Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1USO08)

• DOT Name: Protein Lines homolog 1 (LINS1)
• Synonyms: Wnt-signaling molecule Lines homolog 1
• Gene Name: LINS1
• Related Disease:
  Complex neurodevelopmental disorder
  Intellectual disability, autosomal recessive 27
  Intellectual disability
  Isolated congenital microcephaly
  Autosomal recessive non-syndromic intellectual disability
• UniProt ID: LINES_HUMAN
• Pfam ID: PF14695 ; PF14694
• Sequence:
  MKVFCEVLEELYKKVLLGATLENDSHDYIFYLNPAVSDQDCSTATSLEWANTCGIQGRHQ
  PISVGVAPIAVAPVCLKTNSQMSGSREVMLLQLTVIKVMTTRILSVKTEFHAKEQYRDVI
  KILLESAKVDSKLICMFQNSDKLLSHMAAQCLALLLYFQLREKITLSNSWIAFCQKNLSE
  YSESNKAIYCLWTLTAIIKEIFKDSCSQKTEILKQFLTHFDTIFEVFYNSLFSQHFENCR
  DTSKIVNILMCFLDLLELLIASRIHLKLHFTCQRILFLKPSCMLEVITWPIQAFVKRKVI
  IFLKKCLLCKVGEDLCRGSVPALMPPDHHVAVDMLALANAVLQAVNSGLLKTLSVYEKHS
  FFGGDEVQPECELITSPDHVILRAASLVIMKSLEIKFQNYSSASEVKVDLQRFMSELLTF
  LKPHLQPSLQLHNPCKWLSRVFIEQDDDMLEAAKASLGIYLTLTRGCEATESLTQGKEMW
  DHHTHENGYNPHCIFLFFLKNIGFDSTVLLDFLISSETCFLEYFVRYLKLLQKDWDNFFT
  ICNNFDATESKYDISICGCVPSLVQDQSSNQTIPHRLTAPHSHRDVCARHSWASDAPSEP
  LKAVMSKGAHTMCASSLSSPRASQSLVDYDSSDDSDVESTEQCLANSKQTSLHQQATKEI
  QDAAGTSRDKKEFSLEPPSRPLVLKEFDTAFSFDCEVAPNDVVSEVGIFYRIVKCFQELQ
  DAICRLQKKNLFPYNPTALLKLLKYIEVISNKTMNTL
• Tissue Specificity: Expressed in adult testis, prostate, prostate, spleen, thymus, skeletal muscle, fetal kidney and brain.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal recessive	[1]
Intellectual disability, autosomal recessive 27	DIS09LQR	Strong	Autosomal recessive	[2]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[3]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[4]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[4]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Protein Lines homolog 1 (LINS1) affects the response to substance of Temozolomide.	[11]
DTI-015	DMXZRW0	Approved	Protein Lines homolog 1 (LINS1) affects the response to substance of DTI-015.	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Protein Lines homolog 1 (LINS1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein Lines homolog 1 (LINS1).	[6]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Protein Lines homolog 1 (LINS1).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Protein Lines homolog 1 (LINS1).	[8]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Protein Lines homolog 1 (LINS1).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein Lines homolog 1 (LINS1).	[10]

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] Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. 2011 Sep 21;478(7367):57-63. doi: 10.1038/nature10423.
• [3] Novel LINS1 missense mutation in a family with non-syndromic intellectual disability.Am J Med Genet A. 2017 Apr;173(4):1041-1046. doi: 10.1002/ajmg.a.38089. Epub 2017 Feb 9.
• [4] LINS, a modulator of the WNT signaling pathway, is involved in human cognition. Orphanet J Rare Dis. 2013 Jun 17;8:87. doi: 10.1186/1750-1172-8-87.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [8] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [9] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [10] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [11] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.