Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2BG2Z3)

• DOT Name: AP-4 complex subunit mu-1 (AP4M1)
• Synonyms: AP-4 adaptor complex mu subunit; Adaptor-related protein complex 4 subunit mu-1; Mu subunit of AP-4; Mu-adaptin-related protein 2; mu-ARP2; Mu4-adaptin; mu4
• Gene Name: AP4M1
• Related Disease:
  AP-4 deficiency syndrome
  Hereditary spastic paraplegia 2
  Hereditary spastic paraplegia 47
  Hereditary spastic paraplegia 51
  Hereditary spastic paraplegia 52
  Alzheimer disease
  Cerebral palsy
  Hereditary spastic paraplegia
  Hereditary spastic paraplegia 50
  Movement disorder
  Intellectual disability
  Neurodevelopmental disorder
  Vascular purpura
  Obsolete AP4-related intellectual disability and spastic paraplegia
• UniProt ID: AP4M1_HUMAN
• PDB ID: 3L81; 4MDR
• Pfam ID: PF00928 ; PF01217
• Sequence:
  MISQFFILSSKGDPLIYKDFRGDSGGRDVAELFYRKLTGLPGDESPVVMHHHGRHFIHIR
  HSGLYLVVTTSENVSPFSLLELLSRLATLLGDYCGSLGEGTISRNVALVYELLDEVLDYG
  YVQTTSTEMLRNFIQTEAVVSKPFSLFDLSSVGLFGAETQQSKVAPSSAASRPVLSSRSD
  QSQKNEVFLDVVERLSVLIASNGSLLKVDVQGEIRLKSFLPSGSEMRIGLTEEFCVGKSE
  LRGYGPGIRVDEVSFHSSVNLDEFESHRILRLQPPQGELTVMRYQLSDDLPSPLPFRLFP
  SVQWDRGSGRLQVYLKLRCDLLSKSQALNVRLHLPLPRGVVSLSQELSSPEQKAELAEGA
  LRWDLPRVQGGSQLSGLFQMDVPGPPGPPSHGLSTSASPLGLGPASLSFELPRHTCSGLQ
  VRFLRLAFRPCGNANPHKWVRHLSHSDAYVIRI
• Function: Component of the adaptor protein complex 4 (AP-4). Adaptor protein complexes are vesicle coat components involved both in vesicle formation and cargo selection. They control the vesicular transport of proteins in different trafficking pathways. AP-4 forms a non clathrin-associated coat on vesicles departing the trans-Golgi network (TGN) and may be involved in the targeting of proteins from the trans-Golgi network (TGN) to the endosomal-lysosomal system. It is also involved in protein sorting to the basolateral membrane in epithelial cells and the proper asymmetric localization of somatodendritic proteins in neurons. Within AP-4, the mu-type subunit AP4M1 is directly involved in the recognition and binding of tyrosine-based sorting signals found in the cytoplasmic part of cargos. The adaptor protein complex 4 (AP-4) may also recognize other types of sorting signal.
• Tissue Specificity: Ubiquitous. Highly expressed in testis and lowly expressed in brain and lung.
• KEGG Pathway: Lysosome (hsa04142)
• Reactome Pathway: Lysosome Vesicle Biogenesis (R-HSA-432720)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
AP-4 deficiency syndrome	DISCF43Z	Definitive	Autosomal recessive	[1]
Hereditary spastic paraplegia 2	DIS0TD1L	Definitive	Genetic Variation	[2]
Hereditary spastic paraplegia 47	DIS25W9X	Definitive	Genetic Variation	[3]
Hereditary spastic paraplegia 51	DIS3DFPG	Definitive	Genetic Variation	[3]
Hereditary spastic paraplegia 52	DISQ4O7P	Definitive	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[4]
Cerebral palsy	DIS82ODL	Strong	Genetic Variation	[5]
Hereditary spastic paraplegia	DISGZQV1	Strong	Biomarker	[3]
Hereditary spastic paraplegia 50	DISCCZ2O	Strong	Autosomal recessive	[6]
Movement disorder	DISOJJ2D	Strong	CausalMutation	[7]
Intellectual disability	DISMBNXP	moderate	Biomarker	[8]
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[9]
Vascular purpura	DIS6ZZMF	moderate	Genetic Variation	[9]
Obsolete AP4-related intellectual disability and spastic paraplegia	DISFYNHU	Supportive	Autosomal recessive	[10]

4 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 AP-4 complex subunit mu-1 (AP4M1).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of AP-4 complex subunit mu-1 (AP4M1).	[12]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of AP-4 complex subunit mu-1 (AP4M1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of AP-4 complex subunit mu-1 (AP4M1).	[14]

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] Locus and allelic heterogeneity in five families with hereditary spastic paraplegia.J Hum Genet. 2019 Jan;64(1):17-21. doi: 10.1038/s10038-018-0523-y. Epub 2018 Oct 18.
• [3] Generation and characterization of six human induced pluripotent stem cell lines (iPSC) from three families with AP4B1-associated hereditary spastic paraplegia (SPG47).Stem Cell Res. 2019 Oct;40:101575. doi: 10.1016/j.scr.2019.101575. Epub 2019 Sep 11.
• [4] GWAS on family history of Alzheimer's disease.Transl Psychiatry. 2018 May 18;8(1):99. doi: 10.1038/s41398-018-0150-6.
• [5] A novel AP4M1 mutation in autosomal recessive cerebral palsy syndrome and clinical expansion of AP-4 deficiency.BMC Med Genet. 2014 Dec 14;15:133. doi: 10.1186/s12881-014-0133-2.
• [6] Autosomal recessive spastic tetraplegia caused by AP4M1 and AP4B1 gene mutation: expansion of the facial and neuroimaging features. Am J Med Genet A. 2014 Jul;164A(7):1677-85. doi: 10.1002/ajmg.a.36514. Epub 2014 Apr 3.
• [7] An AP4B1 frameshift mutation in siblings with intellectual disability and spastic tetraplegia further delineates the AP-4 deficiency syndrome.Eur J Hum Genet. 2015 Feb;23(2):256-9. doi: 10.1038/ejhg.2014.73. Epub 2014 Apr 30.
• [8] A novel homozygous AP4B1 mutation in two brothers with AP-4 deficiency syndrome and ocular anomalies.Am J Med Genet A. 2018 Apr;176(4):985-991. doi: 10.1002/ajmg.a.38628. Epub 2018 Feb 12.
• [9] Genotype-phenotype correlations and expansion of the molecular spectrum of AP4M1-related hereditary spastic paraplegia.Orphanet J Rare Dis. 2017 Nov 2;12(1):172. doi: 10.1186/s13023-017-0721-2.
• [10] Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy. Am J Hum Genet. 2009 Jul;85(1):40-52. doi: 10.1016/j.ajhg.2009.06.004. Epub 2009 Jun 25.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [14] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.