Recessive, Deleterious Variants in SMG8 Expand the Role of Nonsense-Mediated Decay in Developmental Disorders in Humans

  • Am J Hum Genet. 2020 Dec 3;107(6):1178-1185. doi: 10.1016/j.ajhg.2020.11.007.
Fatema Alzahrani  1 ,  Hiroyuki Kuwahara  2 ,  Yongkang Long  2 ,  Mohammed Al-Owain  3 ,  Mohamed Tohary  3 ,  Moeenaldeen AlSayed  3 ,  Mohammed Mahnashi  4 ,  Lana Fathi  4 ,  Maha Alnemer  5 ,  Mohamed H Al-Hamed  1 ,  Gabrielle Lemire  6 ,  Kym M Boycott  6 ,  Mais Hashem  1 ,  Wenkai Han  2 ,  Almundher Al-Maawali  7 ,  Feisal Al Mahrizi  8 ,  Khalid Al-Thihli  7 ,  Xin Gao  9 ,  Fowzan S Alkuraya  10
Affiliations
  • 1. Deparment of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
  • 2. Computational Bioscience Research Center, Computer, Electrical, and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal 23955, Saudi Arabia.
  • 3. Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
  • 4. Division of Genetics, Department of Pediatrics, King Fahad Central Hospital, Jazan 82666, Saudi Arabia.
  • 5. Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
  • 6. Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada.
  • 7. 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.
  • 8. Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat 123, Oman.
  • 9. 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: [email protected].
  • 10. 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: [email protected].
PMID: 33242396 DOI: 10.1016/j.ajhg.2020.11.007
Abstract

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.

Keywords
NMD; RNA-seq; SMG1C; cataract; congenital heart disease; intellectual disability; microcephaly.