Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3B7721)

• DOT Name: Desert hedgehog protein (DHH)
• Synonyms: DHH; EC 3.1.-.-; HHG-3
• Gene Name: DHH
• Related Disease:
  46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome
  Bipolar disorder
  Cryptorchidism
  Gastric cancer
  Neoplasm
  Peripheral neuropathy
  46,XY complete gonadal dysgenesis
• UniProt ID: DHH_HUMAN
• PDB ID: 2WFQ; 2WFR; 2WG3; 3N1G; 3N1Q
• EC Number: 3.1.-.-
• Pfam ID: PF01085 ; PF01079
• Sequence:
  MALLTNLLPLCCLALLALPAQSCGPGRGPVGRRRYARKQLVPLLYKQFVPGVPERTLGAS
  GPAEGRVARGSERFRDLVPNYNPDIIFKDEENSGADRLMTERCKERVNALAIAVMNMWPG
  VRLRVTEGWDEDGHHAQDSLHYEGRALDITTSDRDRNKYGLLARLAVEAGFDWVYYESRN
  HVHVSVKADNSLAVRAGGCFPGNATVRLWSGERKGLRELHRGDWVLAADASGRVVPTPVL
  LFLDRDLQRRASFVAVETEWPPRKLLLTPWHLVFAARGPAPAPGDFAPVFARRLRAGDSV
  LAPGGDALRPARVARVAREEAVGVFAPLTAHGTLLVNDVLASCYAVLESHQWAHRAFAPL
  RLLHALGALLPGGAVQPTGMHWYSRLLYRLAEELLG
• Function: [Desert hedgehog protein]: The C-terminal part of the desert hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity. Both activities result in the cleavage of the full-length protein into two parts (N-product and C-product) followed by the covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-product. Both activities occur in the reticulum endoplasmic. Functions in cell-cell mediated juxtacrine signaling. Promotes endothelium integrity. Binds to PTCH1 receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes in endothelial cells. In Schwann cells, controls the development of the peripheral nerve sheath and the transition of mesenchymal cells to form the epithelium-like structure of the perineurial tube; [Desert hedgehog protein N-product]: The dually lipidated desert hedgehog protein N-product is essential for a variety of patterning events during development. Binds to the patched (PTCH1) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes. Required for normal testis development and spermatogenesis, namely for the formation of adult-type Leydig cells and normal development of peritubular cells and seminiferous tubules. Activates primary cilia signaling on neighboring valve interstitial cells through a paracrine mechanism. May induce motor neurons in lateral neural tube and may have a polarizing activity. Prevents the desert hedgehog protein precursor binding to PTCH1.
• KEGG Pathway: Hedgehog sig.ling pathway (hsa04340)
• Reactome Pathway:
  Hedgehog ligand biogenesis (R-HSA-5358346)
  Release of Hh-Np from the secreting cell (R-HSA-5362798)
  Ligand-receptor interactions (R-HSA-5632681)
  Hedgehog 'on' state (R-HSA-5632684)
  Activation of SMO (R-HSA-5635838)
  HHAT G278V doesn't palmitoylate Hh-Np (R-HSA-5658034)
  Transcriptional regulation of testis differentiation (R-HSA-9690406)
  Class B/2 (Secretin family receptors) (R-HSA-373080)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome	DISNCRZ4	Strong	Autosomal recessive	[1]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[2]
Cryptorchidism	DISYUD2P	Strong	Genetic Variation	[3]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[6]
46,XY complete gonadal dysgenesis	DISLF3LT	Supportive	Autosomal dominant	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Desert hedgehog protein (DHH).	[8]

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 decreases the methylation of Desert hedgehog protein (DHH).	[9]

References

• [1] Schwann cell-derived Desert hedgehog controls the development of peripheral nerve sheaths. Neuron. 1999 Aug;23(4):713-24. doi: 10.1016/s0896-6273(01)80030-1.
• [2] A genetic variant in 12q13, a possible risk factor for bipolar disorder, is associated with depressive state, accounting for stressful life events.PLoS One. 2014 Dec 17;9(12):e115135. doi: 10.1371/journal.pone.0115135. eCollection 2014.
• [3] In vitro functional characterization of the novel DHH mutations p.(Asn337Lysfs*24) and p.(Glu212Lys) associated with gonadal dysgenesis.Hum Mutat. 2018 Dec;39(12):2097-2109. doi: 10.1002/humu.23664. Epub 2018 Oct 22.
• [4] Understanding h-prune biology in the fight against cancer.Clin Exp Metastasis. 2007;24(8):637-45. doi: 10.1007/s10585-007-9109-3. Epub 2007 Oct 19.
• [5] Involvement of hedgehog pathway in early onset, aggressive molecular subtypes and metastatic potential of breast cancer.Cell Commun Signal. 2018 Jan 8;16(1):3. doi: 10.1186/s12964-017-0213-y.
• [6] Novel Familial Variant of the Desert Hedgehog Gene: Clinical Findings in Two Sisters with 46,XY Gonadal Dysgenesis or 46,XX Karyotype and Literature Review.Horm Res Paediatr. 2018;89(3):141-149. doi: 10.1159/000485507. Epub 2018 Feb 22.
• [7] Nonsyndromic Disorders of Testicular Development Overview. 2008 May 21 [updated 2022 Aug 18]. 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.
• [8] 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.
• [9] 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.