TY - JOUR
T1 - De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome
AU - Jansen, Sandra
AU - Geuer, Sinje
AU - Pfundt, Rolph
AU - Brough, Rachel
AU - Ghongane, Priyanka
AU - Herkert, Johanna C.
AU - Marco, Elysa J.
AU - Willemsen, Marjolein H.
AU - Kleefstra, Tjitske
AU - Hannibal, Mark
AU - Shieh, Joseph T.
AU - Lynch, Sally Ann
AU - Flinter, Frances
AU - FitzPatrick, David R.
AU - Gardham, Alice
AU - Bernhard, Birgitta
AU - Ragge, Nicola
AU - Newbury-Ecob, Ruth
AU - Bernier, Raphael
AU - Kvarnung, Malin
AU - Magnusson, E. A. Helena
AU - Wessels, Marja W.
AU - van Slegtenhorst, Marjon A.
AU - Monaghan, Kristin G.
AU - de Vries, Petra
AU - Veltman, Joris A.
AU - Lord, Christopher J.
AU - Vissers, Lisenka E. L. M.
AU - de Vries, Bert B. A.
AU - Deciphering Dev Disorders Study
PY - 2017/4/6
Y1 - 2017/4/6
N2 - Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in similar to 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.
AB - Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in similar to 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.
KW - DOMINANT ROBINOW SYNDROME
KW - SCHIZOPHRENIA
KW - FRAMESHIFT
KW - SPECTRUM
KW - DISEASE
KW - AUTISM
KW - CANCER
KW - BLOOD
KW - GENE
KW - WIP1
U2 - 10.1016/j.ajhg.2017.02.005
DO - 10.1016/j.ajhg.2017.02.005
M3 - Article
C2 - 28343630
SN - 0002-9297
VL - 100
SP - 650
EP - 658
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -