Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9G0MCT)

• DOT Name: Collagen alpha-4(IV) chain (COL4A4)
• Synonyms: Collagen alpha-4(IV) chain
• Gene Name: COL4A4
• Related Disease:
  Alport syndrome
  Autosomal recessive Alport syndrome
  Deafness
  Hereditary nephritis
  Alzheimer disease
  Andersen-Tawil syndrome
  Arterial tortuosity syndrome
  Chronic renal failure
  End-stage renal disease
  Hematuria, benign familial
  Hematuria, benign familial, 1
  Kidney failure
  Nephropathy
  Osteoporosis
  Chronic kidney disease
  Sensorineural hearing loss disorder
  Autosomal dominant Alport syndrome
  X-linked hydrocephalus with stenosis of the aqueduct of Sylvius
• UniProt ID: CO4A4_HUMAN
• PDB ID: 5NB1; 6WKU
• Pfam ID: PF01413 ; PF01391
• Sequence:
  MWSLHIVLMRCSFRLTKSLATGPWSLILILFSVQYVYGSGKKYIGPCGGRDCSVCHCVPE
  KGSRGPPGPPGPQGPIGPLGAPGPIGLSGEKGMRGDRGPPGAAGDKGDKGPTGVPGFPGL
  DGIPGHPGPPGPRGKPGMSGHNGSRGDPGFPGGRGALGPGGPLGHPGEKGEKGNSVFILG
  AVKGIQGDRGDPGLPGLPGSWGAGGPAGPTGYPGEPGLVGPPGQPGRPGLKGNPGVGVKG
  QMGDPGEVGQQGSPGPTLLVEPPDFCLYKGEKGIKGIPGMVGLPGPPGRKGESGIGAKGE
  KGIPGFPGPRGDPGSYGSPGFPGLKGELGLVGDPGLFGLIGPKGDPGNRGHPGPPGVLVT
  PPLPLKGPPGDPGFPGRYGETGDVGPPGPPGLLGRPGEACAGMIGPPGPQGFPGLPGLPG
  EAGIPGRPDSAPGKPGKPGSPGLPGAPGLQGLPGSSVIYCSVGNPGPQGIKGKVGPPGGR
  GPKGEKGNEGLCACEPGPMGPPGPPGLPGRQGSKGDLGLPGWLGTKGDPGPPGAEGPPGL
  PGKHGASGPPGNKGAKGDMVVSRVKGHKGERGPDGPPGFPGQPGSHGRDGHAGEKGDPGP
  PGDHEDATPGGKGFPGPLGPPGKAGPVGPPGLGFPGPPGERGHPGVPGHPGVRGPDGLKG
  QKGDTISCNVTYPGRHGPPGFDGPPGPKGFPGPQGAPGLSGSDGHKGRPGTPGTAEIPGP
  PGFRGDMGDPGFGGEKGSSPVGPPGPPGSPGVNGQKGIPGDPAFGHLGPPGKRGLSGVPG
  IKGPRGDPGCPGAEGPAGIPGFLGLKGPKGREGHAGFPGVPGPPGHSCERGAPGIPGQPG
  LPGYPGSPGAPGGKGQPGDVGPPGPAGMKGLPGLPGRPGAHGPPGLPGIPGPFGDDGLPG
  PPGPKGPRGLPGFPGFPGERGKPGAEGCPGAKGEPGEKGMSGLPGDRGLRGAKGAIGPPG
  DEGEMAIISQKGTPGEPGPPGDDGFPGERGDKGTPGMQGRRGEPGRYGPPGFHRGEPGEK
  GQPGPPGPPGPPGSTGLRGFIGFPGLPGDQGEPGSPGPPGFSGIDGARGPKGNKGDPASH
  FGPPGPKGEPGSPGCPGHFGASGEQGLPGIQGPRGSPGRPGPPGSSGPPGCPGDHGMPGL
  RGQPGEMGDPGPRGLQGDPGIPGPPGIKGPSGSPGLNGLHGLKGQKGTKGASGLHDVGPP
  GPVGIPGLKGERGDPGSPGISPPGPRGKKGPPGPPGSSGPPGPAGATGRAPKDIPDPGPP
  GDQGPPGPDGPRGAPGPPGLPGSVDLLRGEPGDCGLPGPPGPPGPPGPPGYKGFPGCDGK
  DGQKGPVGFPGPQGPHGFPGPPGEKGLPGPPGRKGPTGLPGPRGEPGPPADVDDCPRIPG
  LPGAPGMRGPEGAMGLPGMRGPSGPGCKGEPGLDGRRGVDGVPGSPGPPGRKGDTGEDGY
  PGGPGPPGPIGDPGPKGFGPGYLGGFLLVLHSQTDQEPTCPLGMPRLWTGYSLLYLEGQE
  KAHNQDLGLAGSCLPVFSTLPFAYCNIHQVCHYAQRNDRSYWLASAAPLPMMPLSEEAIR
  PYVSRCAVCEAPAQAVAVHSQDQSIPPCPQTWRSLWIGYSFLMHTGAGDQGGGQALMSPG
  SCLEDFRAAPFLECQGRQGTCHFFANKYSFWLTTVKADLQFSSAPAPDTLKESQAQRQKI
  SRCQVCVKYS
• Function: Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a 'chicken-wire' meshwork together with laminins, proteoglycans and entactin/nidogen.
• Tissue Specificity: Expressed in Bruch's membrane, outer plexiform layer, inner nuclear layer, inner plexiform layer, ganglion cell layer, inner limiting membrane and around the blood vessels of the retina (at protein level) . Alpha 3 and alpha 4 type IV collagens are colocalized and present in kidney, eye, basement membranes of lens capsule, cochlea, lung, skeletal muscle, aorta, synaptic fibers, fetal kidney and fetal lung. PubMed:8083201 reports similar levels of expression of alpha 3 and alpha 4 type IV collagens in kidney, but PubMed:7523402 reports that in kidney levels of alpha 3 type IV collagen are significantly lower than those of alpha 4 type IV collagen. Highest levels of expression of alpha 4 type IV collagen are detected in kidney, calvaria, neuroretina and cardiac muscle. Lower levels of expression are observed in brain, lung and thymus, and no expression is detected in choroid plexus, liver, adrenal, pancreas, ileum or skin.
• KEGG Pathway:
  PI3K-Akt sig.ling pathway (hsa04151)
  Focal adhesion (hsa04510)
  ECM-receptor interaction (hsa04512)
  Cytoskeleton in muscle cells (hsa04820)
  Relaxin sig.ling pathway (hsa04926)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Protein digestion and absorption (hsa04974)
  Amoebiasis (hsa05146)
  Human papillomavirus infection (hsa05165)
  Pathways in cancer (hsa05200)
  Small cell lung cancer (hsa05222)
• Reactome Pathway:
  Extracellular matrix organization (R-HSA-1474244)
  Collagen biosynthesis and modifying enzymes (R-HSA-1650814)
  Signaling by PDGF (R-HSA-186797)
  Assembly of collagen fibrils and other multimeric structures (R-HSA-2022090)
  Integrin cell surface interactions (R-HSA-216083)
  Anchoring fibril formation (R-HSA-2214320)
  Crosslinking of collagen fibrils (R-HSA-2243919)
  Laminin interactions (R-HSA-3000157)
  Non-integrin membrane-ECM interactions (R-HSA-3000171)
  ECM proteoglycans (R-HSA-3000178)
  NCAM1 interactions (R-HSA-419037)
  Collagen chain trimerization (R-HSA-8948216)
  Collagen degradation (R-HSA-1442490)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alport syndrome	DIS25AB4	Definitive	Semidominant	[1]
Autosomal recessive Alport syndrome	DISFOQZB	Definitive	Autosomal recessive	[1]
Deafness	DISKCLH4	Definitive	Genetic Variation	[2]
Hereditary nephritis	DISECBR1	Definitive	Genetic Variation	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[4]
Andersen-Tawil syndrome	DIS3IWZ7	Strong	Biomarker	[5]
Arterial tortuosity syndrome	DISWG36B	Strong	Biomarker	[5]
Chronic renal failure	DISGG7K6	Strong	Genetic Variation	[6]
End-stage renal disease	DISXA7GG	Strong	Genetic Variation	[6]
Hematuria, benign familial	DISCWU1L	Strong	Genetic Variation	[7]
Hematuria, benign familial, 1	DISSUA8W	Strong	Autosomal dominant	[8]
Kidney failure	DISOVQ9P	Strong	Genetic Variation	[9]
Nephropathy	DISXWP4P	Strong	Genetic Variation	[10]
Osteoporosis	DISF2JE0	Strong	Biomarker	[11]
Chronic kidney disease	DISW82R7	moderate	Genetic Variation	[12]
Sensorineural hearing loss disorder	DISJV45Z	moderate	Biomarker	[13]
Autosomal dominant Alport syndrome	DIS3MD0D	Supportive	Autosomal dominant	[14]
X-linked hydrocephalus with stenosis of the aqueduct of Sylvius	DIS6QXIR	Limited	Genetic Variation	[15]

9 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 Collagen alpha-4(IV) chain (COL4A4).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Collagen alpha-4(IV) chain (COL4A4).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Collagen alpha-4(IV) chain (COL4A4).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Collagen alpha-4(IV) chain (COL4A4).	[19]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Collagen alpha-4(IV) chain (COL4A4).	[20]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Collagen alpha-4(IV) chain (COL4A4).	[21]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Collagen alpha-4(IV) chain (COL4A4).	[22]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Collagen alpha-4(IV) chain (COL4A4).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Collagen alpha-4(IV) chain (COL4A4).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Collagen alpha-4(IV) chain (COL4A4).	[24]

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] Three novel COL4A4 mutations resulting in stop codons and their clinical effects in autosomal recessive Alport syndrome.Hum Mutat. 2002 Oct;20(4):321-2. doi: 10.1002/humu.9065.
• [3] Sixteen novel mutations identified in COL4A3, COL4A4, and COL4A5 genes in Slovenian families with Alport syndrome and benign familial hematuria.Kidney Int. 2007 Jun;71(12):1287-95. doi: 10.1038/sj.ki.5002221. Epub 2007 Mar 28.
• [4] Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3.Mol Psychiatry. 2016 Nov;21(11):1608-1612. doi: 10.1038/mp.2015.218. Epub 2016 Feb 2.
• [5] Identification of 47 novel mutations in patients with Alport syndrome and thin basement membrane nephropathy.Pediatr Nephrol. 2016 Jun;31(6):941-55. doi: 10.1007/s00467-015-3302-4. Epub 2016 Jan 25.
• [6] Possible Digenic Disease in a Caucasian Family with COL4A3 and COL4A5 Mutations.Nephron. 2019;141(3):213-218. doi: 10.1159/000495764. Epub 2019 Jan 18.
• [7] The COL4A3 and COL4A4 Digenic Mutations in cis Result in Benign Familial Hematuria in a Large Chinese Family.Cytogenet Genome Res. 2018;154(3):132-136. doi: 10.1159/000488163. Epub 2018 May 9.
• [8] 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.
• [9] X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations.PLoS One. 2016 Sep 14;11(9):e0161802. doi: 10.1371/journal.pone.0161802. eCollection 2016.
• [10] Three Novel Heterozygous COL4A4 Mutations Result in Three Different Collagen Type IV Kidney Disease Phenotypes.Cytogenet Genome Res. 2018;154(1):30-36. doi: 10.1159/000486979. Epub 2018 Feb 15.
• [11] BFH-OSTM, a new predictive screening tool for identifying osteoporosis in elderly Han Chinese males.Clin Interv Aging. 2017 Jul 31;12:1167-1174. doi: 10.2147/CIA.S140553. eCollection 2017.
• [12] The role of molecular genetics in diagnosing familial hematuria(s).Pediatr Nephrol. 2012 Aug;27(8):1221-31. doi: 10.1007/s00467-011-1935-5. Epub 2011 Jun 19.
• [13] Simultaneous sequencing of 24 genes associated with steroid-resistant nephrotic syndrome.Clin J Am Soc Nephrol. 2013 Apr;8(4):637-48. doi: 10.2215/CJN.07200712. Epub 2013 Jan 24.
• [14] Autosomal dominant Alport syndrome linked to the type IV collage alpha 3 and alpha 4 genes (COL4A3 and COL4A4). Nephrol Dial Transplant. 1997 Aug;12(8):1595-9. doi: 10.1093/ndt/12.8.1595.
• [15] Effect of heterozygous pathogenic COL4A3 or COL4A4 variants on patients with X-linked Alport syndrome.Mol Genet Genomic Med. 2019 May;7(5):e647. doi: 10.1002/mgg3.647. Epub 2019 Mar 18.
• [16] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [17] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [18] 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.
• [19] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [20] Primary Human Hepatocyte Spheroids as Tools to Study the Hepatotoxic Potential of Non-Pharmaceutical Chemicals. Int J Mol Sci. 2021 Oct 12;22(20):11005. doi: 10.3390/ijms222011005.
• [21] Increased matrix proteins, collagen and transforming growth factor are early markers of hepatotoxicity in patients on long-term methotrexate therapy. J Toxicol Clin Toxicol. 1996;34(3):301-5. doi: 10.3109/15563659609013794.
• [22] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [23] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [24] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.