title: Mutations in DCPS and EDC3 in autosomal recessive intellectual disability indicate a crucial role for mRNA decapping in neurodevelopment.
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.
authors.affiliation: 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.
authors.forename: Iltaf
authors.initials: I
authors.lastname: Ahmed
authors.affiliation: Institute of Human Genetics and.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Buchert
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Mi
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Xinfu
authors.initials: X
authors.lastname: Jiao
authors.affiliation: 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.
authors.forename: Kirti
authors.initials: K
authors.lastname: Mittal
authors.affiliation: 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.
authors.forename: Taimoor I
authors.initials: TI
authors.lastname: Sheikh
authors.affiliation: Institute of Human Genetics and.
authors.forename: Ute
authors.initials: U
authors.lastname: Scheller
authors.affiliation: 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.
authors.forename: Nasim
authors.initials: N
authors.lastname: Vasli
authors.affiliation: 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.
authors.forename: Muhammad Arshad
authors.initials: MA
authors.lastname: Rafiq
authors.affiliation: Sir Cowasji Jehangir Institute of Psychiatry, Hyderabad, Sindh 71000, Pakistan.
authors.forename: M Qasim
authors.initials: MQ
authors.lastname: Brohi
authors.affiliation: 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.
authors.forename: Anna
authors.initials: A
authors.lastname: Mikhailov
authors.affiliation: Lahore Institute of Research and Development, Lahore 51000, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ayaz
authors.affiliation: Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan.
authors.forename: Attya
authors.initials: A
authors.lastname: Bhatti
authors.affiliation: Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen 91054, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
authors.affiliation: Department of Psychiatry, Mayo Hospital, Lahore 54000, Pakistan Department of Psychiatry, Chaudhary Hospital, Gujranwala 52250, Pakistan.
authors.forename: Tanveer
authors.initials: T
authors.lastname: Nasr
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada M5G1X8.
authors.forename: Melissa T
authors.initials: MT
authors.lastname: Carter
authors.affiliation: Institute of Human Genetics and.
authors.forename: Steffen
authors.initials: S
authors.lastname: Uebe
authors.affiliation: Institute of Human Genetics and.
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.affiliation: Lahore Institute of Research and Development, Lahore 51000, Pakistan Division of Developmental Disabilities, Department of Psychiatry, Queen's University, Kingston, Ontario, Canada K7L 3N6.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ayub
authors.affiliation: Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan.
authors.forename: Peter
authors.initials: P
authors.lastname: John
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA kiledjian@biology.rutgers.edu john.vincent@camh.ca john_vincent@camh.net Rami.AbouJamra@uk-erlangen.de.
authors.forename: Megerditch
authors.initials: M
authors.lastname: Kiledjian
authors.affiliation: 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 kiledjian@biology.rutgers.edu john.vincent@camh.ca john_vincent@camh.net Rami.AbouJamra@uk-erlangen.de.
authors.forename: John B
authors.initials: JB
authors.lastname: Vincent
authors.affiliation: Institute of Human Genetics and kiledjian@biology.rutgers.edu john.vincent@camh.ca john_vincent@camh.net Rami.AbouJamra@uk-erlangen.de.
authors.forename: Rami Abou
authors.initials: RA
authors.lastname: Jamra
mesh_terms: D000293:Adolescent; D002648:Child; D003241:Consanguinity; D004722:Endoribonucleases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005808:Genes, Recessive; D056726:Genetic Association Studies; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D022821:RNA Splice Sites; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017411:Ribonucleoproteins, Small Nuclear / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C525042:EDC3 protein, human; D020033:Protein Isoforms; D022821:RNA Splice Sites; D012333:RNA, Messenger; D017411:Ribonucleoproteins, Small Nuclear; D004722:Endoribonucleases; C485332:DcpS protein, human