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

Journal article


Publication Details

Author(s): Ahmed I, Buchert R, Zhou M, Jiao X, Mittal K, Sheikh TI, Scheller U, Vasli N, Rafiq MA, Brohi MQ, Mikhailov A, Ayaz M, Bhatti A, Sticht H, Nasr T, Carter MT, Uebe S, Reis A, Ayub M, John P, Kiledjian M, Vincent JB, Jamra RA
Journal: Human Molecular Genetics
Publisher: Oxford University Press (OUP): Policy B - Oxford Open Option B
Publication year: 2015
Volume: 24
Journal issue: 11
Pages range: 3172-80
ISSN: 0964-6906


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.



FAU Authors / FAU Editors

Buchert, Rebecca
Lehrstuhl für Humangenetik
Sticht, Heinrich Prof. Dr.
Professur für Bioinformatik
Uebe, Steffen Dr. rer. nat.
Humangenetisches Institut


External institutions with authors

Centre for Addiction and Mental Health (CAMH)
Mayo Hospital
National University of Sciences and Technology (NUST) / قومی جامع علم اور صنعت و حرفت‎
Sir Cowasjee Jehangir Institute of Psychiatry
The Hospital for Sick Children (SickKids)
The State University of New Jersey (Rutgers)
University of Gujrat (UOG)


How to cite

APA:
Ahmed, I., Buchert, R., Zhou, M., Jiao, X., Mittal, K., Sheikh, T.I.,... Jamra, R.A. (2015). Mutations in DCPS and EDC3 in autosomal recessive intellectual disability indicate a crucial role for mRNA decapping in neurodevelopment. Human Molecular Genetics, 24(11), 3172-80. https://dx.doi.org/10.1093/hmg/ddv069

MLA:
Ahmed, Iltaf, et al. "Mutations in DCPS and EDC3 in autosomal recessive intellectual disability indicate a crucial role for mRNA decapping in neurodevelopment." Human Molecular Genetics 24.11 (2015): 3172-80.

BibTeX: 

Last updated on 2018-10-10 at 08:24