F, FitzPatrick, D R, Gardham, A, Bernhard, B, Ragge, N, Newbury-Ecob, R, Bernier, R, Kvarnung, M, Magnusson, E A H, Wessels, M W, van Slegtenhorst, M A, Monaghan, K G, de Vries, P, Veltman, J A, Lord, C J & Vissers, L E L M & de Vries, B B A 2017, ' De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome ', American Journal of Human Genetics, vol. 100, no. 4, pp. 650-658 . https://doi.org/10.1016/j.ajhg.2017.02.005
- Accession number :
- edsair.doi.dedup.....64f6f001693f21f3acd7e4693f296397