Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO04K1T)

• DOT Name: Sperm flagellar protein 2 (SPEF2)
• Synonyms: Protein KPL2
• Gene Name: SPEF2
• Related Disease:
  Hydrocephalus
  Multiple sclerosis
  Pancreatitis
  Primary ciliary dyskinesia 1
  Spermatogenic failure 43
  Obsolete non-syndromic male infertility due to sperm motility disorder
  Primary ciliary dyskinesia
• UniProt ID: SPEF2_HUMAN
• Pfam ID: PF00406 ; PF06294
• Sequence:
  MSEILCQWLNKELKVSRTVSPKSFAKAFSSGYLLGEVLHKFELQDDFSEFLDSRVSSAKL
  NNFSRLEPTLNLLGVQFDQNVAHGIITEKPGVATKLLYQLYIALQKKKKSGLTGVEMQTM
  QRLTNLRLQNMKSDTFQERLRHMIPRQTDFNLMRITYRFQEKYKHVKEDLAHLHFEKLER
  FQKLKEEQRCFDIEKQYLNRRRQNEIMAKIQAAIIQIPKPASNRTLKALEAQKMMKKKKE
  AEDVADEIKKFEALIKKDLQAKESASKTSLDTAGQTTTDLLNTYSDDEYIKKIQKRLEED
  AFAREQREKRRRKLLMDQLIAHEAQEEAYREEQLINRLMRQSQQERRIAVQLMHVRHEKE
  VLWQNRIFREKQHEERRLKDFQDALDREAALAKQAKIDFEEQFLKEKRFHDQIAVERAQA
  RYEKHYSVCAEILDQIVDLSTKVADYRMLTNNLIPYKLMHDWKELFFNAKPIYEQASVKT
  LPANPSREQLTELEKRDLLDTNDYEEYKNMVGEWALPEEMVDNLPPSNNCILGHILHRLA
  EKSLPPRAESTTPELPSFAVKGCLLGKTLSGKTTILRSLQKDFPIQILSIDTLVQEAIQA
  FHDNEKVSEVLPIQKNDEEDALPVLQEEIKESQDPQHVFSAGPVSDEVLPETEGETMLSA
  NADKTPKAEEVKSSDSFLKLTTRAQLGAKSEQLLKKGKSIPDVLLVDIIVNAINEIPVNQ
  DCILDGFPMTLNQAQLLEEALTGCNRNLTEVERKKAQKSTLAIDPATSKEIPLPSPAFDF
  VILLDVSDTSSMSRMNDIIAEELSYKTAHEDISQRVAAENQDKDGDQNLRDQIQHRIIGF
  LDNWPLLEQWFSEPENILIKINAEIDKESLCEKVKEILTTEIAKKKNKVEKKLEEKEAEK
  KAAASLAELPLPTPPPAPPPEPEKEKEIHQSHVASKTPTAKGKPQSEAPHGKQESLQEGK
  GKKGETALKRKGSPKGKSSGGKVPVKKSPADSTDTSPVAIVPQPPKPGSEEWVYVNEPVP
  EEMPLFLVPYWELIENSYINTIKTVLRHLREDQHTVLAYLYEIRTSFQEFLKRPDHKQDF
  VAQWQADFNSLPDDLWDDEETKAELHQRVNDLRDRLWDICDARKEEAEQERLDIINESWL
  QDTLGMTMNHFFSLMQAELNRFQDTKRLLQDYYWGMESKIPVEDNKRFTRIPLVQLDSKD
  NSESQLRIPLVPRISISLETVTPKPKTKSVLKGKMDNSLENVESNFEADEKLVMDTWQQA
  SLAVSHMVAAEIHQRLMEEEKENQPADPKEKSPQMGANKKVKKEPPKKKQEDKKPKGKSP
  PMAEATPVIVTTEEIAEIKRKNELRVKIKEEHLAALQFEEIATQFRLELIKTKALALLED
  LVTKVVDVYKLMEKWLGERYLNEMASTEKLTDVARYHIETSTKIQNELYLSQEDFFINGN
  IKVFPDPPPSIRPPPVEKEEDGTLTIEQLDSLRDQFLDMAPKGIIGNKAFTDILIDLVTL
  NLGTNNFPSNWMHLTQPELQELTSLLTVNSEFVDWRKFLLVTSMPWPIPLEEELLETLQK
  FKAVDKEQLGTITFEQYMQAGLWFTGDEDIKIPENPLEPLPFNRQEHLIEFFFRLFADYE
  KDPPQLDYTQMLLYFACHPDTVEGVYRALSVAVGTHVFQQVKASIPSAEKTSSTDAGPAE
  EFPEPEENAAREERKLKDDTEKREQKDEEIPENANNEKMSMETLLKVFKGGSEAQDSNRF
  ASHLKIENIYAEGFIKTFQDLGAKNLEPIEVAVLLKHPFIQDLISNYSDYKFPDIKIILQ
  RSEHVQGSDGERSPSRHTEEKK
• Function: Required for correct axoneme development in spermatozoa. Important for normal development of the manchette and sperm head morphology. Essential for male fertility. Plays a role in localization of the intraflagellar transport protein IFT20 to the manchette, suggesting function as an adapter for dynein-mediated protein transport during spermatogenesis. Also plays a role in bone growth where it seems to be required for normal osteoblast differentiation.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hydrocephalus	DISIZUF7	Definitive	Biomarker	[1]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[2]
Pancreatitis	DIS0IJEF	Strong	Genetic Variation	[3]
Primary ciliary dyskinesia 1	DISPGX6H	Strong	GermlineCausalMutation	[4]
Spermatogenic failure 43	DISW2NX3	Strong	Autosomal recessive	[5]
Obsolete non-syndromic male infertility due to sperm motility disorder	DISG7641	Supportive	Autosomal recessive	[6]
Primary ciliary dyskinesia	DISOBC7V	Supportive	Autosomal dominant	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Sperm flagellar protein 2 (SPEF2).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sperm flagellar protein 2 (SPEF2).	[8]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Sperm flagellar protein 2 (SPEF2).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Sperm flagellar protein 2 (SPEF2).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Sperm flagellar protein 2 (SPEF2).	[12]

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 Sperm flagellar protein 2 (SPEF2).	[10]

References

• [1] Cilia-related protein SPEF2 regulates osteoblast differentiation.Sci Rep. 2018 Jan 16;8(1):859. doi: 10.1038/s41598-018-19204-5.
• [2] Modeling the cumulative genetic risk for multiple sclerosis from genome-wide association data.Genome Med. 2011 Jan 18;3(1):3. doi: 10.1186/gm217.
• [3] Whole-exome sequencing identified genetic risk factors for asparaginase-related complications in childhood ALL patients.Oncotarget. 2017 Jul 4;8(27):43752-43767. doi: 10.18632/oncotarget.17959.
• [4] SPEF2- and HYDIN-Mutant Cilia Lack the Central Pair-associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics. Am J Respir Cell Mol Biol. 2020 Mar;62(3):382-396. doi: 10.1165/rcmb.2019-0086OC.
• [5] 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.
• [6] Loss-of-function mutations in SPEF2 cause multiple morphological abnormalities of the sperm flagella (MMAF). J Med Genet. 2019 Oct;56(10):678-684. doi: 10.1136/jmedgenet-2018-105952. Epub 2019 May 31.
• [7] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [10] 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.
• [11] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [12] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.