Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMPMD6W)

• DOT Name: Kelch-like protein 40 (KLHL40)
• Synonyms: Kelch repeat and BTB domain-containing protein 5; Sarcosynapsin
• Gene Name: KLHL40
• Related Disease:
  Fetal akinesia deformation sequence 1
  Nemaline myopathy 8
  Congenital myopathy
  Neuromuscular disease
  Severe congenital nemaline myopathy
• UniProt ID: KLH40_HUMAN
• PDB ID: 4ASC
• Pfam ID: PF07707 ; PF00651 ; PF01344
• Sequence:
  MALGLEQAEEQRLYQQTLLQDGLKDMLDHGKFLDCVVRAGEREFPCHRLVLAACSPYFRA
  RFLAEPERAGELHLEEVSPDVVAQVLHYLYTSEIALDEASVQDLFAAAHRFQIPSIFTIC
  VSFLQKRLCLSNCLAVFRLGLLLDCARLAVAARDFICAHFTLVARDADFLGLSADELIAI
  ISSDGLNVEKEEAVFEAVMRWAGSGDAEAQAERQRALPTVFESVRCRLLPRAFLESRVER
  HPLVRAQPELLRKVQMVKDAHEGRITTLRKKKKGKDGAGAKEADKGTSKAKAEEDEEAER
  ILPGILNDTLRFGMFLQDLIFMISEEGAVAYDPAANECYCASLSNQVPKNHVSLVTKENQ
  VFVAGGLFYNEDNKEDPMSAYFLQFDHLDSEWLGMPPLPSPRCLFGLGEALNSIYVVGGR
  EIKDGERCLDSVMCYDRLSFKWGESDPLPYVVYGHTVLSHMDLVYVIGGKGSDRKCLNKM
  CVYDPKKFEWKELAPMQTARSLFGATVHDGRIIVAAGVTDTGLTSSAEVYSITDNKWAPF
  EAFPQERSSLSLVSLVGTLYAIGGFATLETESGELVPTELNDIWRYNEEEKKWEGVLREI
  AYAAGATFLPVRLNVLCLTKM
• Function: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a key regulator of skeletal muscle development. The BCR(KLHL40) complex acts by mediating ubiquitination and degradation of TFDP1, thereby regulating the activity of the E2F:DP transcription factor complex. Promotes stabilization of LMOD3 by acting as a negative regulator of LMOD3 ubiquitination; the molecular process by which it negatively regulates ubiquitination of LMOD3 is however unclear.
• Tissue Specificity: Highly expressed in fetal (19, 23 and 31 weeks of gestation) and adult skeletal muscle; expression levels tend to be higher in fetal compared to postnatal muscles (at protein level). Also expressed in fetal and adult heart.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fetal akinesia deformation sequence 1	DISKDI9L	Definitive	Genetic Variation	[1]
Nemaline myopathy 8	DISY8GH0	Definitive	Autosomal recessive	[2]
Congenital myopathy	DISLSK9G	Strong	Genetic Variation	[3]
Neuromuscular disease	DISQTIJZ	Strong	Genetic Variation	[1]
Severe congenital nemaline myopathy	DISJR7WP	Supportive	Autosomal recessive	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Kelch-like protein 40 (KLHL40).	[5]

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 affects the methylation of Kelch-like protein 40 (KLHL40).	[6]

References

• [1] Identification of KLHL40 mutations by targeted next-generation sequencing facilitated a prenatal diagnosis in a family with three consecutive affected fetuses with fetal akinesia deformation sequence.Prenat Diagn. 2016 Dec;36(12):1135-1138. doi: 10.1002/pd.4949. Epub 2016 Nov 18.
• [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] Founder Mutation c.1516A>C in KLHL40 Is a Frequent Cause of Nemaline Myopathy With Hyponatremia in Ethnic Chinese.J Neuropathol Exp Neurol. 2019 Sep 1;78(9):854-864. doi: 10.1093/jnen/nlz056.
• [4] Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy. Am J Hum Genet. 2013 Jul 11;93(1):6-18. doi: 10.1016/j.ajhg.2013.05.004. Epub 2013 Jun 6.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [6] 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.