A hemizygous loss-of-function variant in BCORL1 is associated with male infertility and oligoasthenoteratozoospermia.

Publisher: Munksgaard Country of Publication: Denmark NLM ID: 0253664 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1399-0004 (Electronic) Linking ISSN: 00099163 NLM ISO Abbreviation: Clin Genet Subsets: MEDLINE

Original Publication: Copenhagen, Munksgaard.

Repressor Proteins*/genetics ; Infertility, Male*/genetics ; Infertility, Male*/pathology ; Exome Sequencing*; Male ; Humans ; Oligospermia/genetics ; Oligospermia/pathology ; Adult ; Pedigree ; Azoospermia/genetics ; Azoospermia/pathology ; Loss of Function Mutation/genetics ; Genetic Predisposition to Disease ; Protein-Arginine N-Methyltransferases/genetics ; Mutation, Missense/genetics ; Spermatogenesis/genetics

Oligoasthenoteratozoospermia (OAT) is a common type of male infertility; however, its genetic causes remain largely unknown. Some of the genetic determinants of OAT are gene defects affecting spermatogenesis. BCORL1 (BCL6 corepressor like 1) is a transcriptional corepressor that exhibits the OAT phenotype in a knockout mouse model. A hemizygous missense variant of BCORL1 (c.2615T > G:p.Val872Gly) was reported in an infertile male patient with non-obstructive azoospermia (NOA). Nevertheless, the correlation between BCORL1 variants and OAT in humans remains unknown. In this study, we used whole-exome sequencing to identify a novel hemizygous nonsense variant of BCORL1 (c.1564G > T:p.Glu522*) in a male patient with OAT from a Han Chinese family. Functional analysis showed that the variant produced a truncated protein with altered cellular localization and a dysfunctional interaction with SKP1 (S-phase kinase-associated protein 1). Further population screening identified four BCORL1 missense variants in subjects with both OAT (1 of 325, 0.31%) and NOA (4 of 355, 1.13%), but no pathogenic BCORL1 variants among 362 fertile subjects. In conclusion, our findings indicate that BCORL1 is a potential candidate gene in the pathogenesis of OAT and NOA, expanded its disease spectrum and suggested that BCORL1 may play a role in spermatogenesis by interacting with SKP1.
(© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Agarwal A, Mulgund A, Hamada A, Chyatte MR. A unique view on male infertility around the globe. Reprod Biol Endocrinol. 2015;13:37.
Cocuzza M, Cocuzza MA, Bragais FM, et al. The role of varicocele repair in the new era of assisted reproductive technology. Clinics (Sao Paulo). 2008;63(3):395‐404.
Lotti F, Maggi M. Sexual dysfunction and male infertility. Nat Rev Urol. 2018;15(5):287‐307.
World Health Organization, ed. WHO Laboratory Manual for the Examination and Processing of Human Semen. 6th ed. World Health Organization; 2021.
Colpi GM, Francavilla S, Haidl G, et al. European Academy of Andrology guideline management of oligo‐astheno‐teratozoospermia. Andrology. 2018;6(4):513‐524.
Li Y, Wang WL, Tu CF, et al. A novel homozygous frameshift mutation in MNS1 associated with severe oligoasthenoteratozoospermia in humans. Asian J Androl. 2021;23(2):197‐204.
Hu T, Meng L, Tan C, et al. Biallelic CFAP61 variants cause male infertility in humans and mice with severe oligoasthenoteratozoospermia. J Med Genet. 2023;60(2):144‐153.
Sha Y, Liu W, Tang S, et al. TENT5D disruption causes oligoasthenoteratozoospermia and male infertility. Andrology. 2023;11(6):1121‐1131.
Clement TM, Geyer CB, Willis WD, Goulding EH, Upadhyay S, Eddy EM. Actin‐related protein ACTL7B ablation leads to OAT with multiple morphological abnormalities of the flagellum and male infertility in micedagger. Biol Reprod. 2023;108(3):447‐464.
Miyazaki T, Mori M, Yoshida CA, et al. Galnt3 deficiency disrupts acrosome formation and leads to oligoasthenoteratozoospermia. Histochem Cell Biol. 2013;139(2):339‐354.
Udagawa O, Ito C, Ogonuki N, et al. Oligo‐astheno‐teratozoospermia in mice lacking ORP4, a sterol‐binding protein in the OSBP‐related protein family. Genes Cells. 2014;19(1):13‐27.
Nakamura T, Yao R, Ogawa T, et al. Oligo‐astheno‐teratozoospermia in mice lacking Cnot7, a regulator of retinoid X receptor beta. Nat Genet. 2004;36(5):528‐533.
Pagan JK, Arnold J, Hanchard KJ, et al. A novel corepressor, BCoR‐L1, represses transcription through an interaction with CtBP. J Biol Chem. 2007;282(20):15248‐15257.
Wong SJ, Senkovich O, Artigas JA, et al. Structure and role of BCOR PUFD in noncanonical PRC1 assembly and disease. Biochemistry. 2020;59(29):2718‐2728.
Farcas AM, Blackledge NP, Sudbery I, et al. KDM2B links the Polycomb repressive complex 1 (PRC1) to recognition of CpG islands. Elife. 2012;1:e00205.
Sanchez C, Sanchez I, Demmers JA, et al. Proteomics analysis of Ring1B/Rnf2 interactors identifies a novel complex with the Fbxl10/Jhdm1B histone demethylase and the Bcl6 interacting corepressor. Mol Cell Proteomics. 2007;6(5):820‐834.
Guan Y, Leu NA, Ma J, et al. SKP1 drives the prophase I to metaphase I transition during male meiosis. Sci Adv. 2020;6(13):eaaz2129.
Guan Y, Lin H, Leu NA, et al. SCF ubiquitin E3 ligase regulates DNA double‐strand breaks in early meiotic recombination. Nucleic Acids Res. 2022;50(9):5129‐5144.
Lu C, Zhang Y, Qin Y, et al. Human X chromosome exome sequencing identifies BCORL1 as contributor to spermatogenesis. J Med Genet. 2021;58(1):56‐65.
Schlegel PN, Sigman M, Collura B, et al. Diagnosis and treatment of infertility in men: AUA/ASRM guideline part I. Fertil Steril. 2021;115(1):54‐61.
Meng L, Liu Q, Tan C, et al. Novel homozygous variants in TTC12 cause male infertility with asthenoteratozoospermia owing to dynein arm complex and mitochondrial sheath defects in flagella. Front Cell Dev Biol. 2023;11:1184331.
Hermann BP, Cheng K, Singh A, et al. The mammalian spermatogenesis single‐cell transcriptome, from spermatogonial stem cells to spermatids. Cell Rep. 2018;25(6):1650.e8‐1667.e8.
Shukla A, Girisha KM, Somashekar PH, Nampoothiri S, McClellan R, Vernon HJ. Variants in the transcriptional corepressor BCORL1 are associated with an X‐linked disorder of intellectual disability, dysmorphic features, and behavioral abnormalities. Am J Med Genet A. 2019;179(5):870‐874.
Muthusamy B, Bellad A, Girimaji SC, Pandey A. Shukla‐Vernon syndrome: a second family with a novel variant in the BCORL1 gene. Genes (Basel). 2021;12(3):452.
Gafner M, Michelson M, Argilli E, et al. Major brain malformations: corpus callosum dysgenesis, agenesis of septum pellucidum and polymicrogyria in patients with BCORL1‐related disorders. J Hum Genet. 2022;67(2):95‐101.
Tran KT, Le VS, Dao LTM, et al. Novel findings from family‐based exome sequencing for children with biliary atresia. Sci Rep. 2021;11(1):21815.
Xu L, Yang K, Zhu M, et al. Trio‐based exome sequencing broaden the genetic spectrum in keratoconus. Exp Eye Res. 2023;226:109342.
Ji J, Shen L, Bootwalla M, et al. A Semiautomated Whole‐Exome Sequencing Workflow Leads to Increased Diagnostic Yield and Identification of Novel Candidate Variants. Cold Spring Harb Mol Case Stud. 2019;5(2):a003756.
Liu Q, Guo Q, Guo W, et al. Loss of CEP70 function affects acrosome biogenesis and flagella formation during spermiogenesis. Cell Death Dis. 2021;12(5):478.
Ruan T, Yang Y, Jiang C, Shen G, Li D, Shen Y. Identification of biallelic variations of CEP70 in patients with male infertility. Front Endocrinol (Lausanne). 2023;14:1133222.
Tian S, Tu C, He X, et al. Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA. J Med Genet. 2023;60(8):827‐834.
Li LJ, Lyu F, Song YW, et al. Genotype‐phenotype relationship in a large cohort of osteogenesis imperfecta patients with COL1A1 mutations revealed by a new scoring system. Chin Med J (Engl). 2019;132(2):145‐153.
Maezawa S, Hasegawa K, Yukawa M, et al. Polycomb directs timely activation of germline genes in spermatogenesis. Genes Dev. 2017;31(16):1693‐1703.
Wong SJ, Gearhart MD, Taylor AB, et al. KDM2B recruitment of the Polycomb group complex, PRC1.1, requires cooperation between PCGF1 and BCORL1. Structure. 2016;24(10):1795‐1801.
Nagirnaja L, Morup N, Nielsen JE, et al. Variant PNLDC1, defective piRNA processing, and azoospermia. N Engl J Med. 2021;385(8):707‐719.

2022JJ30772 Hunan Provincial Natural Science Foundation of China; CX20230300 Graduate Research and Innovation Projects of Hunan Province; 82171608 National Natural Science Foundation of China; 81971447 National Natural Science Foundation of China; 2019SK1012 Key Grant of Prevention and Treatment of Birth Defect from Hunan Province; 2022M711119 China Postdoctoral Science Foundation; 2023ZZTS0225 Graduate Research and Innovation Projects of Central South University; 2019SK4012 Hunan Provincial Grant for Innovative Province Construction; 2022YFC2702604 National Key Research and Development Program of China

Keywords: BCORL1; BCORL1‐SKP1 interaction; male infertility; oligoasthenoteratozoospermia; spermatogenesis

0 (Repressor Proteins)
0 (BCORL1 protein, human)
EC 2.1.1.319 (Protein-Arginine N-Methyltransferases)

Date Created: 20240211 Date Completed: 20240603 Latest Revision: 20241002

20241003

10.1111/cge.14500

38342987