Details of Drug Off-Target (DOT)

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

• DOT Name: AFG3-like protein 2 (AFG3L2)
• Synonyms: EC 3.4.24.-; Paraplegin-like protein
• Gene Name: AFG3L2
• Related Disease:
  Progressive external ophthalmoplegia
  Spinocerebellar ataxia type 28
  Action myoclonus-renal failure syndrome
  Autosomal dominant cerebellar ataxia type II
  Cardiac arrest
  Cerebellar disorder
  Charlevoix-Saguenay spastic ataxia
  Coronary heart disease
  Dentatorubral-pallidoluysian atrophy
  Hereditary ataxia
  Hereditary spastic paraplegia 7
  High blood pressure
  Hypercalcaemia
  Macular degeneration
  Mitochondrial disease
  Optic atrophy 12
  Parkinsonian disorder
  Pathologic nystagmus
  Progressive myoclonus epilepsy
  Ptosis
  Spastic ataxia 5
  Spinocerebellar ataxia type 1
  Spinocerebellar ataxia type 2
  Spinocerebellar ataxia type 5
  Spinocerebellar ataxia type 6
  Vascular purpura
  Vitamin D deficiency
  Xerophthalmia
  Isolated congenital microcephaly
  Spastic ataxia
  Cerebellar ataxia
  Hereditary spastic paraplegia
  Spinocerebellar ataxia
• UniProt ID: AFG32_HUMAN
• PDB ID: 2LNA; 6NYY
• EC Number: 3.4.24.-
• Pfam ID: PF00004 ; PF17862 ; PF06480 ; PF01434
• Sequence:
  MAHRCLRLWGRGGCWPRGLQQLLVPGGVGPGEQPCLRTLYRFVTTQARASRNSLLTDIIA
  AYQRFCSRPPKGFEKYFPNGKNGKKASEPKEVMGEKKESKPAATTRSSGGGGGGGGKRGG
  KKDDSHWWSRFQKGDIPWDDKDFRMFFLWTALFWGGVMFYLLLKRSGREITWKDFVNNYL
  SKGVVDRLEVVNKRFVRVTFTPGKTPVDGQYVWFNIGSVDTFERNLETLQQELGIEGENR
  VPVVYIAESDGSFLLSMLPTVLIIAFLLYTIRRGPAGIGRTGRGMGGLFSVGETTAKVLK
  DEIDVKFKDVAGCEEAKLEIMEFVNFLKNPKQYQDLGAKIPKGAILTGPPGTGKTLLAKA
  TAGEANVPFITVSGSEFLEMFVGVGPARVRDLFALARKNAPCILFIDEIDAVGRKRGRGN
  FGGQSEQENTLNQLLVEMDGFNTTTNVVILAGTNRPDILDPALLRPGRFDRQIFIGPPDI
  KGRASIFKVHLRPLKLDSTLEKDKLARKLASLTPGFSGADVANVCNEAALIAARHLSDSI
  NQKHFEQAIERVIGGLEKKTQVLQPEEKKTVAYHEAGHAVAGWYLEHADPLLKVSIIPRG
  KGLGYAQYLPKEQYLYTKEQLLDRMCMTLGGRVSEEIFFGRITTGAQDDLRKVTQSAYAQ
  IVQFGMNEKVGQISFDLPRQGDMVLEKPYSEATARLIDDEVRILINDAYKRTVALLTEKK
  ADVEKVALLLLEKEVLDKNDMVELLGPRPFAEKSTYEEFVEGTGSLDEDTSLPEGLKDWN
  KEREKEKEEPPGEKVAN
• Function: ATP-dependent protease which is essential for axonal and neuron development. In neurons, mediates degradation of SMDT1/EMRE before its assembly with the uniporter complex, limiting the availability of SMDT1/EMRE for MCU assembly and promoting efficient assembly of gatekeeper subunits with MCU. Required for paraplegin (SPG7) maturation. After its cleavage by mitochondrial-processing peptidase (MPP), it converts paraplegin into a proteolytically active mature form. Required for the maturation of PINK1 into its 52kDa mature form after its cleavage by mitochondrial-processing peptidase (MPP). Involved in the regulation of OMA1-dependent processing of OPA1. Contributes to the proteolytic degradation of GHITM upon hyperpolarization of mitochondria. Progressive GHITM degradation upon persistent hyperpolarization leads to respiratory complex I degradation and broad reshaping of the mitochondrial proteome by AFG3L2.
• Tissue Specificity: Ubiquitous. Highly expressed in the cerebellar Purkinje cells.
• KEGG Pathway: Spinocerebellar ataxia (hsa05017)
• Reactome Pathway: Processing of SMDT1 (R-HSA-8949664)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Progressive external ophthalmoplegia	DISX4ATI	Definitive	Genetic Variation	[1]
Spinocerebellar ataxia type 28	DISL571D	Definitive	Autosomal dominant	[2]
Action myoclonus-renal failure syndrome	DISI2BZN	Strong	Biomarker	[3]
Autosomal dominant cerebellar ataxia type II	DIS0PM39	Strong	Biomarker	[2]
Cardiac arrest	DIS9DIA4	Strong	Genetic Variation	[2]
Cerebellar disorder	DIS2O7WM	Strong	Genetic Variation	[4]
Charlevoix-Saguenay spastic ataxia	DISE8X81	Strong	Biomarker	[5]
Coronary heart disease	DIS5OIP1	Strong	Posttranslational Modification	[6]
Dentatorubral-pallidoluysian atrophy	DISHWE0K	Strong	Biomarker	[3]
Hereditary ataxia	DIS6JNI3	Strong	Genetic Variation	[2]
Hereditary spastic paraplegia 7	DIS4A678	Strong	Genetic Variation	[7]
High blood pressure	DISY2OHH	Strong	CausalMutation	[8]
Hypercalcaemia	DISKQ2K7	Strong	CausalMutation	[8]
Macular degeneration	DISLKKHD	Strong	CausalMutation	[8]
Mitochondrial disease	DISKAHA3	Strong	Genetic Variation	[9]
Optic atrophy 12	DISYDOB9	Strong	Autosomal dominant	[10]
Parkinsonian disorder	DISHGY45	Strong	Genetic Variation	[7]
Pathologic nystagmus	DIS1QSPO	Strong	Biomarker	[11]
Progressive myoclonus epilepsy	DISAMCNS	Strong	Biomarker	[3]
Ptosis	DISJZNIY	Strong	Genetic Variation	[12]
Spastic ataxia 5	DIS0OB1V	Strong	Autosomal recessive	[13]
Spinocerebellar ataxia type 1	DISF7BO2	Strong	Biomarker	[2]
Spinocerebellar ataxia type 2	DISF7WDI	Strong	Biomarker	[2]
Spinocerebellar ataxia type 5	DISPYXJ0	Strong	Biomarker	[2]
Spinocerebellar ataxia type 6	DISH7224	Strong	Biomarker	[2]
Vascular purpura	DIS6ZZMF	Strong	Biomarker	[14]
Vitamin D deficiency	DISAWKYI	Strong	CausalMutation	[8]
Xerophthalmia	DIS5B72B	Strong	CausalMutation	[8]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[15]
Spastic ataxia	DISIRRA9	moderate	Genetic Variation	[16]
Cerebellar ataxia	DIS9IRAV	Disputed	Genetic Variation	[17]
Hereditary spastic paraplegia	DISGZQV1	Limited	Genetic Variation	[18]
Spinocerebellar ataxia	DISYMHUK	Limited	Biomarker	[19]

7 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 AFG3-like protein 2 (AFG3L2).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of AFG3-like protein 2 (AFG3L2).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of AFG3-like protein 2 (AFG3L2).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of AFG3-like protein 2 (AFG3L2).	[23]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of AFG3-like protein 2 (AFG3L2).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of AFG3-like protein 2 (AFG3L2).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of AFG3-like protein 2 (AFG3L2).	[26]

References

• [1] Clonal expansion of secondary mitochondrial DNA deletions associated with spinocerebellar ataxia type 28.JAMA Neurol. 2015 Jan;72(1):106-11. doi: 10.1001/jamaneurol.2014.1753.
• [2] Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28. Nat Genet. 2010 Apr;42(4):313-21. doi: 10.1038/ng.544. Epub 2010 Mar 7.
• [3] A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nat Genet. 2015 Jan;47(1):39-46. doi: 10.1038/ng.3144. Epub 2014 Nov 17.
• [4] SCA28: Novel Mutation in the AFG3L2 Proteolytic Domain Causes a Mild Cerebellar Syndrome with Selective Type-1 Muscle Fiber Atrophy.Cerebellum. 2017 Feb;16(1):62-67. doi: 10.1007/s12311-016-0765-1.
• [5] Movement disorders in mitochondrial diseases.Rev Neurol (Paris). 2016 Aug-Sep;172(8-9):524-529. doi: 10.1016/j.neurol.2016.07.003. Epub 2016 Jul 28.
• [6] In Silico Investigation of Traditional Chinese Medicine for Potential Lead Compounds as SPG7 Inhibitors against Coronary Artery Disease.Molecules. 2016 May 5;21(5):588. doi: 10.3390/molecules21050588.
• [7] Concurrent AFG3L2 and SPG7 mutations associated with syndromic parkinsonism and optic atrophy with aberrant OPA1 processing and mitochondrial network fragmentation.Hum Mutat. 2018 Dec;39(12):2060-2071. doi: 10.1002/humu.23658. Epub 2018 Oct 10.
• [8] Missense mutations in the AFG3L2 proteolytic domain account for ?1.5% of European autosomal dominant cerebellar ataxias. Hum Mutat. 2010 Oct;31(10):1117-24. doi: 10.1002/humu.21342.
• [9] Spinocerebellar Ataxia Type 28-Phenotypic and Molecular Characterization of a Family with Heterozygous and Compound-Heterozygous Mutations in AFG3L2.Cerebellum. 2019 Aug;18(4):817-822. doi: 10.1007/s12311-019-01036-2.
• [10] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [11] A novel missense mutation in AFG3L2 associated with late onset and slow progression of spinocerebellar ataxia type 28.J Mol Neurosci. 2014 Apr;52(4):493-6. doi: 10.1007/s12031-013-0187-1. Epub 2013 Nov 29.
• [12] Partial deletion of AFG3L2 causing spinocerebellar ataxia type 28.Neurology. 2014 Jun 10;82(23):2092-100. doi: 10.1212/WNL.0000000000000491. Epub 2014 May 9.
• [13] 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.
• [14] Loss of m-AAA protease in mitochondria causes complex I deficiency and increased sensitivity to oxidative stress in hereditary spastic paraplegia.J Cell Biol. 2003 Nov 24;163(4):777-87. doi: 10.1083/jcb.200304112. Epub 2003 Nov 17.
• [15] Recessive AFG3L2 Mutation Causes Progressive Microcephaly, Early Onset Seizures, Spasticity, and Basal Ganglia Involvement.Pediatr Neurol. 2017 Jun;71:24-28. doi: 10.1016/j.pediatrneurol.2017.03.019. Epub 2017 Apr 5.
• [16] Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases. PLoS Genet. 2011 Oct;7(10):e1002325. doi: 10.1371/journal.pgen.1002325. Epub 2011 Oct 13.
• [17] Mice harbouring a SCA28 patient mutation in AFG3L2 develop late-onset ataxia associated with enhanced mitochondrial proteotoxicity.Neurobiol Dis. 2019 Apr;124:14-28. doi: 10.1016/j.nbd.2018.10.018. Epub 2018 Oct 30.
• [18] m-AAA proteases, mitochondrial calcium homeostasis and neurodegeneration.Cell Res. 2018 Mar;28(3):296-306. doi: 10.1038/cr.2018.17. Epub 2018 Feb 16.
• [19] SCA28, a novel form of autosomal dominant cerebellar ataxia on chromosome 18p11.22-q11.2.Brain. 2006 Jan;129(Pt 1):235-42. doi: 10.1093/brain/awh651. Epub 2005 Oct 26.
• [20] 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.
• [21] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [22] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [23] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [24] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [25] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [26] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.