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

• Published in: Human molecular genetics 2015-06, Vol.24 (11), p.3163-3171
• Main Authors: Ng, Calista K L, Shboul, Mohammad, Taverniti, Valerio, Bonnard, Carine, Lee, Hane, Eskin, Ascia, Nelson, Stanley F, Al-Raqad, Mohammed, Altawalbeh, Samah, Séraphin, Bertrand, Reversade, Bruno
• Format: Article
• Language: English
• Subjects: Abnormalities, Multiple - genetics; Biochemistry, Molecular Biology; Cells, Cultured; Child; Child, Preschool; Consanguinity; DNA Mutational Analysis; Endoribonucleases - deficiency; Endoribonucleases - genetics; Genetic Association Studies; Humans; Intellectual Disability - genetics; Life Sciences; Male; Muscle Hypotonia - genetics; Pedigree; RNA Splice Sites; Syndrome
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddv067

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.