Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDG48P0)

• DOT Name: Sterile alpha motif domain-containing protein 9 (SAMD9)
• Synonyms: SAM domain-containing protein 9
• Gene Name: SAMD9
• Related Disease:
  MIRAGE syndrome
  Advanced cancer
  Alzheimer disease
  Cerebellar ataxia
  Cerebrovascular disease
  Chronic diarrhoea
  Colon cancer
  Colon carcinoma
  Desmoid tumour
  Familial tumoral calcinosis
  Glioma
  Hematologic disease
  Influenza
  Myelodysplastic syndrome
  Neoplasm
  Non-small-cell lung cancer
  Normophosphatemic familial tumoral calcinosis
  Pancytopenia
  Pathologic nystagmus
  Prostate cancer
  Prostate neoplasm
  Rheumatoid arthritis
  46,XY disorder of sex development
  Addison disease
  Adrenocortical insufficiency
  Atherosclerosis
  Autoimmune disease
  Disorder of sexual differentiation
  Fetal growth restriction
  IMAGe syndrome
  Primary adrenal insufficiency
  Sphingolipidosis
  Arteriosclerosis
  Calcinosis
  Intestinal disorder
  Monosomy 7 myelodysplasia and leukemia syndrome 2
• UniProt ID: SAMD9_HUMAN
• PDB ID: 7KSP
• Pfam ID: PF00536
• Sequence:
  MAKQLNLPENTDDWTKEDVNQWLESHKIDQKHREILTEQDVNGAVLKWLKKEHLVDMGIT
  HGPAIQIEELFKELRKTAIEDSIQTSKMGKPSKNAPKDQTVSQKERRETSKQKQKGKENP
  DMANPSAMSTTAKGSKSLKVELIEDKIDYTKERQPSIDLTCVSYPFDEFSNPYRYKLDFS
  LQPETGPGNLIDPIHEFKAFTNTATATEEDVKMKFSNEVFRFASACMNSRTNGTIHFGVK
  DKPHGKIVGIKVTNDTKEALINHFNLMINKYFEDHQVQQAKKCIREPRFVEVLLPNSTLS
  DRFVIEVDIIPQFSECQYDYFQIKMQNYNNKIWEQSKKFSLFVRDGTSSKDITKNKVDFR
  AFKADFKTLAESRKAAEEKFRAKTNKKEREGPKLVKLLTGNQDLLDNSYYEQYILVTNKC
  HPDQTKHLDFLKEIKWFAVLEFDPESNINGVVKAYKESRVANLHFPSVYVEQKTTPNETI
  STLNLYHQPSWIFCNGRLDLDSEKYKPFDPSSWQRERASDVRKLISFLTHEDIMPRGKFL
  VVFLLLSSVDDPRDPLIETFCAFYQDLKGMENILCICVHPHIFQGWKDLLEARLIKHQDE
  ISSQCISALSLEEINGTILKLKSVTQSSKRLLPSIGLSTVLLKKEEDIMTALEIICENEC
  EGTLLEKDKNKFLEFKASKEEDFYRGGKVSWWNFYFSSESYSSPFVKRDKYERLEAMIQN
  CADSSKPTSTKIIHLYHHPGCGGTTLAMHILWELRKKFRCAVLKNKTVDFSEIGEQVTSL
  ITYGAMNRQEYVPVLLLVDDFEEQDNVYLLQYSIQTAIAKKYIRYEKPLVIILNCMRSQN
  PEKSARIPDSIAVIQQLSPKEQRAFELKLKEIKEQHKNFEDFYSFMIMKTNFNKEYIENV
  VRNILKGQNIFTKEAKLFSFLALLNSYVPDTTISLSQCEKFLGIGNKKAFWGTEKFEDKM
  GTYSTILIKTEVIECGNYCGVRIIHSLIAEFSLEELKKSYHLNKSQIMLDMLTENLFFDT
  GMGKSKFLQDMHTLLLTRHRDEHEGETGNWFSPFIEALHKDEGNEAVEAVLLESIHRFNP
  NAFICQALARHFYIKKKDFGNALNWAKQAKIIEPDNSYISDTLGQVYKSKIRWWIEENGG
  NGNISVDDLIALLDLAEHASSAFKESQQQSEDREYEVKERLYPKSKRRYDTYNIAGYQGE
  IEVGLYTIQILQLIPFFDNKNELSKRYMVNFVSGSSDIPGDPNNEYKLALKNYIPYLTKL
  KFSLKKSFDFFDEYFVLLKPRNNIKQNEEAKTRRKVAGYFKKYVDIFCLLEESQNNTGLG
  SKFSEPLQVERCRRNLVALKADKFSGLLEYLIKSQEDAISTMKCIVNEYTFLLEQCTVKI
  QSKEKLNFILANIILSCIQPTSRLVKPVEKLKDQLREVLQPIGLTYQFSEPYFLASLLFW
  PENQQLDQHSEQMKEYAQALKNSFKGQYKHMHRTKQPIAYFFLGKGKRLERLVHKGKIDQ
  CFKKTPDINSLWQSGDVWKEEKVQELLLRLQGRAENNCLYIEYGINEKITIPITPAFLGQ
  LRSGRSIEKVSFYLGFSIGGPLAYDIEIV
• Function: Double-stranded nucleic acid binding that acts as an antiviral factor by playing an essential role in the formation of cytoplasmic antiviral granules. May play a role in the inflammatory response to tissue injury and the control of extra-osseous calcification, acting as a downstream target of TNF-alpha signaling. Involved in the regulation of EGR1, in coordination with RGL2. May be involved in endosome fusion.
• Tissue Specificity: Widely expressed. Very low levels are detected in skeletal muscle. Not detected in brain. Down-regulated in aggressive fibromatosis, as well as in breast and colon cancers. Up-regulated in fibroblasts from patients with normophosphatemic tumoral calcinosis (NFTC).

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
MIRAGE syndrome	DISQS0OS	Definitive	Autosomal dominant	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[4]
Cerebrovascular disease	DISAB237	Strong	Genetic Variation	[5]
Chronic diarrhoea	DISH3PX3	Strong	Genetic Variation	[6]
Colon cancer	DISVC52G	Strong	Altered Expression	[7]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[7]
Desmoid tumour	DISGX357	Strong	Altered Expression	[7]
Familial tumoral calcinosis	DISYJZKG	Strong	Biomarker	[8]
Glioma	DIS5RPEH	Strong	Biomarker	[9]
Hematologic disease	DIS9XD9A	Strong	Genetic Variation	[4]
Influenza	DIS3PNU3	Strong	Biomarker	[10]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[7]
Normophosphatemic familial tumoral calcinosis	DISMVEON	Strong	Autosomal recessive	[13]
Pancytopenia	DISVKEHV	Strong	Biomarker	[4]
Pathologic nystagmus	DIS1QSPO	Strong	Genetic Variation	[14]
Prostate cancer	DISF190Y	Strong	Biomarker	[15]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[15]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[12]
46,XY disorder of sex development	DIS78CGG	moderate	Genetic Variation	[6]
Addison disease	DIS7HNOH	moderate	Genetic Variation	[16]
Adrenocortical insufficiency	DISZ0CPT	moderate	Genetic Variation	[6]
Atherosclerosis	DISMN9J3	moderate	Biomarker	[17]
Autoimmune disease	DISORMTM	moderate	Biomarker	[17]
Disorder of sexual differentiation	DISRMAEZ	moderate	Genetic Variation	[6]
Fetal growth restriction	DIS5WEJ5	moderate	Genetic Variation	[14]
IMAGe syndrome	DISOGW88	moderate	Genetic Variation	[16]
Primary adrenal insufficiency	DISNMBYU	moderate	Genetic Variation	[16]
Sphingolipidosis	DISEC08E	moderate	Genetic Variation	[16]
Arteriosclerosis	DISK5QGC	Disputed	Biomarker	[13]
Calcinosis	DISQP4OR	Limited	Biomarker	[17]
Intestinal disorder	DISGPMUQ	Limited	Genetic Variation	[18]
Monosomy 7 myelodysplasia and leukemia syndrome 2	DISEJ2YJ	Limited	Autosomal dominant	[1]

17 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sterile alpha motif domain-containing protein 9 (SAMD9).	[19]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sterile alpha motif domain-containing protein 9 (SAMD9).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sterile alpha motif domain-containing protein 9 (SAMD9).	[21]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sterile alpha motif domain-containing protein 9 (SAMD9).	[22]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Sterile alpha motif domain-containing protein 9 (SAMD9).	[23]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Sterile alpha motif domain-containing protein 9 (SAMD9).	[24]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Sterile alpha motif domain-containing protein 9 (SAMD9).	[25]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Sterile alpha motif domain-containing protein 9 (SAMD9).	[26]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Sterile alpha motif domain-containing protein 9 (SAMD9).	[26]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Sterile alpha motif domain-containing protein 9 (SAMD9).	[27]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Sterile alpha motif domain-containing protein 9 (SAMD9).	[28]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Sterile alpha motif domain-containing protein 9 (SAMD9).	[29]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Sterile alpha motif domain-containing protein 9 (SAMD9).	[30]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sterile alpha motif domain-containing protein 9 (SAMD9).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Sterile alpha motif domain-containing protein 9 (SAMD9).	[32]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Sterile alpha motif domain-containing protein 9 (SAMD9).	[33]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Sterile alpha motif domain-containing protein 9 (SAMD9).	[34]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes.JCI Insight. 2018 Jul 26;3(14):e121086. doi: 10.1172/jci.insight.121086. eCollection 2018 Jul 26.
• [3] Association of TTR polymorphisms with hippocampal atrophy in Alzheimer disease families.Neurobiol Aging. 2011 Feb;32(2):249-56. doi: 10.1016/j.neurobiolaging.2009.02.014. Epub 2009 Mar 27.
• [4] Outcomes of Hematopoietic Cell Transplantation in Patients with Germline SAMD9/SAMD9L Mutations.Biol Blood Marrow Transplant. 2019 Nov;25(11):2186-2196. doi: 10.1016/j.bbmt.2019.07.007. Epub 2019 Jul 12.
• [5] Association of distinct variants in SORL1 with cerebrovascular and neurodegenerative changes related to Alzheimer disease.Arch Neurol. 2008 Dec;65(12):1640-8. doi: 10.1001/archneur.65.12.1640.
• [6] MIRAGE syndrome is a rare cause of 46,XY DSD born SGA without adrenal insufficiency.PLoS One. 2018 Nov 7;13(11):e0206184. doi: 10.1371/journal.pone.0206184. eCollection 2018.
• [7] Overexpression of SAMD9 suppresses tumorigenesis and progression during non small cell lung cancer.Biochem Biophys Res Commun. 2014 Nov 7;454(1):157-61. doi: 10.1016/j.bbrc.2014.10.054. Epub 2014 Oct 17.
• [8] Human sterile alpha motif domain 9, a novel gene identified as down-regulated in aggressive fibromatosis, is absent in the mouse.BMC Genomics. 2007 Apr 3;8:92. doi: 10.1186/1471-2164-8-92.
• [9] Homeobox B8 Targets Sterile Alpha Motif Domain-Containing Protein 9 and Drives Glioma Progression.Neurosci Bull. 2020 Apr;36(4):359-371. doi: 10.1007/s12264-019-00436-y. Epub 2019 Oct 23.
• [10] A host transcriptional signature for presymptomatic detection of infection in humans exposed to influenza H1N1 or H3N2.PLoS One. 2013;8(1):e52198. doi: 10.1371/journal.pone.0052198. Epub 2013 Jan 9.
• [11] Somatic mosaic monosomy 7 and UPD7q in a child with MIRAGE syndrome caused by a novel SAMD9 mutation.Pediatr Blood Cancer. 2019 Apr;66(4):e27589. doi: 10.1002/pbc.27589. Epub 2018 Dec 19.
• [12] SAMD9 is a (epi-) genetically regulated anti-inflammatory factor activated in RA patients.Mol Cell Biochem. 2019 Jun;456(1-2):135-144. doi: 10.1007/s11010-019-03499-7. Epub 2019 Feb 4.
• [13] A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis. Am J Hum Genet. 2006 Oct;79(4):759-64. doi: 10.1086/508069. Epub 2006 Aug 24.
• [14] SAMD9 and SAMD9L in inherited predisposition to ataxia, pancytopenia, and myeloid malignancies.Leukemia. 2018 May;32(5):1106-1115. doi: 10.1038/s41375-018-0074-4. Epub 2018 Feb 25.
• [15] The long tail of oncogenic drivers in prostate cancer.Nat Genet. 2018 May;50(5):645-651. doi: 10.1038/s41588-018-0078-z. Epub 2018 Apr 2.
• [16] Primary adrenal insufficiency: New genetic causes and their long-term consequences.Clin Endocrinol (Oxf). 2020 Jan;92(1):11-20. doi: 10.1111/cen.14109. Epub 2019 Oct 30.
• [17] [SAMD9 mutation in normophosphatemic familial tumoral calcinosis].Ann Dermatol Venereol. 2007 May;134(5 Pt 1):505. doi: 10.1016/s0151-9638(07)89230-1.
• [18] Novel SAMD9 Mutation in a Patient With Immunodeficiency, Neutropenia, Impaired Anti-CMV Response, and Severe Gastrointestinal Involvement.Front Immunol. 2019 Sep 18;10:2194. doi: 10.3389/fimmu.2019.02194. eCollection 2019.
• [19] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [20] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [21] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [22] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [23] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [24] Hypoxia-inducible factor-1 (HIF-1) pathway activation by quercetin in human lens epithelial cells. Exp Eye Res. 2009 Dec;89(6):995-1002. doi: 10.1016/j.exer.2009.08.011. Epub 2009 Sep 1.
• [25] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [26] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [27] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [28] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [29] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [30] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [31] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [32] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [33] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [34] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.