Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT73V6Y4)

• DOT Name: Seipin (BSCL2)
• Synonyms: Bernardinelli-Seip congenital lipodystrophy type 2 protein
• Gene Name: BSCL2
• Related Disease:
  Distal hereditary motor neuropathy
  Amyotrophic lateral sclerosis
  Charcot marie tooth disease
  Congenital generalized lipodystrophy type 2
  Familial partial lipodystrophy
  Fatty liver disease
  Generalized lipodystrophy
  Hereditary spastic paraplegia
  Hereditary spastic paraplegia 17
  Hyperinsulinemia
  Hypertrophic cardiomyopathy
  Infantile epileptic-dyskinetic encephalopathy
  Juvenile amyotrophic lateral sclerosis
  Male infertility
  Monogenic diabetes
  Motor neurone disease
  Neonatal diabetes mellitus
  Neuronopathy, distal hereditary motor, type 5C
  Polyneuropathy
  Progressive myoclonus epilepsy
  Severe neurodegenerative syndrome with lipodystrophy
  Silver-Russell syndrome
  Type-1/2 diabetes
  Azoospermia
  Cardiomyopathy
  Mood disorder
  Peripheral sensory neuropathies
  Berardinelli-Seip congenital lipodystrophy
  Neuronopathy, distal hereditary motor, type 5A
  Charcot-Marie-Tooth disease type 2
  Congenital generalized lipodystrophy type 1
  Lipodystrophy
  Neuronopathy, distal hereditary motor, type 5
  Non-insulin dependent diabetes
  Oligospermia
  Unverricht-Lundborg syndrome
• UniProt ID: BSCL2_HUMAN
• PDB ID: 6DS5
• Pfam ID: PF06775
• Sequence:
  MVNDPPVPALLWAQEVGQVLAGRARRLLLQFGVLFCTILLLLWVSVFLYGSFYYSYMPTV
  SHLSPVHFYYRTDCDSSTTSLCSFPVANVSLTKGGRDRVLMYGQPYRVTLELELPESPVN
  QDLGMFLVTISCYTRGGRIISTSSRSVMLHYRSDLLQMLDTLVFSSLLLFGFAEQKQLLE
  VELYADYRENSYVPTTGAIIEIHSKRIQLYGAYLRIHAHFTGLRYLLYNFPMTCAFIGVA
  SNFTFLSVIVLFSYMQWVWGGIWPRHRFSLQVNIRKRDNSRKEVQRRISAHQPGPEGQEE
  STPQSDVTEDGESPEDPSGTEGQLSEEEKPDQQPLSGEEELEPEASDGSGSWEDAALLTE
  ANLPAPAPASASAPVLETLGSSEPAGGALRQRPTCSSS
• Function: Plays a crucial role in the formation of lipid droplets (LDs) which are storage organelles at the center of lipid and energy homeostasis. In association with LDAF1, defines the sites of LD formation in the ER. Also required for growth and maturation of small nascent LDs into larger mature LDs. Mediates the formation and/or stabilization of endoplasmic reticulum-lipid droplets (ER-LD) contacts, facilitating protein and lipid delivery from the ER into growing LDs. Regulates the maturation of ZFYVE1-positive nascent LDs and the function of the RAB18-ZFYVE1 complex in mediating the formation of ER-LD contacts. Binds anionic phospholipids including phosphatidic acid. Plays an important role in the differentiation and development of adipocytes.
• Tissue Specificity: Expressed in motor neurons in the spinal cord and cortical neurons in the frontal lobe (at protein level). Highly expressed in brain, testis and adipose tissue.

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Distal hereditary motor neuropathy	DISGS2ID	Definitive	Autosomal dominant	[1]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Biomarker	[2]
Charcot marie tooth disease	DIS3BT2L	Strong	Biomarker	[3]
Congenital generalized lipodystrophy type 2	DIS9DL50	Strong	Autosomal recessive	[4]
Familial partial lipodystrophy	DISFVL9J	Strong	Genetic Variation	[5]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[6]
Generalized lipodystrophy	DISC6HI8	Strong	Autosomal recessive	[4]
Hereditary spastic paraplegia	DISGZQV1	Strong	Biomarker	[2]
Hereditary spastic paraplegia 17	DISI7Y7F	Strong	Autosomal dominant	[7]
Hyperinsulinemia	DISIDWT6	Strong	Biomarker	[8]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Biomarker	[9]
Infantile epileptic-dyskinetic encephalopathy	DISD2ZNC	Strong	Genetic Variation	[10]
Juvenile amyotrophic lateral sclerosis	DISKDZC9	Strong	Biomarker	[11]
Male infertility	DISY3YZZ	Strong	Biomarker	[12]
Monogenic diabetes	DISEB8Q0	Strong	CausalMutation	[13]
Motor neurone disease	DISUHWUI	Strong	Genetic Variation	[14]
Neonatal diabetes mellitus	DISFHF9K	Strong	Autosomal recessive	[4]
Neuronopathy, distal hereditary motor, type 5C	DISKMIAU	Strong	Autosomal dominant	[15]
Polyneuropathy	DISB9G3W	Strong	Biomarker	[16]
Progressive myoclonus epilepsy	DISAMCNS	Strong	Genetic Variation	[17]
Severe neurodegenerative syndrome with lipodystrophy	DISB81YD	Strong	Autosomal recessive	[14]
Silver-Russell syndrome	DISSVJ1D	Strong	Biomarker	[2]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[18]
Azoospermia	DIS94181	moderate	Biomarker	[19]
Cardiomyopathy	DISUPZRG	moderate	Biomarker	[9]
Mood disorder	DISLVMWO	moderate	Biomarker	[20]
Peripheral sensory neuropathies	DISYWI6M	moderate	Genetic Variation	[21]
Berardinelli-Seip congenital lipodystrophy	DISKW75N	Supportive	Autosomal recessive	[22]
Neuronopathy, distal hereditary motor, type 5A	DISD3JAD	Supportive	Autosomal dominant	[23]
Charcot-Marie-Tooth disease type 2	DISR30O9	Limited	Genetic Variation	[24]
Congenital generalized lipodystrophy type 1	DISIDEEW	Limited	Genetic Variation	[25]
Lipodystrophy	DIS3SGVD	Limited	Genetic Variation	[26]
Neuronopathy, distal hereditary motor, type 5	DISTSHF6	Limited	Biomarker	[10]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[27]
Oligospermia	DIS6YJF3	Limited	Biomarker	[12]
Unverricht-Lundborg syndrome	DISG4WLX	Limited	Genetic Variation	[17]

10 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 Seipin (BSCL2).	[28]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Seipin (BSCL2).	[29]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Seipin (BSCL2).	[30]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Seipin (BSCL2).	[31]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Seipin (BSCL2).	[32]
Selenium	DM25CGV	Approved	Selenium increases the expression of Seipin (BSCL2).	[33]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Seipin (BSCL2).	[34]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Seipin (BSCL2).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Seipin (BSCL2).	[31]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Seipin (BSCL2).	[35]

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] ALS and MMN mimics in patients with BSCL2 mutations: the expanding clinical spectrum of SPG17 hereditary spastic paraplegia.J Neurol. 2017 Jan;264(1):11-20. doi: 10.1007/s00415-016-8301-2. Epub 2016 Oct 13.
• [3] Screening for SH3TC2, PMP2, and BSCL2 Variants in a Cohort of Chinese Patients with Charcot-Marie-Tooth.Chin Med J (Engl). 2018 Jan 20;131(2):151-155. doi: 10.4103/0366-6999.222331.
• [4] 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.
• [5] Lipodystrophies: disorders of adipose tissue biology.Biochim Biophys Acta. 2009 Jun;1791(6):507-13. doi: 10.1016/j.bbalip.2008.12.014. Epub 2009 Jan 7.
• [6] SEIPIN overexpression in the liver may alleviate hepatic steatosis by influencing the intracellular calcium level.Mol Cell Endocrinol. 2019 May 15;488:70-78. doi: 10.1016/j.mce.2019.03.005. Epub 2019 Mar 12.
• [7] Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases. Ann Neurol. 2007 Mar;61(3):237-50. doi: 10.1002/ana.21070.
• [8] Female adipose tissue-specific Bscl2 knockout mice develop only moderate metabolic dysfunction when housed at thermoneutrality and fed a high-fat diet.Sci Rep. 2018 Dec 14;8(1):17863. doi: 10.1038/s41598-018-36078-9.
• [9] Targeting ATGL to rescue BSCL2 lipodystrophy and its associated cardiomyopathy.JCI Insight. 2019 Jun 11;5(14):e129781. doi: 10.1172/jci.insight.129781.
• [10] A de novo heterozygous missense BSCL2 variant in 2 siblings with intractable developmental and epileptic encephalopathy.Seizure. 2019 Oct;71:161-165. doi: 10.1016/j.seizure.2019.07.019. Epub 2019 Jul 25.
• [11] Phenotypic and genotypic heterogeneity in hereditary motor neuronopathy type V: a clinical, electrophysiological and genetic study.Brain. 2000 Aug;123 ( Pt 8):1612-23. doi: 10.1093/brain/123.8.1612.
• [12] Seipin deficiency increases chromocenter fragmentation and disrupts acrosome formation leading to male infertility.Cell Death Dis. 2015 Jul 16;6(7):e1817. doi: 10.1038/cddis.2015.188.
• [13] A Patient with Congenital Generalized Lipodystrophy Due To a Novel Mutation in BSCL2: Indications for Secondary Mitochondrial Dysfunction.JIMD Rep. 2012;4:47-54. doi: 10.1007/8904_2011_86. Epub 2011 Nov 4.
• [14] A new seipin-associated neurodegenerative syndrome. J Med Genet. 2013 Jun;50(6):401-9. doi: 10.1136/jmedgenet-2013-101525. Epub 2013 Apr 6.
• [15] The Silver syndrome variant of hereditary spastic paraplegia maps to chromosome 11q12-q14, with evidence for genetic heterogeneity within this subtype. Am J Hum Genet. 2001 Jul;69(1):209-15. doi: 10.1086/321267. Epub 2001 May 25.
• [16] A Patient with Berardinelli-Seip Syndrome, Novel AGPAT2 Splicesite Mutation and Concomitant Development of Non-diabetic Polyneuropathy.J Clin Res Pediatr Endocrinol. 2019 Sep 3;11(3):319-326. doi: 10.4274/jcrpe.galenos.2018.2018.0227. Epub 2018 Dec 19.
• [17] Berardinelli-Seip syndrome and progressive myoclonus epilepsy.Epileptic Disord. 2019 Feb 1;21(1):117-121. doi: 10.1684/epd.2019.1038.
• [18] Novel BSCL2 gene mutation E189X in Chinese congenital generalized lipodystrophy child with early onset diabetes mellitus.Eur J Endocrinol. 2007 Dec;157(6):783-7. doi: 10.1530/EJE-07-0393.
• [19] Seipin is necessary for normal brain development and spermatogenesis in addition to adipogenesis.Hum Mol Genet. 2015 Aug 1;24(15):4238-49. doi: 10.1093/hmg/ddv156. Epub 2015 May 1.
• [20] Lack of seipin in neurons results in anxiety- and depression-like behaviors via down regulation of PPAR.Hum Mol Genet. 2014 Aug 1;23(15):4094-102. doi: 10.1093/hmg/ddu126. Epub 2014 Mar 20.
• [21] Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms.Acta Neuropathol. 2013 Sep;126(3):307-28. doi: 10.1007/s00401-013-1115-8. Epub 2013 Jul 30.
• [22] Berardinelli-Seip Congenital Lipodystrophy. 2003 Sep 8 [updated 2016 Dec 8]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [23] Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nat Genet. 2004 Mar;36(3):271-6. doi: 10.1038/ng1313. Epub 2004 Feb 22.
• [24] Clinical and Molecular Characterization of BSCL2 Mutations in a Taiwanese Cohort with Hereditary Neuropathy.PLoS One. 2016 Jan 27;11(1):e0147677. doi: 10.1371/journal.pone.0147677. eCollection 2016.
• [25] Novel mutations of the BSCL2 and AGPAT2 genes in 10 families with Berardinelli-Seip congenital generalized lipodystrophy syndrome.Clin Endocrinol (Oxf). 2009 Oct;71(4):512-7. doi: 10.1111/j.1365-2265.2009.03532.x. Epub 2009 Feb 18.
• [26] Celia's encephalopathy and c.974dupG in BSCL2 gene: a hidden change in a known variant.Neurogenetics. 2019 May;20(2):73-82. doi: 10.1007/s10048-019-00574-5. Epub 2019 Mar 23.
• [27] Localization, cDNA sequence and genomic organization of the rat seipin gene (Bscl2) and sequence analysis in inbred rat models of Type 2 diabetes mellitus.Cytogenet Genome Res. 2002;98(1):71-4. doi: 10.1159/000068538.
• [28] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [29] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [30] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [31] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [32] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [33] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [34] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [35] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.