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.

Name
Email *

	Sorry, but the email address you supplied was invalid.