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  • 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.

Human molecular genetics (2015-02-24)
Iltaf Ahmed, Rebecca Buchert, Mi Zhou, Xinfu Jiao, Kirti Mittal, Taimoor I Sheikh, Ute Scheller, Nasim Vasli, Muhammad Arshad Rafiq, M Qasim Brohi, Anna Mikhailov, Muhammad Ayaz, Attya Bhatti, Heinrich Sticht, Tanveer Nasr, Melissa T Carter, Steffen Uebe, André Reis, Muhammad Ayub, Peter John, Megerditch Kiledjian, John B Vincent, Rami Abou Jamra
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
IPTG, ≥99% (TLC), ≤0.1% Dioxane
Sigma-Aldrich
Isopropyl β-D-1-thiogalactopyranoside, ≥99% (TLC)
Sigma-Aldrich
Isopropyl β-D-thiogalactopyranoside solution, ReadyMade IPTG solution for Blue-white screening
Isopropyl β-D-thiogalactoside, Vetec, reagent grade, ≥99%
SAFC
Isopropyl β-D-1-thiogalactopyranoside