title: Mutations in SMG9, Encoding an Essential Component of Nonsense-Mediated Decay Machinery, Cause a Multiple Congenital Anomaly Syndrome in Humans and Mice.
abstract: Nonsense-mediated decay (NMD) is an important process that is best known for degrading transcripts that contain premature stop codons (PTCs) to mitigate their potentially harmful consequences, although its regulatory role encompasses other classes of transcripts as well. Despite the critical role of NMD at the cellular level, our knowledge about the consequences of deficiency of its components at the organismal level is largely limited to model organisms. In this study, we report two consanguineous families in which a similar pattern of congenital anomalies was found to be most likely caused by homozygous loss-of-function mutations in SMG9, encoding an essential component of the SURF complex that generates phospho-UPF1, the single most important step in NMD. By knocking out Smg9 in mice via CRISPR/Cas9, we were able to recapitulate the major features of the SMG9-related multiple congenital anomaly syndrome we observed in humans. Surprisingly, human cells devoid of SMG9 do not appear to have reduction of PTC-containing transcripts but do display global transcriptional dysregulation. We conclude that SMG9 is required for normal human and murine development, most likely through a transcriptional regulatory role, the precise nature of which remains to be determined.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Ranad
authors.initials: R
authors.lastname: Shaheen
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Shams
authors.initials: S
authors.lastname: Anazi
authors.affiliation: Department of Genetics, Hamad Medical Corporation, Doha, Qatar.
authors.forename: Tawfeg
authors.initials: T
authors.lastname: Ben-Omran
authors.affiliation: Department of Pediatrics, Security Forces Hospital, Riyadh 12625, Saudi Arabia.
authors.forename: Mohammed Zain
authors.initials: MZ
authors.lastname: Seidahmed
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: L Brianna
authors.initials: LB
authors.lastname: Caddle
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Palmer
authors.affiliation: Department of Genetics, Hamad Medical Corporation, Doha, Qatar.
authors.forename: Rehab
authors.initials: R
authors.lastname: Ali
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Tarfa
authors.initials: T
authors.lastname: Alshidi
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Samya
authors.initials: S
authors.lastname: Hagos
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Goodwin
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Mais
authors.initials: M
authors.lastname: Hashem
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Salma M
authors.initials: SM
authors.lastname: Wakil
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abouelhoda
authors.affiliation: Department of Biostatistics, Epidemiology, and Scientific Computing, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Dilek
authors.initials: D
authors.lastname: Colak
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA. Electronic address: steve.murray@jax.org.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Murray
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia. Electronic address: falkuraya@kfshrc.edu.sa.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D059365:Nonsense Mediated mRNA Decay / Q000235:genetics*; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics*; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger; D012529:Saudi Arabia
chemical_list: D018389:Codon, Nonsense; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; C000657406:SMG9 protein, human
keywords: NMD; SMG1; UPF1; brain atrophy; cleft palate; congenital heart disease; developmental delay; microphthalmia