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Journal of Assisted Reproduction and Genetics

03.04.2024 | Genetics

Novel SPEF2 variants cause male infertility and likely primary ciliary dyskinesia

verfasst von: Wenqing Lu, Yong Li, Lanlan Meng, Chen Tan, Hongchuan Nie, Qianjun Zhang, Yuying Song, Huan Zhang, Yue-Qiu Tan, Chaofeng Tu, Haichun Guo, Longxiang Wu, Juan Du

Erschienen in: Journal of Assisted Reproduction and Genetics

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Abstract

Purpose

This study aimed to identify the genetic causes of male infertility and primary ciliary dyskinesia (PCD)/PCD-like phenotypes in three unrelated Han Chinese families.

Methods

We conducted whole-exome sequencing of three patients with male infertility and PCD/PCD-like phenotypes from three unrelated Chinese families. Ultrastructural and immunostaining analyses of patient spermatozoa and respiratory cilia and in vitro analyses were performed to analyze the effects of SPEF2 variants. Intracytoplasmic sperm injection (ICSI) was administered to three affected patients.

Results

We identified four novel SPEF2 variants, including one novel homozygous splicing site variant [NC_000005.10(NM_024867.4): c.4447 + 1G > A] of the SPEF2 gene in family 1, novel compound heterozygous nonsense variants [NC_000005.10(NM_024867.4): c.1339C > T (p.R447*) and NC_000005.10(NM_024867.4): c.1645G > T (p.E549*)] in family 2, and one novel homozygous missense variant [NC_000005.10(NM_024867.4): c.2524G > A (p.D842N)] in family 3. All the patients presented with male infertility and PCD/likely PCD. All variants were present at very low levels in public databases, predicted to be deleterious in silico prediction tools, and were further confirmed deleterious by in vitro analyses. Ultrastructural analyses of the spermatozoa of the patients revealed the absence of the central pair complex in the sperm flagella. Immunostaining of the spermatozoa and respiratory cilia of the patients validated the pathogenicity of the SPEF2 variants. All patients carrying SPEF2 variants underwent one ICSI cycle and delivered healthy infants.

Conclusion

Our study reported four novel pathogenic variants of SPEF2 in three male patients with infertility and PCD/PCD-like phenotypes, which not only extend the spectrum of SPEF2 mutations but also provide information for genetic counseling and treatment of such conditions.

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Zegers-Hochschild F, Adamson GD, Dyer S, Racowsky C, De Mouzon J, Sokol R, et al. The international glossary on infertility and fertility care, 2017. Hum Reprod. 2017;32(9):1786–801. https://doi.org/10.1093/humrep/dex234.CrossRefPubMedPubMedCentral

Sharlip ID, Jarow JP, Belker AM, Lipshultz LI, Sigman M, Thomas AJ, et al. Best practice policies for male infertility. Fertil Steril. 2002;77(5):873–82. https://doi.org/10.1016/s0015-0282(02)03105-9.CrossRefPubMed

Vander Borght M, Wyns C Fertility and infertility: definition and epidemiology. Clin Biochem. 2018;622–10. https://doi.org/10.1016/j.clinbiochem.2018.03.012.

Cooper TG, Noonan E, Von Eckardstein S, Auger J, Baker HW, Behre HM, et al. World Health Organization reference values for human semen characteristics. Hum Reprod Update. 2010;16(3):231–45. https://doi.org/10.1093/humupd/dmp048.CrossRefPubMed

He X, Liu C, Yang X, Lv M, Ni X, Li Q, et al. Bi-allelic loss-of-function variants in CFAP58 cause flagellar axoneme and mitochondrial sheath defects and asthenoteratozoospermia in humans and mice. Am J Hum Genet. 2020;107(3):514–26. https://doi.org/10.1016/j.ajhg.2020.07.010.CrossRefPubMedPubMedCentral

Tu C, Cong J, Zhang Q, He X, Zheng R, Yang X, et al. Bi-allelic mutations of DNAH10 cause primary male infertility with asthenoteratozoospermia in humans and mice. Am J Hum Genet. 2021;108(8):1466–77. https://doi.org/10.1016/j.ajhg.2021.06.010.CrossRefPubMedPubMedCentral

Paff T, Omran H, Nielsen KG, Haarman EG. Current and future treatments in primary ciliary dyskinesia. Int J Mol Sci. 2021;22(18). https://doi.org/10.3390/ijms22189834.

Sironen A, Shoemark A, Patel M, Loebinger MR, Mitchison HM. Sperm defects in primary ciliary dyskinesia and related causes of male infertility. Cell Mol Life Sci. 2020;77(11):2029–48. https://doi.org/10.1007/s00018-019-03389-7.CrossRefPubMed

Jayasena CN, Sironen A. diagnostics and management of male infertility in primary ciliary dyskinesia. Diagnostics (Basel). 2021;11(9). https://doi.org/10.3390/diagnostics11091550.

10.

Newman L, Chopra J, Dossett C, Shepherd E, Bercusson A, Carroll M, et al. The impact of primary ciliary dyskinesia on female and male fertility: a narrative review. Hum Reprod Update. 2023;29(3):347–67. https://doi.org/10.1093/humupd/dmad003.CrossRefPubMedPubMedCentral

11.

Li Y, Li Y, Wang Y, Meng L, Tan C, Du J, et al. Identification of novel biallelic LRRC6 variants in male Chinese patients with primary ciliary dyskinesia and infertility. J Assist Reprod Genet. 2023;40(1):41–51. https://doi.org/10.1007/s10815-022-02681-z.CrossRefPubMed

12.

Blanchon S, Legendre M, Copin B, Duquesnoy P, Montantin G, Kott E, et al. Delineation of CCDC39/CCDC40 mutation spectrum and associated phenotypes in primary ciliary dyskinesia. J Med Genet. 2012;49(6):410–6. https://doi.org/10.1136/jmedgenet-2012-100867.CrossRefPubMed

13.

Li Y, Wang WL, Tu CF, Meng LL, Hu TY, Du J, et al. A novel homozygous frameshift mutation in MNS1 associated with severe oligoasthenoteratozoospermia in humans. Asian J Androl. 2021;23(2):197–204. https://doi.org/10.4103/aja.aja_56_20.CrossRefPubMed

14.

Leslie JS, Rawlins LE, Chioza BA, Olubodun OR, Salter CG, Fasham J, et al. MNS1 variant associated with situs inversus and male infertility. Eur J Hum Genet. 2020;28(1):50–5. https://doi.org/10.1038/s41431-019-0489-z.CrossRefPubMed

15.

Ta-Shma A, Hjeij R, Perles Z, Dougherty GW, Abu Zahira I, Letteboer SJF, et al. Homozygous loss-of-function mutations in MNS1 cause laterality defects and likely male infertility. PLoS Genet. 2018;14(8):e1007602. https://doi.org/10.1371/journal.pgen.1007602.CrossRefPubMedPubMedCentral

16.

Zuccarello D, Ferlin A, Cazzadore C, Pepe A, Garolla A, Moretti A, et al. Mutations in dynein genes in patients affected by isolated non-syndromic asthenozoospermia. Hum Reprod. 2008;23(8):1957–62. https://doi.org/10.1093/humrep/den193.CrossRefPubMed

17.

Zhu D, Zhang H, Wang R, Liu X, Jiang Y, Feng T, et al. Association of DNAH11 gene polymorphisms with asthenozoospermia in Northeast Chinese patients. Biosci Rep. 2019;39(6). 10.1042/BSR20181450.

18.

Knowles MR, Leigh MW, Carson JL, Davis SD, Dell SD, Ferkol TW, et al. Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure. Thorax. 2012;67(5):433–41. https://doi.org/10.1136/thoraxjnl-2011-200301.CrossRefPubMed

19.

Ostrowski LE, Andrews K, Potdar P, Matsuura H, Jetten A, Nettesheim P. Cloning and characterization of KPL2, a novel gene induced during ciliogenesis of tracheal epithelial cells. Am J Respir Cell Mol Biol. 1999;20(4):675–83. https://doi.org/10.1165/ajrcmb.20.4.3496.CrossRefPubMed

20.

Sironen A, Thomsen B, Andersson M, Ahola V, Vilkki J. An intronic insertion in KPL2 results in aberrant splicing and causes the immotile short-tail sperm defect in the pig. Proc Natl Acad Sci U S A. 2006;103(13):5006–11. https://doi.org/10.1073/pnas.0506318103.CrossRefPubMedPubMedCentral

21.

Sironen A, Hansen J, Thomsen B, Andersson M, Vilkki J, Toppari J, et al. Expression of SPEF2 during mouse spermatogenesis and identification of IFT20 as an interacting protein. Biol Reprod. 2010;82(3):580–90. https://doi.org/10.1095/biolreprod.108.074971.CrossRefPubMed

22.

Cindric S, Dougherty GW, Olbrich H, Hjeij R, Loges NT, Amirav I, et al. SPEF2- and HYDIN-mutant cilia lack the central pair-associated protein SPEF2, aiding primary ciliary dyskinesia diagnostics. Am J Respir Cell Mol Biol. 2020;62(3):382–96. https://doi.org/10.1165/rcmb.2019-0086OC.CrossRefPubMed

23.

Tu C, Nie H, Meng L, Wang W, Li H, Yuan S, et al. Novel mutations in SPEF2 causing different defects between flagella and cilia bridge: the phenotypic link between MMAF and PCD. Hum Genet. 2020;139(2):257–71. https://doi.org/10.1007/s00439-020-02110-0.CrossRefPubMed

24.

Liu C, Lv M, He X, Zhu Y, Amiri-Yekta A, Li W, et al. Homozygous mutations in SPEF2 induce multiple morphological abnormalities of the sperm flagella and male infertility. J Med Genet. 2020;57(1):31–7. https://doi.org/10.1136/jmedgenet-2019-106011.CrossRefPubMed

25.

Sha Y, Liu W, Wei X, Zhu X, Luo X, Liang L, et al. Biallelic mutations in sperm flagellum 2 cause human multiple morphological abnormalities of the sperm flagella (MMAF) phenotype. Clin Genet. 2019;96(5):385–93. https://doi.org/10.1111/cge.13602.CrossRefPubMed

26.

Guo F, Yang B, Ju ZH, Wang XG, Qi C, Zhang Y, et al. Alternative splicing, promoter methylation, and functional SNPs of sperm flagella 2 gene in testis and mature spermatozoa of Holstein bulls. Reproduction. 2014;147(2):241–52. https://doi.org/10.1530/REP-13-0343.CrossRefPubMed

27.

Sironen A, Kotaja N, Mulhern H, Wyatt TA, Sisson JH, Pavlik JA, et al. Loss of SPEF2 function in mice results in spermatogenesis defects and primary ciliary dyskinesia. Biol Reprod. 2011;85(4):690–701. https://doi.org/10.1095/biolreprod.111.091132.CrossRefPubMedPubMedCentral

28.

Mckenzie CW, Lee L. Genetic interaction between central pair apparatus genes CFAP221, CFAP54, and SPEF2 in mouse models of primary ciliary dyskinesia. Sci Rep. 2020;10(1):12337. https://doi.org/10.1038/s41598-020-69359-3.CrossRefPubMedPubMedCentral

29.

Liu W, Sha Y, Li Y, Mei L, Lin S, Huang X, et al. Loss-of-function mutations in SPEF2 cause multiple morphological abnormalities of the sperm flagella (MMAF). J Med Genet. 2019;56(10):678–84. https://doi.org/10.1136/jmedgenet-2018-105952.CrossRefPubMed

30.

Mori M, Kido T, Sakamoto N, Ozasa M, Kido K, Noguchi Y, et al. Novel SPEF2 variant in a Japanese patient with primary ciliary dyskinesia: a case report and literature review. J Clin Med. 2022;12(1). https://doi.org/10.3390/jcm12010317.

31.

Lucas JS, Barbato A, Collins SA, Goutaki M, Behan L, Caudri D, et al. European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia. Eur Respir J. 2017;49(1). https://doi.org/10.1183/13993003.01090-2016.

32.

Leigh MW, Hazucha MJ, Chawla KK, Baker BR, Shapiro AJ, Brown DE, et al. Standardizing nasal nitric oxide measurement as a test for primary ciliary dyskinesia. Ann Am Thorac Soc. 2013;10(6):574–81. https://doi.org/10.1513/AnnalsATS.201305-110OC.CrossRefPubMedPubMedCentral

33.

Tan YQ, Tu C, Meng L, Yuan S, Sjaarda C, Luo A, et al. Loss-of-function mutations in TDRD7 lead to a rare novel syndrome combining congenital cataract and nonobstructive azoospermia in humans. Genet Med. 2019;21(5):1209–17. https://doi.org/10.1038/gim.2017.130.CrossRefPubMed

34.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24. https://doi.org/10.1038/gim.2015.30.CrossRefPubMedPubMedCentral

35.

Gu YF, Zhou QW, Zhang SP, Lu CF, Gong F, Shi Y, et al. The clinical and neonatal outcomes after stimulation of immotile spermatozoa using SperMagic medium. Andrologia. 2018;50(7):e13056. https://doi.org/10.1111/and.13056.CrossRefPubMed

Titel: Novel SPEF2 variants cause male infertility and likely primary ciliary dyskinesia
verfasst von: Wenqing Lu
Yong Li
Lanlan Meng
Chen Tan
Hongchuan Nie
Qianjun Zhang
Yuying Song
Huan Zhang
Yue-Qiu Tan
Chaofeng Tu
Haichun Guo
Longxiang Wu
Juan Du
Publikationsdatum: 03.04.2024
Verlag: Springer US
Erschienen in: Journal of Assisted Reproduction and Genetics
Print ISSN: 1058-0468
Elektronische ISSN: 1573-7330
DOI: https://doi.org/10.1007/s10815-024-03106-9

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