SMG9 Gene

Name	SMG9 nonsense mediated mRNA decay factor
Description	This gene encodes a regulatory subunit of the SMG1 complex, which plays a critical role in nonsense-mediated mRNA decay (NMD). Binding of the encoded protein to the SMG1 complex kinase scaffold protein results in the inhibition of its kinase activity. Mutations in this gene cause a multiple congenital anomaly syndrome in human patients, characterized by brain malformation, congenital heart disease and other features. [provided by RefSeq, Jul 2016]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSMG9 is a key regulatory component of the nonsense‐mediated mRNA decay (NMD) pathway that functions as part of the SMG1–SMG8–SMG9 complex, which is essential for the phosphorylation of UPF1 – a critical step in RNA surveillance. Structural studies have revealed that SMG9, together with SMG8, regulates SMG1 kinase activity through conformational changes (via GTP hydrolysis) that relieve inhibitory contacts, thereby permitting substrate phosphorylation at conserved serine/threonine‐glutamine motifs."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical role in mRNA quality control, SMG9 has been implicated in broader transcriptional regulation and normal development. Loss‐of‐function mutations in SMG9 cause congenital syndromes characterized by heart and brain malformations and developmental delay. RNA sequencing of patient‐derived cells indicates that SMG9 deficiency leads to global transcriptional dysregulation without necessarily altering the steady‐state levels of premature termination codon–containing transcripts, suggesting that SMG9 may govern additional regulatory networks critical for organismal development."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSMG9 also exhibits non‐canonical functions independent of its role in NMD. In human cancer cells, SMG9 acts as a selective driver of ferroptosis by directly interacting with and promoting the degradation of GPX4 – a key antioxidant enzyme – thereby facilitating mitochondrial oxidative damage and sensitizing cells to ferroptotic cell death. Moreover, regulation of SMG9 expression by microRNA (miR‑4651) has been shown to modulate NMD efficiency through downregulation of SMG9, which in turn alters the levels of classical NMD substrate genes. In addition, tyrosine phosphorylation of SMG9 modulates its interaction with the actin regulator IQGAP, linking SMG9 to cytoskeletal dynamics in response to growth factor stimulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}, {"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, emerging evidence underscores an interplay between the SMG proteins: the overlapping clinical features observed in disorders caused by mutations in SMG9 and those in SMG8 further support the notion of coordinated regulation within the NMD complex. This interaction highlights the multifaceted roles of SMG9 – spanning mRNA surveillance, transcriptional regulation during development, modulation of cell death pathways, and possibly cytoskeletal organization – all of which contribute to its essential functions in human and murine physiology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Saori Takeda, Ai Fujimoto, Emiko Yamauchi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of a tyrosine phosphorylation of SMG-9 in binding of SMG-9 to IQGAP and the NMD complex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2011.05.099"}], "href": "https://doi.org/10.1016/j.bbrc.2011.05.099"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21640080"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21640080"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Li Zhu, Liang Li, Yilun Qi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cryo-EM structure of SMG1-SMG8-SMG9 complex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Res (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41422-019-0255-3"}], "href": "https://doi.org/10.1038/s41422-019-0255-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31729466"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31729466"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yair Gat, Jan Michael Schuller, Mahesh Lingaraju, et al. "}, {"type": "b", "children": [{"type": "t", "text": "InsP"}, {"type": "a", "children": [{"type": "t", "text": "sub"}], "href": "sub"}, {"type": "t", "text": "6"}, {"type": "a", "children": [{"type": "t", "text": "/sub"}], "href": "/sub"}, {"type": "t", "text": " binding to PIKK kinases revealed by the cryo-EM structure of an SMG1-SMG8-SMG9 complex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Struct Mol Biol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41594-019-0342-7"}], "href": "https://doi.org/10.1038/s41594-019-0342-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31792449"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31792449"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Lukas M Langer, Yair Gat, Fabien Bonneau, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure of substrate-bound SMG1-8-9 kinase complex reveals molecular basis for phosphorylation specificity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.57127"}], "href": "https://doi.org/10.7554/eLife.57127"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32469312"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32469312"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Ranad Shaheen, Shams Anazi, Tawfeg Ben-Omran, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in SMG9, Encoding an Essential Component of Nonsense-Mediated Decay Machinery, Cause a Multiple Congenital Anomaly Syndrome in Humans and Mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2016.02.010"}], "href": "https://doi.org/10.1016/j.ajhg.2016.02.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27018474"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27018474"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Elisa Rahikkala, Lea Urpa, Bishwa Ghimire, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel variant in SMG9 causes intellectual disability, confirming a role for nonsense-mediated decay components in neurocognitive development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41431-022-01046-5"}], "href": "https://doi.org/10.1038/s41431-022-01046-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35087184"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35087184"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Qi Yang, Zailong Qin, Qinle Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of a novel compound heterozygous SMG9 variants in a Chinese family with heart and brain malformation syndrome using whole exome sequencing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Med Genomics (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12920-022-01217-9"}], "href": "https://doi.org/10.1186/s12920-022-01217-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35321723"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35321723"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Yanjie Tan, Zhenfa Ma, Yi Jin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA 4651 regulates nonsense-mediated mRNA decay by targeting SMG9 mRNA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gene.2019.03.031"}], "href": "https://doi.org/10.1016/j.gene.2019.03.031"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30902786"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30902786"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Leng Han, Lulu Bai, Xue Fang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SMG9 drives ferroptosis by directly inhibiting GPX4 degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2021.06.038"}], "href": "https://doi.org/10.1016/j.bbrc.2021.06.038"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34146907"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34146907"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Ghada M H Abdel-Salam, Ruizhi Duan, Mohamed S Abdel-Hamid, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expanding the phenotypic and allelic spectrum of SMG8: Clinical observations reveal overlap with SMG9-associated disease trait."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.62561"}], "href": "https://doi.org/10.1002/ajmg.a.62561"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34761517"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34761517"}]}]}]}
Synonyms	C19ORF61, F17127_1, HBMS
Proteins	SMG9_HUMAN
NCBI Gene ID	56006
API
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Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

SMG9 has 5,855 functional associations with biological entities spanning 9 categories (molecular profile, organism, chemical, disease, phenotype or trait, functional term, phrase or reference, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 108 datasets.

Click the + buttons to view associations for SMG9 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

SMG9 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of SMG9 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of SMG9 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of SMG9 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of SMG9 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of SMG9 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of SMG9 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of SMG9 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of SMG9 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of SMG9 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of SMG9 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of SMG9 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of SMG9 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with SMG9 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with SMG9 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of SMG9 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of SMG9 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of SMG9 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	ClinVar Gene-Phenotype Associations 2025	phenotypes associated with SMG9 gene from the curated ClinVar Gene-Phenotype Associations 2025 dataset.
	CM4AI KOLF21J CRISPRi Gene Perturbation Atlas	gene perturbations changing expression of SMG9 gene from the CM4AI KOLF21J CRISPRi Gene Perturbation Atlas dataset.
	CM4AI U2OS Cell Map Protein Localization Assemblies	assemblies containing SMG9 protein from integrated AP-MS and IF data from the CM4AI U2OS Cell Map Protein Localization Assemblies dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of SMG9 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing SMG9 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing SMG9 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing SMG9 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores 2025	cellular components containing SMG9 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with SMG9 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with SMG9 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of SMG9 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with SMG9 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of SMG9 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by SMG9 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with SMG9 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with SMG9 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with SMG9 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with SMG9 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at SMG9 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of SMG9 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of SMG9 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing SMG9 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GeneRIF Biological Term Annotations	biological terms co-occuring with SMG9 gene in literature-supported statements describing functions of genes from the GeneRIF Biological Term Annotations dataset.