2. Academic Validation
  3. Mutations in DCPS and EDC3 in autosomal recessive intellectual disability indicate a crucial role for mRNA decapping in neurodevelopment

Mutations in DCPS and EDC3 in autosomal recessive intellectual disability indicate a crucial role for mRNA decapping in neurodevelopment

  • Hum Mol Genet. 2015 Jun 1;24(11):3172-80. doi: 10.1093/hmg/ddv069.
Iltaf Ahmed 1,  Rebecca Buchert 2,  Mi Zhou 3,  Xinfu Jiao 3,  Kirti Mittal 4,  Taimoor I Sheikh 4,  Ute Scheller 2,  Nasim Vasli 4,  Muhammad Arshad Rafiq 4,  M Qasim Brohi 5,  Anna Mikhailov 4,  Muhammad Ayaz 6,  Attya Bhatti 7,  Heinrich Sticht 8,  Tanveer Nasr 9,  Melissa T Carter 10,  Steffen Uebe 2,  André Reis 2,  Muhammad Ayub 11,  Peter John 7,  Megerditch Kiledjian 12,  John B Vincent 13,  Rami Abou Jamra 14
Affiliations

Affiliations

  • 1 Molecular Neuropsychiatry and Development Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8 Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan.
  • 2 Institute of Human Genetics and.
  • 3 Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
  • 4 Molecular Neuropsychiatry and Development Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8.
  • 5 Sir Cowasji Jehangir Institute of Psychiatry, Hyderabad, Sindh 71000, Pakistan.
  • 6 Lahore Institute of Research and Development, Lahore 51000, Pakistan.
  • 7 Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan.
  • 8 Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen 91054, Germany.
  • 9 Department of Psychiatry, Mayo Hospital, Lahore 54000, Pakistan Department of Psychiatry, Chaudhary Hospital, Gujranwala 52250, Pakistan.
  • 10 Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada M5G1X8.
  • 11 Lahore Institute of Research and Development, Lahore 51000, Pakistan Division of Developmental Disabilities, Department of Psychiatry, Queen's University, Kingston, Ontario, Canada K7L 3N6.
  • 12 Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA [email protected] [email protected] [email protected] [email protected].
  • 13 Molecular Neuropsychiatry and Development Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8 Department of Psychiatry and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5S 2J7 [email protected] [email protected] [email protected] [email protected].
  • 14 Institute of Human Genetics and [email protected] [email protected] [email protected] [email protected].
PMID: 25701870 DOI: 10.1093/hmg/ddv069
Abstract

There are two known mRNA degradation pathways, 3' to 5' and 5' to 3'. We identified likely pathogenic variants in two genes involved in these two pathways in individuals with intellectual disability. In a large family with multiple branches, we identified biallelic variants in DCPS in three affected individuals; a splice site variant (c.636+1G>A) that results in an in-frame insertion of 45 nucleotides and a missense variant (c.947C>T; p.Thr316Met). DCPS decaps the cap structure generated by 3' to 5' exonucleolytic degradation of mRNA. In vitro decapping assays showed an ablation of decapping function for both variants in DCPS. In another family, we identified a homozygous mutation (c.161T>C; p.Phe54Ser) in EDC3 in two affected children. EDC3 stimulates DCP2, which decaps mRNAs at the beginning of the 5' to 3' degradation pathway. In vitro decapping assays showed that altered EDC3 is unable to enhance DCP2 decapping at low concentrations and even inhibits DCP2 decapping at high concentration. We show that individuals with biallelic mutations in these genes of seemingly central functions are viable and that these possibly lead to impairment of neurological functions linking mRNA decapping to normal cognition. Our results further affirm an emerging theme linking aberrant mRNA metabolism to neurological defects.

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