Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDARQT3)

• DOT Name: MutS protein homolog 5 (MSH5)
• Synonyms: hMSH5
• Gene Name: MSH5
• Related Disease:
  Hepatocellular carcinoma
  Ovarian cancer
  Prostate cancer
  Prostate carcinoma
  Advanced cancer
  Azoospermia
  Barrett esophagus
  Coeliac disease
  Common variable immunodeficiency
  Leukoencephalopathy with vanishing white matter
  Lung adenocarcinoma
  Lupus
  Male infertility
  Myasthenia gravis
  Non-hodgkin lymphoma
  Oligospermia
  Rheumatoid arthritis
  Schizophrenia
  Sjogren syndrome
  Spermatogenic failure 74
  Systemic sclerosis
  Type-1 diabetes
  Female hypogonadism
  Non-insulin dependent diabetes
  Premature ovarian failure 13
  Ulcerative colitis
• UniProt ID: MSH5_HUMAN
• Pfam ID: PF05192 ; PF05190 ; PF00488
• Sequence:
  MASLGANPRRTPQGPRPGAASSGFPSPAPVPGPREAEEEEVEEEEELAEIHLCVLWNSGY
  LGIAYYDTSDSTIHFMPDAPDHESLKLLQRVLDEINPQSVVTSAKQDENMTRFLGKLASQ
  EHREPKRPEIIFLPSVDFGLEISKQRLLSGNYSFIPDAMTATEKILFLSSIIPFDCLLTV
  RALGGLLKFLGRRRIGVELEDYNVSVPILGFKKFMLTHLVNIDQDTYSVLQIFKSESHPS
  VYKVASGLKEGLSLFGILNRCHCKWGEKLLRLWFTRPTHDLGELSSRLDVIQFFLLPQNL
  DMAQMLHRLLGHIKNVPLILKRMKLSHTKVSDWQVLYKTVYSALGLRDACRSLPQSIQLF
  RDIAQEFSDDLHHIASLIGKVVDFEGSLAENRFTVLPNIDPEIDEKKRRLMGLPSFLTEV
  ARKELENLDSRIPSCSVIYIPLIGFLLSIPRLPSMVEASDFEINGLDFMFLSEEKLHYRS
  ARTKELDALLGDLHCEIRDQETLLMYQLQCQVLARAAVLTRVLDLASRLDVLLALASAAR
  DYGYSRPRYSPQVLGVRIQNGRHPLMELCARTFVPNSTECGGDKGRVKVITGPNSSGKSI
  YLKQVGLITFMALVGSFVPAEEAEIGAVDAIFTRIHSCESISLGLSTFMIDLNQVAKAVN
  NATAQSLVLIDEFGKGTNTVDGLALLAAVLRHWLARGPTCPHIFVATNFLSLVQLQLLPQ
  GPLVQYLTMETCEDGNDLVFFYQVCEGVAKASHASHTAAQAGLPDKLVARGKEVSDLIRS
  GKPIKPVKDLLKKNQMENCQTLVDKFMKLDLEDPNLDLNVFMSQEVLPAATSIL
• Function: Involved in DNA mismatch repair and meiotic recombination processes. Facilitates crossovers between homologs during meiosis.
• Tissue Specificity: Widely expressed, with high levels in testis and ovary, including granulosa cells . Also expressed in fetal ovary and adrenal gland .
• Reactome Pathway: Meiotic recombination (R-HSA-912446)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Ovarian cancer	DISZJHAP	Definitive	Genetic Variation	[2]
Prostate cancer	DISF190Y	Definitive	Genetic Variation	[2]
Prostate carcinoma	DISMJPLE	Definitive	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Azoospermia	DIS94181	Strong	Genetic Variation	[4]
Barrett esophagus	DIS416Y7	Strong	Biomarker	[5]
Coeliac disease	DISIY60C	Strong	Genetic Variation	[6]
Common variable immunodeficiency	DISHE7JQ	Strong	Genetic Variation	[7]
Leukoencephalopathy with vanishing white matter	DIS3J8NN	Strong	Biomarker	[5]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[8]
Lupus	DISOKJWA	Strong	Biomarker	[9]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[3]
Myasthenia gravis	DISELRCI	Strong	Genetic Variation	[10]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Genetic Variation	[11]
Oligospermia	DIS6YJF3	Strong	Genetic Variation	[4]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[12]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[13]
Sjogren syndrome	DISUBX7H	Strong	Genetic Variation	[14]
Spermatogenic failure 74	DIS8RSNV	Strong	Autosomal recessive	[15]
Systemic sclerosis	DISF44L6	Strong	Genetic Variation	[16]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[17]
Female hypogonadism	DISWASB4	moderate	Genetic Variation	[18]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[19]
Premature ovarian failure 13	DIS17J15	Limited	Unknown	[20]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of MutS protein homolog 5 (MSH5).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of MutS protein homolog 5 (MSH5).	[23]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of MutS protein homolog 5 (MSH5).	[25]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of MutS protein homolog 5 (MSH5).	[26]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of MutS protein homolog 5 (MSH5).	[26]
Selenium	DM25CGV	Approved	Selenium decreases the expression of MutS protein homolog 5 (MSH5).	[27]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of MutS protein homolog 5 (MSH5).	[28]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of MutS protein homolog 5 (MSH5).	[29]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of MutS protein homolog 5 (MSH5).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of MutS protein homolog 5 (MSH5).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of MutS protein homolog 5 (MSH5).	[31]
CH-223191	DMMJZYC	Investigative	CH-223191 increases the expression of MutS protein homolog 5 (MSH5).	[32]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of MutS protein homolog 5 (MSH5).	[24]

References

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• [5] Genome-wide association study identifies new susceptibility loci for cutaneous lupus erythematosus.Exp Dermatol. 2015 Jul;24(7):510-5. doi: 10.1111/exd.12708. Epub 2015 May 4.
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• [10] Risk for myasthenia gravis maps to a (151) ProAla change in TNIP1 and to human leukocyte antigen-B*08.Ann Neurol. 2012 Dec;72(6):927-35. doi: 10.1002/ana.23691. Epub 2012 Oct 10.
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• [15] Bi-allelic variants in DNA mismatch repair proteins MutS Homolog MSH4 and MSH5 cause infertility in both sexes. Hum Reprod. 2021 Dec 27;37(1):178-189. doi: 10.1093/humrep/deab230.
• [16] Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus.Nat Genet. 2010 May;42(5):426-9. doi: 10.1038/ng.565. Epub 2010 Apr 11.
• [17] Several loci in the HLA class III region are associated with T1D risk after adjusting for DRB1-DQB1.Diabetes Obes Metab. 2009 Feb;11 Suppl 1(Suppl 1):46-52. doi: 10.1111/j.1463-1326.2008.01002.x.
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• [20] Exome sequencing analysis reveals variants in primary immunodeficiency genes in patients with very early onset inflammatory bowel disease. Gastroenterology. 2015 Nov;149(6):1415-24. doi: 10.1053/j.gastro.2015.07.006. Epub 2015 Jul 17.
• [21] Genome-wide association scan in north Indians reveals three novel HLA-independent risk loci for ulcerative colitis.Gut. 2015 Apr;64(4):571-9. doi: 10.1136/gutjnl-2013-306625. Epub 2014 May 16.
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