Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFDLU5S)

• DOT Name: Patched domain-containing protein 1 (PTCHD1)
• Gene Name: PTCHD1
• Related Disease:
  Autism, susceptibility to, X-linked 4
  Non-syndromic X-linked intellectual disability
  Autism spectrum disorder
  Intellectual disability, X-linked 1
  X-linked intellectual disability
  Autism
  Movement disorder
  Neurodevelopmental disorder
  Attention deficit hyperactivity disorder
  Intellectual disability
  Pervasive developmental disorder
• UniProt ID: PTHD1_HUMAN
• Pfam ID: PF02460
• Sequence:
  MLRQVLHRGLRTCFSRLGHFIASHPVFFASAPVLISILLGASFSRYQVEESVEHLLAPQH
  SLAKIERNLVNSLFPVNRSKHRLYSDLQTPGRYGRVIVTSFQKANMLDQHHTDLILKLHA
  AVTKIQVPRPGFNYTFAHICILNNDKTCIVDDIVHVLEELKNARATNRTNFAITYPITHL
  KDGRAVYNGHQLGGVTVHSKDRVKSAEAIQLTYYLQSINSLNDMVAERWESSFCDTVRLF
  QKSNSKVKMYPYTSSSLREDFQKTSRVSERYLVTSLILVVTMAILCCSMQDCVRSKPWLG
  LLGLVTISLATLTAAGIINLTGGKYNSTFLGVPFVMLGHGLYGTFEMLSSWRKTREDQHV
  KERTAAVYADSMLSFSLTTAMYLVTFGIGASPFTNIEAARIFCCNSCIAIFFNYLYVLSF
  YGSSLVFTGYIENNYQHSIFCRKVPKPEALQEKPAWYRFLLTARFSEDTAEGEEANTYES
  HLLVCFLKRYYCDWITNTYVKPFVVLFYLIYISFALMGYLQVSEGSDLSNIVATATQTIE
  YTTAQQKYFSNYSPVIGFYIYESIEYWNTSVQEDVLEYTKGFVRISWFESYLNYLRKLNV
  STGLPKKNFTDMLRNSFLKAPQFSHFQEDIIFSKKYNDEVDVVASRMFLVAKTMETNREE
  LYDLLETLRRLSVTSKVKFIVFNPSFVYMDRYASSLGAPLHNSCISALFLLFFSAFLVAD
  SLINVWITLTVVSVEFGVIGFMTLWKVELDCISVLCLIYGINYTIDNCAPMLSTFVLGKD
  FTRTKWVKNALEVHGVAILQSYLCYIVGLIPLAAVPSNLTCTLFRCLFLIAFVTFFHCFA
  ILPVILTFLPPSKKKRKEKKNPENREEIECVEMVDIDSTRVVDQITTV
• Function: Required for the development and function of the thalamic reticular nucleus (TRN), a part of the thalamus that is critical for thalamocortical transmission, generation of sleep rhythms, sensorimotor processing and attention.
• Tissue Specificity: Widely expressed, including in various regions of the brain with highest expression in the gray and white cerebellum, followed by the cerebellar vermis and the pituitary gland.

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism, susceptibility to, X-linked 4	DIS8N012	Definitive	X-linked	[1]
Non-syndromic X-linked intellectual disability	DIS71AI3	Definitive	X-linked	[2]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[3]
Intellectual disability, X-linked 1	DISET38E	Strong	Genetic Variation	[4]
X-linked intellectual disability	DISYJBY3	Strong	Biomarker	[4]
Autism	DISV4V1Z	moderate	Biomarker	[5]
Movement disorder	DISOJJ2D	moderate	CausalMutation	[6]
Neurodevelopmental disorder	DIS372XH	moderate	Biomarker	[3]
Attention deficit hyperactivity disorder	DISL8MX9	Limited	Biomarker	[7]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[7]
Pervasive developmental disorder	DIS51975	Limited	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Patched domain-containing protein 1 (PTCHD1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Patched domain-containing protein 1 (PTCHD1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Patched domain-containing protein 1 (PTCHD1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Patched domain-containing protein 1 (PTCHD1).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Patched domain-containing protein 1 (PTCHD1).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Patched domain-containing protein 1 (PTCHD1).	[12]

References

• [1] 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.
• [2] 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.
• [3] Synaptic Dysfunction in Human Neurons With Autism-Associated Deletions in PTCHD1-AS.Biol Psychiatry. 2020 Jan 15;87(2):139-149. doi: 10.1016/j.biopsych.2019.07.014. Epub 2019 Jul 29.
• [4] Deletion in Xp22.11: PTCHD1 is a candidate gene for X-linked intellectual disability with or without autism.Clin Genet. 2011 Jan;79(1):79-85. doi: 10.1111/j.1399-0004.2010.01590.x. Epub 2010 Nov 22.
• [5] Cellular Functions of the Autism Risk Factor PTCHD1 in Mice.J Neurosci. 2017 Dec 6;37(49):11993-12005. doi: 10.1523/JNEUROSCI.1393-17.2017. Epub 2017 Nov 8.
• [6] Contribution of common and rare variants of the PTCHD1 gene to autism spectrum disorders and intellectual disability.Eur J Hum Genet. 2015 Dec;23(12):1694-701. doi: 10.1038/ejhg.2015.37. Epub 2015 Mar 18.
• [7] Altered kynurenine pathway metabolites in a mouse model of human attention-deficit hyperactivity/autism spectrum disorders: A potential new biological diagnostic marker.Sci Rep. 2019 Sep 12;9(1):13182. doi: 10.1038/s41598-019-49781-y.
• [8] Phenotypic spectrum associated with PTCHD1 deletions and truncating mutations includes intellectual disability and autism spectrum disorder.Clin Genet. 2015 Sep;88(3):224-33. doi: 10.1111/cge.12482. Epub 2014 Oct 14.
• [9] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.