Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLF5T11)

• DOT Name: Molecular chaperone MKKS (MKKS)
• Synonyms: Bardet-Biedl syndrome 6 protein; McKusick-Kaufman/Bardet-Biedl syndromes putative chaperonin
• Gene Name: MKKS
• Related Disease:
  McKusick-Kaufman syndrome
  Postaxial polydactyly
  Advanced cancer
  Alstrom syndrome
  Bardet-Biedl syndrome 1
  Bardet-Biedl syndrome 6
  Chromosomal disorder
  High blood pressure
  HIV infectious disease
  Immunodeficiency
  Joubert syndrome
  Joubert syndrome with oculorenal defect
  Nephronophthisis
  Nephropathy
  Nijmegen breakage syndrome
  Plasma cell myeloma
  Polydactyly
  Retinitis pigmentosa
  Retinoblastoma
  Tetralogy of fallot
  Transposition of the great arteries
  Trichohepatoenteric syndrome
  Type-1/2 diabetes
  Xanthinuria type I
  Xanthinuria type II
  Bardet biedl syndrome
  Neoplasm
  Ciliopathy
  Congenital heart disease
  Kabuki syndrome
• UniProt ID: MKKS_HUMAN
• Pfam ID: PF00118
• Sequence:
  MSRLEAKKPSLCKSEPLTTERVRTTLSVLKRIVTSCYGPSGRLKQLHNGFGGYVCTTSQS
  SALLSHLLVTHPILKILTASIQNHVSSFSDCGLFTAILCCNLIENVQRLGLTPTTVIRLN
  KHLLSLCISYLKSETCGCRIPVDFSSTQILLCLVRSILTSKPACMLTRKETEHVSALILR
  AFLLTIPENAEGHIILGKSLIVPLKGQRVIDSTVLPGILIEMSEVQLMRLLPIKKSTALK
  VALFCTTLSGDTSDTGEGTVVVSYGVSLENAVLDQLLNLGRQLISDHVDLVLCQKVIHPS
  LKQFLNMHRIIAIDRIGVTLMEPLTKMTGTQPIGSLGSICPNSYGSVKDVCTAKFGSKHF
  FHLIPNEATICSLLLCNRNDTAWDELKLTCQTALHVLQLTLKEPWALLGGGCTETHLAAY
  IRHKTHNDPESILKDDECTQTELQLIAEAFCSALESVVGSLEHDGGEILTDMKYGHLWSV
  QADSPCVANWPDLLSQCGCGLYNSQEELNWSFLRSTRRPFVPQSCLPHEAVGSASNLTLD
  CLTAKLSGLQVAVETANLILDLSYVIEDKN
• Function: Probable molecular chaperone that assists the folding of proteins upon ATP hydrolysis. Plays a role in the assembly of BBSome, a complex involved in ciliogenesis regulating transports vesicles to the cilia. May play a role in protein processing in limb, cardiac and reproductive system development. May play a role in cytokinesis.
• Tissue Specificity: Widely expressed in adult and fetal tissues.
• Reactome Pathway: BBSome-mediated cargo-targeting to cilium (R-HSA-5620922)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
McKusick-Kaufman syndrome	DIS8JXFP	Definitive	Autosomal recessive	[1]
Postaxial polydactyly	DIS085OV	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Alstrom syndrome	DISFVX55	Strong	Genetic Variation	[3]
Bardet-Biedl syndrome 1	DISRLPZE	Strong	Genetic Variation	[4]
Bardet-Biedl syndrome 6	DIS7U0YK	Strong	Autosomal recessive	[5]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[6]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[7]
HIV infectious disease	DISO97HC	Strong	Biomarker	[8]
Immunodeficiency	DIS093I0	Strong	Biomarker	[8]
Joubert syndrome	DIS7P5CO	Strong	Biomarker	[9]
Joubert syndrome with oculorenal defect	DISU0IPO	Strong	Biomarker	[9]
Nephronophthisis	DISXU4HY	Strong	Biomarker	[10]
Nephropathy	DISXWP4P	Strong	Genetic Variation	[9]
Nijmegen breakage syndrome	DIS98HVL	Strong	Genetic Variation	[11]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[12]
Polydactyly	DIS25BMZ	Strong	Genetic Variation	[13]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[13]
Retinoblastoma	DISVPNPB	Strong	Altered Expression	[14]
Tetralogy of fallot	DISMHFNW	Strong	Genetic Variation	[15]
Transposition of the great arteries	DISPXJ8X	Strong	Genetic Variation	[16]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[17]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[7]
Xanthinuria type I	DISIRVYD	Strong	Genetic Variation	[16]
Xanthinuria type II	DISRWX6S	Strong	Genetic Variation	[16]
Bardet biedl syndrome	DISTBNZW	Supportive	Autosomal recessive	[18]
Neoplasm	DISZKGEW	Disputed	Genetic Variation	[12]
Ciliopathy	DIS10G4I	Limited	Genetic Variation	[19]
Congenital heart disease	DISQBA23	Limited	Biomarker	[20]
Kabuki syndrome	DISZN97H	Limited	Genetic Variation	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Molecular chaperone MKKS (MKKS).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Molecular chaperone MKKS (MKKS).	[23]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Molecular chaperone MKKS (MKKS).	[24]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Molecular chaperone MKKS (MKKS).	[25]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Molecular chaperone MKKS (MKKS).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Molecular chaperone MKKS (MKKS).	[26]

References

• [1] Mutation of a gene encoding a putative chaperonin causes McKusick-Kaufman syndrome. Nat Genet. 2000 May;25(1):79-82. doi: 10.1038/75637.
• [2] Efficacy and Mechanism of Antitumor Activity of an Antibody Targeting Transferrin Receptor 1 in Mouse Models of Human Multiple Myeloma.J Immunol. 2018 May 15;200(10):3485-3494. doi: 10.4049/jimmunol.1700787. Epub 2018 Apr 13.
• [3] Mutations in chaperonin-like BBS genes are a major contributor to disease development in a multiethnic Bardet-Biedl syndrome patient population.J Med Genet. 2010 Jul;47(7):453-63. doi: 10.1136/jmg.2009.073205. Epub 2010 May 14.
• [4] Sequence variants in four genes underlying Bardet-Biedl syndrome in consanguineous families.Mol Vis. 2017 Jul 21;23:482-494. eCollection 2017.
• [5] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [6] Two human myeloma cell lines, amylase-producing KMS-12-PE and amylase-non-producing KMS-12-BM, were established from a patient, having the same chromosome marker, t(11;14)(q13;q32).Br J Haematol. 1989 Oct;73(2):199-204. doi: 10.1111/j.1365-2141.1989.tb00252.x.
• [7] Mkks-null mice have a phenotype resembling Bardet-Biedl syndrome.Hum Mol Genet. 2005 May 1;14(9):1109-18. doi: 10.1093/hmg/ddi123. Epub 2005 Mar 16.
• [8] Congenital Tracheobronchomegaly (Mounier-Kuhn Syndrome) in a Woman with Human Immunodeficiency Virus: A Case Report.Cureus. 2017 Apr 4;9(4):e1136. doi: 10.7759/cureus.1136.
• [9] The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat Genet. 2007 Jul;39(7):875-81. doi: 10.1038/ng2039. Epub 2007 Jun 10.
• [10] MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Transition Zone.PLoS Biol. 2016 Mar 16;14(3):e1002416. doi: 10.1371/journal.pbio.1002416. eCollection 2016 Mar.
• [11] Bardet-Biedl Syndrome as a Chaperonopathy: Dissecting the Major Role of Chaperonin-Like BBS Proteins (BBS6-BBS10-BBS12).Front Mol Biosci. 2017 Jul 31;4:55. doi: 10.3389/fmolb.2017.00055. eCollection 2017.
• [12] An IgG1 Version of the Anti-transferrin Receptor 1 Antibody ch128.1 Shows Significant Antitumor Activity Against Different Xenograft Models of Multiple Myeloma: A Brief Communication.J Immunother. 2020 Feb/Mar;43(2):48-52. doi: 10.1097/CJI.0000000000000304.
• [13] A novel H395R mutation in MKKS/BBS6 causes retinitis pigmentosa and polydactyly without other findings of Bardet-Biedl or McKusick-Kaufman syndrome.Mol Vis. 2016 Jan 24;22:73-81. eCollection 2016.
• [14] Alteration in the retinoblastoma gene associated with immortalization of human fibroblasts treated with 60Co gamma rays.J Cancer Res Clin Oncol. 1993;119(9):522-6. doi: 10.1007/BF01686461.
• [15] A female with complete lack of Mllerian fusion, postaxial polydactyly, and tetralogy of fallot: genetic heterogeneity of McKusick-Kaufman syndrome or a unique syndrome?.Am J Med Genet A. 2004 Aug 15;129A(1):69-72. doi: 10.1002/ajmg.a.30071.
• [16] Mutation of human molybdenum cofactor sulfurase gene is responsible for classical xanthinuria type II. Biochem Biophys Res Commun. 2001 Apr 20;282(5):1194-200. doi: 10.1006/bbrc.2001.4719.
• [17] Genetic and mutational analyses of a large multiethnic Bardet-Biedl cohort reveal a minor involvement of BBS6 and delineate the critical intervals of other loci.Am J Hum Genet. 2001 Mar;68(3):606-16. doi: 10.1086/318794. Epub 2001 Feb 1.
• [18] Bardet-Biedl Syndrome Overview. 2003 Jul 14 [updated 2023 Mar 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [19] Functional analysis of new human Bardet-Biedl syndrome loci specific variants in the zebrafish model.Sci Rep. 2019 Sep 10;9(1):12936. doi: 10.1038/s41598-019-49217-7.
• [20] Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein.PLoS Genet. 2017 Jul 28;13(7):e1006936. doi: 10.1371/journal.pgen.1006936. eCollection 2017 Jul.
• [21] Cutis laxa in Kabuki make-up syndrome.J Am Acad Dermatol. 2005 Nov;53(5 Suppl 1):S247-51. doi: 10.1016/j.jaad.2005.02.007.
• [22] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [27] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.