Recessive, Deleterious Variants in SMG8 Expand the Role of Nonsense-Mediated Decay in Developmental Disorders in Humans.
Al-Hamed, Mohamed H
Boycott, Kym M
Al Mahrizi, Feisal
Alkuraya, Fowzan S
KAUST DepartmentComputational Bioscience Research Center (CBRC)
Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
Computer Science Program
KAUST Grant NumberBAS/1/1624-01
Online Publication Date2020-11-25
Print Publication Date2020-11
Embargo End Date2021-05-26
Permanent link to this recordhttp://hdl.handle.net/10754/666138
MetadataShow full item record
AbstractWe have previously described a heart-, eye-, and brain-malformation syndrome caused by homozygous loss-of-function variants in SMG9, which encodes a critical component of the nonsense-mediated decay (NMD) machinery. Here, we describe four consanguineous families with four different likely deleterious homozygous variants in SMG8, encoding a binding partner of SMG9. The observed phenotype greatly resembles that linked to SMG9 and comprises severe global developmental delay, microcephaly, facial dysmorphism, and variable congenital heart and eye malformations. RNA-seq analysis revealed a general increase in mRNA expression levels with significant overrepresentation of core NMD substrates. We also identified increased phosphorylation of UPF1, a key SMG1-dependent step in NMD, which most likely represents the loss of SMG8--mediated inhibition of SMG1 kinase activity. Our data show that SMG8 and SMG9 deficiency results in overlapping developmental disorders that most likely converge mechanistically on impaired NMD.
CitationAlzahrani, F., Kuwahara, H., Long, Y., Al-Owain, M., Tohary, M., AlSayed, M., … Alkuraya, F. S. (2020). Recessive, Deleterious Variants in SMG8 Expand the Role of Nonsense-Mediated Decay in Developmental Disorders in Humans. The American Journal of Human Genetics. doi:10.1016/j.ajhg.2020.11.007
SponsorsWe thank the study participants for their enthusiastic participation. We also thank the Sequencing and Genotyping Core Facilities at KFSRHC for their technical help. This work was supported by King Abdullah University of Science and Technology, Office of Sponsored Research under Awards BAS/1/1624-01, FCC/1/1976-18-01, FCC/1/1976-23-01, FCC/1/1976-25-01, FCC/1/1976-26-01, REI/1/0018-01-01, REI/1/4216-01-01, and URF/1/4098-01-01. This work was also supported by His Majesty Trust Funds at the Sultan Qaboos University, study code SR/MED/GENT/16/01.
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