Loss of the scavenger mRNA decapping enzyme DCPS causes syndromic intellectual disability with neuromuscular defects

  • Hum Mol Genet. 2015 Jun 1;24(11):3163-71. doi: 10.1093/hmg/ddv067.
Calista K L Ng  1 ,  Mohammad Shboul  1 ,  Valerio Taverniti  2 ,  Carine Bonnard  1 ,  Hane Lee  3 ,  Ascia Eskin  4 ,  Stanley F Nelson  5 ,  Mohammed Al-Raqad  6 ,  Samah Altawalbeh  6 ,  Bertrand Séraphin  7 ,  Bruno Reversade  8
Affiliations
  • 1. Institute of Medical Biology, A*STAR, 8A Biomedical Grove, Singapore 138648, Singapore.
  • 2. IGBMC, CNRS UMR 1704/INSERM U964/Université de Strasbourg, Illkirch, France.
  • 3. Department of Pathology and Laboratory Medicine.
  • 4. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
  • 5. Department of Pathology and Laboratory Medicine Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
  • 6. Queen Rania Paediatric Hospital, King Hussein Medical Centre, Royal Medical Services, Amman, Jordan.
  • 7. IGBMC, CNRS UMR 1704/INSERM U964/Université de Strasbourg, Illkirch, France [email protected] [email protected].
  • 8. Institute of Medical Biology, A*STAR, 8A Biomedical Grove, Singapore 138648, Singapore Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore [email protected] [email protected].
PMID: 25712129 DOI: 10.1093/hmg/ddv067
Abstract

mRNA decay is an essential and active process that allows cells to continuously adapt gene expression to internal and environmental cues. There are two mRNA degradation pathways: 3' to 5' and 5' to 3'. The DCPS protein is the scavenger mRNA decapping enzyme which functions in the last step of the 3' end mRNA decay pathway. We have identified a DCPS pathogenic mutation in a large family with three affected individuals presenting with a novel recessive syndrome consisting of craniofacial anomalies, intellectual disability and neuromuscular defects. Using patient's primary cells, we show that this homozygous splice mutation results in a DCPS loss-of-function allele. Diagnostic biochemical analyses using various m7G cap derivatives as substrates reveal no DCPS enzymatic activity in patient's cells. Our results implicate DCPS and more generally RNA catabolism, as a critical cellular process for neurological development, normal cognition and organismal homeostasis in humans.