Recessive, Deleterious Variants in SMG8 Expand the Role of Nonsense-Mediated Decay in Developmental Disorders in Humans.
Fatema Alzahrani, Hiroyuki Kuwahara, Yongkang Long, Mohammed Al-Owain, Mohamed Tohary, Moeenaldeen AlSayed, Mohammed Mahnashi, Lana Fathi, Maha Alnemer, Mohamed H Al-Hamed, Gabrielle Lemire, Kym M Boycott, Mais Hashem, Wenkai Han, Almundher Al-Maawali, Feisal Al Mahrizi, Khalid Al-Thihli, Xin Gao, Fowzan S Alkuraya
Author Information
Fatema Alzahrani: Deparment of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Hiroyuki Kuwahara: Computational Bioscience Research Center, Computer, Electrical, and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal 23955, Saudi Arabia.
Yongkang Long: Computational Bioscience Research Center, Computer, Electrical, and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal 23955, Saudi Arabia.
Mohammed Al-Owain: Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Mohamed Tohary: Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Moeenaldeen AlSayed: Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Mohammed Mahnashi: Division of Genetics, Department of Pediatrics, King Fahad Central Hospital, Jazan 82666, Saudi Arabia.
Lana Fathi: Division of Genetics, Department of Pediatrics, King Fahad Central Hospital, Jazan 82666, Saudi Arabia.
Maha Alnemer: Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Mohamed H Al-Hamed: Deparment of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Gabrielle Lemire: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada.
Kym M Boycott: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada.
Mais Hashem: Deparment of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Wenkai Han: Computational Bioscience Research Center, Computer, Electrical, and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal 23955, Saudi Arabia.
Almundher Al-Maawali: Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat 123, Oman; Genetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, Muscat 123, Oman.
Feisal Al Mahrizi: Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat 123, Oman.
Khalid Al-Thihli: Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat 123, Oman; Genetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, Muscat 123, Oman.
Xin Gao: Computational Bioscience Research Center, Computer, Electrical, and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal 23955, Saudi Arabia. Electronic address: xin.gao@kaust.edu.sa.
Fowzan S Alkuraya: Deparment of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Deparment of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia. Electronic address: falkuraya@kfshrc.edu.sa.
We 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.
