Whole exome sequencing identifies hemizygous deletions in the UGT2B28 and USP17L2 genes in a three‑generation family with endometriosis

Albertsen,Hans M.; Matalliotaki,Charoula; Matalliotakis,Michail; Zervou,Maria I.; Matalliotakis,Ioannis; Spandidos,Demetrios A.; Chettier,Rakesh; Ward,Kenneth; Goulielmos,George N.

doi:10.3892/mmr.2019.9818

Whole exome sequencing identifies hemizygous deletions in the UGT2B28 and USP17L2 genes in a three‑generation family with endometriosis

Authors:
- Hans M. Albertsen
- Charoula Matalliotaki
- Michail Matalliotakis
- Maria I. Zervou
- Ioannis Matalliotakis
- Demetrios A. Spandidos
- Rakesh Chettier
- Kenneth Ward
- George N. Goulielmos
View Affiliations

Affiliations: Juneau Biosciences, LLC, Salt Lake City, UT, USA, 3rd Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki, Thessaloniki 541 24, Greece, Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, University of Crete, Heraklion 710 03, Crete, Greece, Department of Obstetrics and Gynecology, Venizeleio General Hospital of Heraklion, Heraklion 714 09, Greece, Laboratory of Clinical Virology, Medical School, University of Crete, Heraklion 710 03, Crete, Greece
Published online on: January 3, 2019 https://doi.org/10.3892/mmr.2019.9818
Pages: 1716-1720
Copyright: © Albertsen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Endometriosis is an enigmatic condition with an unknown etiology and a poorly understood pathogenesis. It is considered to appear from the interplay of many genetic and environmental factors, affecting up to 10% of women and represents a major cause of pain and infertility. The familial association of endometriosis, as demonstrated through monozygotic twin and family studies suggests a genetic contribution to the disease, with further case‑control and genome‑wide association studies (GWAS) detecting various endometriosis risk factors. In a recent study, we described a unique, three‑generation family of Cretan origin (Greece) with 7 females with surgically confirmed endometriosis (grandmother, 3 daughters and 3 granddaughters). All the affected members of this family displayed a variety of clinical manifestations and complications. In the present study, to further analyze the genetic variants conferring the risk of developing endometriosis, whole exome sequencing (WES) was performed, using the AmpliSeq technology on the Ion Proton platform. An initial analysis of 64 variants that were detected across the 14 genes previously confirmed to be associated with endometriosis, did not identify any deleterious exonic variants in these genes. However, further analysis revealed 2 hemizygous deletions in the grandmother that segregate in several of her affected offspring. The first deletion was found in the UGT2B28 locus, spanning 7 informative sequence variants across at least 14 kb. The second deletion, located in USP17L2, spans 3 informative variants across at least 2 kb. On the whole, the findings of the presents study implicate 2 additional genes in the pathogenesis of endometriosis, apart from those already identified by GWAS.

View Figures

View References

1	Burney RO and Giudice LC: Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 98:511–519. 2012. View Article : Google Scholar : PubMed/NCBI
2	Halis G and Arici A: Endometriosis and inflammation in infertility. Ann N Y Acad Sci 1034. 300–315. 2004. View Article : Google Scholar
3	Simpson JL, Elias S, Malinak LR and Buttram VC Jr: Heritable aspects of endometriosis. I. Genetic studies. Am J Obstet Gynecol. 137:327–331. 1980. View Article : Google Scholar : PubMed/NCBI
4	Hadfield RM, Mardon HJ, Barlow DH and Kennedy SH: Endometriosis in monozygotic twins. Fertil Steril. 68:941–942. 1997. View Article : Google Scholar : PubMed/NCBI
5	Treloar SA, O'Connor DT, O'Connor VM and Martin NG: Genetic influences on endometriosis in an Australian twin sample. simplesueT@qimr.edu.au. Fertil Steril. 71:701–710. 1999. View Article : Google Scholar : PubMed/NCBI
6	Saha R, Pettersson HJ, Svedberg P, Olovsson M, Bergqvist A, Marions L, Tornvall P and Kuja-Halkola R: Heritability of endometriosis. Fertil Steril. 104:947–952. 2015. View Article : Google Scholar : PubMed/NCBI
7	Kobayashi H, Imanaka S, Nakamura H and Tsuji A: Understanding the role of epigenomic, genomic and genetic alterations in the development of endometriosis (review). Mol Med Rep. 9:1483–1505. 2014. View Article : Google Scholar : PubMed/NCBI
8	Sapkota Y, Steinthorsdottir V, Morris AP, Fassbender A, Rahmioglu N, De Vivo I, Buring JE, Zhang F, Edwards TL, Jones S, et al iPSYCH-SSI-Broad Group, : Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism. Nat Commun. 8:155392017. View Article : Google Scholar : PubMed/NCBI
9	Gao L, Emond MJ, Louie T, Cheadle C, Berger AE, Rafaels N, Vergara C, Kim Y, Taub MA, Ruczinski I, et al National Heart, Lung, and Blood Institute GO Exome Sequencing Project, : Identification of rare variants in ATP8B4 as a risk factor for systemic sclerosis by whole-exome sequencing. Arthritis Rheumatol. 68:191–200. 2016. View Article : Google Scholar : PubMed/NCBI
10	Ng SB, Turner EH, Robertson PD, Flygare SD, Bigham AW, Lee C, Shaffer T, Wong M, Bhattacharjee A, Eichler EE, et al: Targeted capture and massively parallel sequencing of 12 human exomes. Nature. 461:272–276. 2009. View Article : Google Scholar : PubMed/NCBI
11	Matalliotakis M, Zervou MI, Matalliotaki C, Arici A, Spandidos DA, Matalliotakis I and Goulielmos GN: Genetic association study in a three-generation family with seven members with endometriosis. Mol Med Rep. 16:6077–6080. 2017. View Article : Google Scholar : PubMed/NCBI
12	Matalliotaki C, Matalliotakis M, Zervou MI, Trivli A, Matalliotakis I, Mavromatidis G, Spandidos DA, Albertsen HM, Chettier R, Ward K and Goulielmos GN: Co-existence of endometriosis with 13 non-gynecological co-morbidities: Mutation analysis by whole exome sequencing. Mol Med Rep. 18:5053–5057. 2018.PubMed/NCBI
13	Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ and Sham PC: PLINK: A tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 81:559–575. 2007. View Article : Google Scholar : PubMed/NCBI
14	Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM, Huff CD, Shannon PT, Jabs EW, Nickerson DA, et al: Exome sequencing identifies the cause of a mendelian disorder. Nat Genet. 42:30–35. 2010. View Article : Google Scholar : PubMed/NCBI
15	Girard SL, Gauthier J, Noreau A, Xiong L, Zhou S, Jouan L, Dionne-Laporte A, Spiegelman D, Henrion E, Diallo O, et al: Increased exonic de novo mutation rate in individuals with schizophrenia. Nat Genet. 43:860–863. 2011. View Article : Google Scholar : PubMed/NCBI
16	Choi M, Scholl UI, Ji W, Liu T, Tikhonova IR, Zumbo P, Nayir A, Bakkaloğlu A, Ozen S, Sanjad S, et al: Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci USA. 106:19096–19101. 2009. View Article : Google Scholar : PubMed/NCBI
17	Tephly TR and Burchell B: UDP-glucuronosyltransferases: A family of detoxifying enzymes. Trends Pharmacol Sci. 11:276–279. 1990. View Article : Google Scholar : PubMed/NCBI
18	Guillemette C, Lévesque E, Harvey M, Bellemare J and Menard V: UGT genomic diversity: Beyond gene duplication. Drug Metab Rev. 42:24–44. 2010. View Article : Google Scholar : PubMed/NCBI
19	Brønstad I, Wolff AS, Løvås K, Knappskog PM and Husebye ES: Genome-wide copy number variation (CNV) in patients with autoimmune Addison's disease. BMC Med Genet. 12:1112011. View Article : Google Scholar : PubMed/NCBI
20	Karypidis AH, Olsson M, Andersson S-O, Rane A and Ekström L: Deletion polymorphism of the UGT2B17 gene is associated with increased risk for prostate cancer and correlated to gene expression in the prostate. Pharmacogenomics J. 8:147–151. 2008. View Article : Google Scholar : PubMed/NCBI
21	Nadeau G, Bellemare J, Audet-Walsh É, Flageole C, Huang SP, Bao BY, Douville P, Caron P, Fradet Y, Lacombe L, et al: Deletions of the androgen-metabolizing UGT2B genes have an effect on circulating steroid levels and biochemical recurrence after radical prostatectomy in localized prostate cancer. J Clin Endocrinol Metab. 96:E1550–E1557. 2011. View Article : Google Scholar : PubMed/NCBI
22	Belledant A, Hovington H, Garcia L, Caron P, Brisson H, Villeneuve L, Simonyan D, Têtu B, Fradet Y, Lacombe L, et al: The UGT2B28 sex-steroid inactivation pathway is a regulator of steroidogenesis and modifies the risk of prostate cancer progression. Eur Urol. 69:601–609. 2016. View Article : Google Scholar : PubMed/NCBI
23	Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK and Bernards R: A genomic and functional inventory of deubiquitinating enzymes. Cell. 123:773–786. 2005. View Article : Google Scholar : PubMed/NCBI
24	Burrows JF, McGrattan MJ, Rascle A, Humbert M, Baek KH and Johnston JA: DUB-3, a cytokine-inducible deubiquitinating enzyme that blocks proliferation. J Biol Chem. 279:13993–14000. 2004. View Article : Google Scholar : PubMed/NCBI
25	Shin JM, Yoo KJ, Kim MS, Kim D and Baek KH: Hyaluronan- and RNA-binding deubiquitinating enzymes of USP17 family members associated with cell viability. BMC Genomics. 7:2922006. View Article : Google Scholar : PubMed/NCBI
26	Ilad RS, Fleming SD, Bebington CR and Murphy CR: Ubiquitin is associated with the survival of ectopic stromal cells in endometriosis. Reprod Biol Endocrinol. 2:692004. View Article : Google Scholar : PubMed/NCBI
27	Zhou B, Shu B, Xi T, Su N and Liu J: Dub3 expression correlates with tumor progression and poor prognosis in human epithelial ovarian cancer. Biomed Pharmacother. 70:84–89. 2015. View Article : Google Scholar : PubMed/NCBI
28	Lin Y, Wang Y, Shi Q, Yu Q, Liu C, Feng J, Deng J, Evers BM, Zhou BP and Wu Y: Stabilization of the transcription factors slug and twist by the deubiquitinase dub3 is a key requirement for tumor metastasis. Oncotarget. 8:75127–75140. 2017.PubMed/NCBI
29	Blanco MJ, Moreno-Bueno G, Sarrio D, Locascio A, Cano A, Palacios J and Nieto MA: Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene. 21:3241–3246. 2002. View Article : Google Scholar : PubMed/NCBI
30	Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M and Hung MC: Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol. 6:931–940. 2004. View Article : Google Scholar : PubMed/NCBI
31	Thiery JP and Sleeman JP: Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 7:131–142. 2006. View Article : Google Scholar : PubMed/NCBI
32	Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI
33	Albertsen HM and Ward K: Genes linked to endometriosis by GWAS are integral to cytoskeleton regulation and suggests that mesothelial barrier homeostasis is a factor in the pathogenesis of endometriosis. Reprod Sci. 24:803–811. 2017. View Article : Google Scholar : PubMed/NCBI