Mutations in SMG9, Encoding an Essential Component of Nonsense-Mediated Decay Machinery, Cause a Multiple Congenital Anomaly Syndrome in Humans and Mice.

TitleMutations in SMG9, Encoding an Essential Component of Nonsense-Mediated Decay Machinery, Cause a Multiple Congenital Anomaly Syndrome in Humans and Mice.
Publication TypeJournal Article
Year of Publication2016
AuthorsShaheen R, Anazi S, Ben-Omran T, Seidahmed MZain, L Caddle B, Palmer K, Ali R, Alshidi T, Hagos S, Goodwin L, Hashem M, Wakil SM, Abouelhoda M, Colak D, Murray SA, Alkuraya FS
JournalAm J Hum Genet
Volume98
Issue4
Pagination643-52
Date Published2016 Apr 07
ISSN1537-6605
KeywordsAbnormalities, Multiple, Adult, Alleles, Amino Acid Sequence, Animals, Case-Control Studies, Child, Child, Preschool, Codon, Nonsense, Female, Gene Expression Profiling, Gene Expression Regulation, Humans, Male, Mice, Molecular Sequence Data, Mutation, Nonsense Mediated mRNA Decay, Pedigree, Phosphoproteins, Phosphorylation, Polymorphism, Single Nucleotide, RNA, Messenger, Saudi Arabia
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.

DOI10.1016/j.ajhg.2016.02.010
Custom 1

https://www.ncbi.nlm.nih.gov/pubmed/27018474?dopt=Abstract

Alternate JournalAm. J. Hum. Genet.
PubMed ID27018474
PubMed Central IDPMC4833216
Grant ListP30 CA034196 / CA / NCI NIH HHS / United States
U42 OD011185 / OD / NIH HHS / United States
OD011185 / OD / NIH HHS / United States

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