Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZWO8A5)

• DOT Name: Ras-related protein Rab-40A-like (RAB40AL)
• Synonyms: Ras-like GTPase
• Gene Name: RAB40AL
• Related Disease:
  Cognitive impairment
  X-linked intellectual disability
  Duchenne muscular dystrophy
  Hepatocellular carcinoma
  Intellectual disability
  Advanced cancer
  Neurodevelopmental disorder
  Benign neoplasm
  X-linked syndromic intellectual disability
• UniProt ID: RB40L_HUMAN
• Pfam ID: PF00071 ; PF07525
• Sequence:
  MSAPGSPDQAYDFLLKFLLVGDRDVGKSEILESLQDGTAESPYSHLGGIDYKTTTILLDG
  QRVKLKLWDTSGQGRFCTIFRSYSRGAQGVILVYDIANRWSFEGMDRWIKKIEEHAPGVP
  KILVGNRLHLAFKRQVPREQAQAYAERLGVTFFEVSPLCNFNIIESFTELARIVLLRHRL
  NWLGRPSKVLSLQDLCCRTIVSCTPVHLVDKLPLPIALRSHLKSFSMAKGLNARMMRGLS
  YSLTTSSTHKRSSLCKVKIVCPPQSPPKNCTRNSCKIS
• Function: May be a substrate-recognition component of a SCF-like ECS (Elongin-Cullin-SOCS-box protein) E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
• Tissue Specificity: Expressed in brain, lung, heart, skeletal muscle, kidney and liver. Highest expression in brain. Expressed in fetal brain and kidney.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cognitive impairment	DISH2ERD	Definitive	Biomarker	[1]
X-linked intellectual disability	DISYJBY3	Definitive	Biomarker	[1]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Genetic Variation	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[4]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[5]
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[4]
Benign neoplasm	DISDUXAD	Limited	Biomarker	[5]
X-linked syndromic intellectual disability	DISG1YOH	Refuted	X-linked	[6]

2 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 Ras-related protein Rab-40A-like (RAB40AL).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Ras-related protein Rab-40A-like (RAB40AL).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Ras-related protein Rab-40A-like (RAB40AL).	[8]

References

• [1] Disruption of RAB40AL function leads to Martin--Probst syndrome, a rare X-linked multisystem neurodevelopmental human disorder.J Med Genet. 2012 May;49(5):332-40. doi: 10.1136/jmedgenet-2011-100575.
• [2] The Xq22 inversion breakpoint interrupted a novel Ras-like GTPase gene in a patient with Duchenne muscular dystrophy and profound mental retardation.Am J Hum Genet. 2002 Sep;71(3):637-45. doi: 10.1086/342208. Epub 2002 Jul 23.
• [3] An X-chromosomal association study identifies a susceptibility locus at Xq22.1 for hepatitis B virus-related hepatocellular carcinoma.Clin Res Hepatol Gastroenterol. 2013 Dec;37(6):586-95. doi: 10.1016/j.clinre.2013.09.002. Epub 2013 Oct 25.
• [4] Mutation in the X-linked RAB40AL gene (Martin-Probst syndrome) with mental retardation, sensorineural hearing loss, and anomalies of the craniofacies and genitourinary tract: a second case report.Eur J Pediatr. 2014 Jul;173(7):967-9. doi: 10.1007/s00431-014-2339-x. Epub 2014 May 27.
• [5] Correlation between BRAF mutation and promoter methylation of TIMP3, RAR2 and RASSF1A in thyroid cancer.Epigenetics. 2012 Jul;7(7):710-9. doi: 10.4161/epi.20524. Epub 2012 Jul 1.
• [6] 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.
• [7] 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.
• [8] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [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.