Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTME92T5)

• DOT Name: Meckelin (TMEM67)
• Synonyms: Meckel syndrome type 3 protein; Transmembrane protein 67
• Gene Name: TMEM67
• Related Disease:
  Ciliopathy
  COACH syndrome 1
  Meckel syndrome, type 3
  Nephronophthisis 11
  NPHP3-related Meckel-like syndrome
  Autosomal recessive polycystic kidney disease
  Bardet biedl syndrome
  Bardet-Biedl syndrome 14
  Cerebellar ataxia
  Corpus callosum, agenesis of
  Hydrocephalus
  Joubert syndrome 1
  Joubert syndrome 6
  Meckel syndrome, type 1
  Microcephaly
  Movement disorder
  Obsolete COACH syndrome 1
  Polycystic kidney disease
  Polydactyly
  Transitional cell carcinoma
  Trichohepatoenteric syndrome
  Urothelial carcinoma
  Bardet-Biedl syndrome 1
  Nephronophthisis
  Joubert syndrome
  Meckel syndrome
  Senior-Boichis syndrome
  Liver cirrhosis
  COACH syndrome
  Coloboma
  Johanson-Blizzard syndrome
  Nephropathy
• UniProt ID: MKS3_HUMAN
• PDB ID: 7FH1
• Pfam ID: PF09773
• Sequence:
  MATRGGAGVAMAVWSLLSARAVTAFLLLFLPRFLQAQTFSFPFQQPEKCDNNQYFDISAL
  SCVPCGANQRQDARGTSCVCLPGFQMISNNGGPAIICKKCPENMKGVTEDGWNCISCPSD
  LTAEGKCHCPIGHILVERDINGTLLSQATCELCDGNENSFMVVNALGDRCVRCEPTFVNT
  SRSCACSEPNILTGGLCFSSTGNFPLRRISAARYGEVGMSLTSEWFAKYLQSSAAACWVY
  ANLTSCQALGNMCVMNMNSYDFATFDACGLFQFIFENTAGLSTVHSISFWRQNLPWLFYG
  DQLGLAPQVLSSTSLPTNFSFKGENQNTKLKFVAASYDIRGNFLKWQTLEGGVLQLCPDT
  ETRLNAAYSFGTTYQQNCEIPISKILIDFPTPIFYDVYLEYTDENQHQYILAVPVLNLNL
  QHNKIFVNQDSNSGKWLLTRRIFLVDAVSGRENDLGTQPRVIRVATQISLSVHLVPNTIN
  GNIYPPLITIAYSDIDIKDANSQSVKVSFSVTYEMDHGEAHVQTDIALGVLGGLAVLASL
  LKTAGWKRRIGSPMIDLQTVVKFLVYYAGDLANVFFIITVGTGLYWLIFFKAQKSVSVLL
  PMPIQEERFVTYVGCAFALKALQFLHKLISQITIDVFFIDWERPKGKVLKAVEGEGGVRS
  ATVPVSIWRTYFVANEWNEIQTVRKINSLFQVLTVLFFLEVVGFKNLALMDSSSSLSRNP
  PSYIAPYSCILRYAVSAALWLAIGIIQVVFFAVFYERFIEDKIRQFVDLCSMSNISVFLL
  SHKCFGYYIHGRSVHGHADTNMEEMNMNLKREAENLCSQRGLVPNTDGQTFEIAISNQMR
  QHYDRIHETLIRKNGPARLLSSSASTFEQSIKAYHMMNKFLGSFIDHVHKEMDYFIKDKL
  LLERILGMEFMEPMEKSIFYNDEGYSFSSVLYYGNEATLLIFDLLFFCVVDLACQNFILA
  SFLTYLQQEIFRYIRNTVGQKNLASKTLVDQRFLI
• Function: Required for ciliary structure and function. Part of the tectonic-like complex which is required for tissue-specific ciliogenesis and may regulate ciliary membrane composition. Involved in centrosome migration to the apical cell surface during early ciliogenesis. Involved in the regulation of cilia length and appropriate number through the control of centrosome duplication. Is a key regulator of stereociliary bundle orientation. Required for epithelial cell branching morphology. Essential for endoplasmic reticulum-associated degradation (ERAD) of surfactant protein C (SFTPC). Involved in the negative regulation of canonical Wnt signaling, and activation of the non-canonical cascade stimulated by WNT5A. In non-canonical Wnt signaling, it may act as ROR2 coreceptor.
• Tissue Specificity: Widely expressed in adult and fetal tissues. Expressed at higher level in spinal cord.
• Reactome Pathway: Anchoring of the basal body to the plasma membrane (R-HSA-5620912)

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ciliopathy	DIS10G4I	Definitive	Autosomal recessive	[1]
COACH syndrome 1	DISQXOF1	Definitive	Autosomal recessive	[2]
Meckel syndrome, type 3	DISJIYCP	Definitive	Autosomal recessive	[3]
Nephronophthisis 11	DISFGV8H	Definitive	Autosomal recessive	[4]
NPHP3-related Meckel-like syndrome	DIS2QQIV	Definitive	Genetic Variation	[5]
Autosomal recessive polycystic kidney disease	DISPUS40	Strong	Biomarker	[6]
Bardet biedl syndrome	DISTBNZW	Strong	Biomarker	[7]
Bardet-Biedl syndrome 14	DISJLM82	Strong	Biomarker	[8]
Cerebellar ataxia	DIS9IRAV	Strong	CausalMutation	[4]
Corpus callosum, agenesis of	DISO9P40	Strong	Genetic Variation	[9]
Hydrocephalus	DISIZUF7	Strong	Genetic Variation	[6]
Joubert syndrome 1	DISC9Q82	Strong	GermlineCausalMutation	[10]
Joubert syndrome 6	DISYSPXV	Strong	Autosomal recessive	[3]
Meckel syndrome, type 1	DIS4YWZU	Strong	Genetic Variation	[6]
Microcephaly	DIS2GRD8	Strong	Genetic Variation	[11]
Movement disorder	DISOJJ2D	Strong	CausalMutation	[12]
Obsolete COACH syndrome 1	DISM57KK	Strong	Autosomal recessive	[3]
Polycystic kidney disease	DISWS3UY	Strong	Genetic Variation	[6]
Polydactyly	DIS25BMZ	Strong	Biomarker	[2]
Transitional cell carcinoma	DISWVVDR	Strong	Altered Expression	[13]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[14]
Urothelial carcinoma	DISRTNTN	Strong	Altered Expression	[13]
Bardet-Biedl syndrome 1	DISRLPZE	moderate	Genetic Variation	[9]
Nephronophthisis	DISXU4HY	moderate	Genetic Variation	[15]
Joubert syndrome	DIS7P5CO	Supportive	Autosomal recessive	[10]
Meckel syndrome	DISXPHOY	Supportive	Autosomal recessive	[16]
Senior-Boichis syndrome	DISQ4EJN	Supportive	Autosomal recessive	[4]
Liver cirrhosis	DIS4G1GX	Disputed	Biomarker	[4]
COACH syndrome	DISVDRSD	Limited	Biomarker	[14]
Coloboma	DISP39N5	Limited	Genetic Variation	[17]
Johanson-Blizzard syndrome	DISYNPE8	Limited	Biomarker	[18]
Nephropathy	DISXWP4P	Limited	Genetic Variation	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Meckelin (TMEM67).	[19]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Meckelin (TMEM67).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Meckelin (TMEM67).	[21]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Meckelin (TMEM67).	[22]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Meckelin (TMEM67).	[23]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Meckelin (TMEM67).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Meckelin (TMEM67).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Meckelin (TMEM67).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Meckelin (TMEM67).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Meckelin (TMEM67).	[26]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the acetylation of Meckelin (TMEM67).	[28]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Molecular diagnostics of Meckel-Gruber syndrome highlights phenotypic differences between MKS1 and MKS3. Hum Genet. 2007 Jun;121(5):591-9. doi: 10.1007/s00439-007-0341-3. Epub 2007 Mar 22.
• [3] 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.
• [4] Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11). J Med Genet. 2009 Oct;46(10):663-70. doi: 10.1136/jmg.2009.066613. Epub 2009 Jun 8.
• [5] An ovine hepatorenal fibrocystic model of a Meckel-like syndrome associated with dysmorphic primary cilia and TMEM67 mutations.Sci Rep. 2017 May 9;7(1):1601. doi: 10.1038/s41598-017-01519-4.
• [6] Hydrocephalus in a rat model of Meckel Gruber syndrome with a TMEM67 mutation.Sci Rep. 2019 Jan 31;9(1):1069. doi: 10.1038/s41598-018-37620-5.
• [7] Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. Nat Genet. 2008 Apr;40(4):443-8. doi: 10.1038/ng.97. Epub 2008 Mar 9.
• [8] A missense mutation in TMEM67 causes Meckel-Gruber syndrome type 3 (MKS3): a family from China.Int J Clin Exp Pathol. 2015 May 1;8(5):5379-86. eCollection 2015.
• [9] The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat.Nat Genet. 2006 Feb;38(2):191-6. doi: 10.1038/ng1713. Epub 2006 Jan 15.
• [10] The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome. Am J Hum Genet. 2007 Jan;80(1):186-94. doi: 10.1086/510499. Epub 2006 Nov 15.
• [11] Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability. Mol Psychiatry. 2017 Nov;22(11):1604-1614. doi: 10.1038/mp.2016.109. Epub 2016 Jul 26.
• [12] Joubert syndrome: genotyping a Northern European patient cohort.Eur J Hum Genet. 2016 Feb;24(2):214-20. doi: 10.1038/ejhg.2015.84. Epub 2015 Apr 29.
• [13] Low expression of TMEM67 is a critical predictor of poor prognosis in human urothelial carcinoma of the bladder.Urol Oncol. 2017 Apr;35(4):152.e7-152.e12. doi: 10.1016/j.urolonc.2016.10.014. Epub 2017 Feb 1.
• [14] Functional validation of novel MKS3/TMEM67 mutations in COACH syndrome.Sci Rep. 2017 Aug 31;7(1):10222. doi: 10.1038/s41598-017-10652-z.
• [15] High-throughput mutation analysis in patients with a nephronophthisis-associated ciliopathy applying multiplexed barcoded array-based PCR amplification and next-generation sequencing.J Med Genet. 2012 Dec;49(12):756-67. doi: 10.1136/jmedgenet-2012-100973.
• [16] Molecular genetics and pathogenic mechanisms for the severe ciliopathies: insights into neurodevelopment and pathogenesis of neural tube defects. Mol Neurobiol. 2011 Feb;43(1):12-26. doi: 10.1007/s12035-010-8154-0. Epub 2010 Nov 27.
• [17] Characteristics of Liver Disease in 100 Individuals With Joubert Syndrome Prospectively Evaluated at a Single Center.J Pediatr Gastroenterol Nutr. 2018 Mar;66(3):428-435. doi: 10.1097/MPG.0000000000001816.
• [18] CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype-phenotype correlation.Hum Mutat. 2009 Nov;30(11):1574-82. doi: 10.1002/humu.21116.
• [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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [21] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [22] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [23] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [24] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [25] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [26] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [27] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [28] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.