Deficiency of MFSD6L, an acrosome membrane protein, causes oligoasthenoteratozoospermia in humans and mice

Dapeng Zhou; Huan Wu; Lingbo Wang; Xuemei Wang; Shuyan Tang; Yiling Zhou; Jiaxiong Wang; Bangguo Wu; Jianan Tang; Xuehai Zhou; Shixiong Tian; Shuang Liu; Mingrong Lv; Xiaojin He; Li Jin; Huijuan Shi; Feng Zhang; Yunxia Cao; Chunyu Liu

doi:10.1016/j.jgg.2024.06.008

Volume 51 Issue 10

Oct. 2024

Turn off MathJax

Article Contents

Article Navigation > Journal of Genetics and Genomics > 2024 > 51(10): 1007-1019

PDF( 3830 KB)

Deficiency of MFSD6L, an acrosome membrane protein, causes oligoasthenoteratozoospermia in humans and mice

doi: 10.1016/j.jgg.2024.06.008

a. State Key Laboratory of Genetic Engineering, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, Shanghai 200438, China;
b. Institute of Medical Genetics and Genomics, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China;
c. Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China;
d. NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui 230032, China;
e. Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People's Republic of China, Hefei, Anhui 230032, China;
f. Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Institute of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200433, China;
g. Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Pharmacy, Fudan University, Shanghai 200237, China;
h. State Key Laboratory of Reproductive Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215002, China;
i. Suzhou Municipal Hospital, Suzhou, Jiangsu 215002, China;
j. Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China;
k. Shanghai Key Laboratory of Embryo Original Diseases, Soong Ching Ling Institute of Maternity and Child Health, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China

Funds:

This study was supported by the National Key Research and Development Program of China (2021YFC2701400 and 2023YFC2705600) and the National Natural Science Foundation of China (32288101, 32100480, 32370654, 82271639, 32322017, and 32200485).

Received Date: 2024-04-18
Accepted Date: 2024-06-13
Rev Recd Date: 2024-06-05

Available Online: 2025-06-06

Publish Date: 2024-06-21

Abstract

Abstract

Oligoasthenoteratozoospermia is an important factor affecting male fertility and has been found to be associated with genetic factors. However, there are still a proportion of oligoasthenoteratozoospermia cases that cannot be explained by known pathogenic genetic variants. Here, we perform genetic analyses and identify bi-allelic loss-of-function variants of MFSD6L from an oligoasthenoteratozoospermia-affected family. Mfsd6l knock-out male mice also present male subfertility with reduced sperm concentration, motility, and deformed acrosomes. Further mechanistic analyses reveal that MFSD6L, as an acrosome membrane protein, plays an important role in the formation of acrosome by interacting with the inner acrosomal membrane protein SPACA1. Moreover, poor embryonic development is consistently observed after intracytoplasmic sperm injection treatment using spermatozoa from the MFSD6L-deficient man and male mice. Collectively, our findings reveal that MFSD6L is required for the anchoring of sperm acrosome and head shaping. The deficiency of MFSD6L affects male fertility and causes oligoasthenoteratozoospermia in humans and mice.
- Male fertility,
- Oligoasthenoteratozoospermia,
- MFSD6L,
- Acrosome,
- ICSI

FullText(HTML)

References(62)

References

Agarwal, A., Baskaran, S., Parekh, N., Cho, C.-L., Henkel, R., Vij, S., Arafa, M., Panner Selvam, M.K., Shah, R., 2021. Male infertility. Lancet. 397, 319-333.

Ben Khelifa, M., Coutton, C., Zouari, R., Karaouzene, T., Rendu, J., Bidart, M., Yassine, S., Pierre, V., Delaroche, J., Hennebicq, S., et al., 2014. Mutations in DNAH1, which encodes an inner arm heavy chain dynein, lead to male infertility from multiple morphological abnormalities of the sperm flagella. Am. J. Hum. Genet. 94, 95-104.

Campos, G., Sciorio, R., Esteves, S.C., 2023. Total fertilization failure after ICSI: insights into pathophysiology, diagnosis, and management through artificial oocyte activation. Hum. Reprod. Update. 29, 369-394.

Chen, P., Saiyin, H., Shi, R., Liu, B., Han, X., Gao, Y., Ye, X., Zhang, X., Sun, Y., 2021. Loss of SPACA1 function causes autosomal recessive globozoospermia by damaging the acrosome-acroplaxome complex. Hum. Reprod. 36, 2587-2596.

Cheung, S., Xie, P., Parrella, A., Keating, D., Rosenwaks, Z., Palermo, G.D., 2020. Identification and treatment of men with phospholipase Cζ-defective spermatozoa. Fertil. Steril. 114, 535-544.

Cong, J., Wang, X., Amiri-Yekta, A., Wang, L., Kherraf, Z.E., Liu, C., Cazin, C., Tang, S., Hosseini, S.H., Tian, S., et al., 2022. Homozygous mutations in CCDC34 cause male infertility with oligoasthenoteratozoospermia in humans and mice. J. Med. Genet. 59, 710-718.

Coutton, C., Escoffier, J., Martinez, G., Arnoult, C., Ray, P.F., 2015. Teratozoospermia: spotlight on the main genetic actors in the human. Hum. Reprod. Update. 21, 455-485.

Da Costa, R., Bordessoules, M., Guilleman, M., Carmignac, V., Lhussiez, V., Courot, H., Bataille, A., Chlemaire, A., Bruno, C., Fauque, P., et al., 2019. Vps13b is required for acrosome biogenesis through functions in Golgi dynamic and membrane trafficking. Cell. Mol. Life Sci. 77, 511-529.

Dai, J., Zhang, T., Guo, J., Zhou, Q., Gu, Y., Zhang, J., Hu, L., Zong, Y., Song, J., Zhang, S., et al., 2021. Homozygous pathogenic variants in ACTL9 cause fertilization failure and male infertility in human and mouse. Am. J. Hum. Genet. 36, 396-396.

Dam, A.H.D.M., Koscinski, I., Kremer, J.A.M., Moutou, C., Jaeger, A.S., Oudakker, A.R., Tournaye, H., Charlet, N., Lagier-Tourenne, C., van Bokhoven, H., et al., 2007. Homozygous mutation in SPATA16 is associated with male infertility in human globozoospermia. Am. J. Hum. Genet. 81, 813-820.

Dieterich, K., Rifo, R.S., Faure, A.K., Hennebicq, S., Ben Amar, B., Zahi, M., Perrin, J., Martinez, D., Sele, B., Jouk, P.S., et al., 2007. Homozygous mutation of AURKC yields large-headed polyploid spermatozoa and causes male infertility. Nat. Genet. 39, 661-665.

Doran, J., Walters, C., Kyle, V., Wooding, P., Hammett-Burke, R., Colledge, W.H., 2016. Mfsd14a (Hiat1) gene disruption causes globozoospermia and infertility in male mice. Reproduction. 152, 91-99.

Fujihara, Y., Satouh, Y., Inoue, N., Isotani, A., Ikawa, M., Okabe, M., 2012. SPACA1-deficient male mice are infertile with abnormally shaped sperm heads reminiscent of globozoospermia. Development. 139, 3583-3589.

Geyer, C.B., Inselman, A.L., Sunman, J.A., Bornstein, S., Handel, M.A., Eddy, E.M., 2009. A missense mutation in the Capza3 gene and disruption of F-actin organization in spermatids of repro32 infertile male mice. Dev. Biol. 330, 142-152.

Hachem, A., Godwin, J., Ruas, M., Lee, H.C., Ferrer Buitrago, M., Ardestani, G., Bassett, A., Fox, S., Navarrete, F., de Sutter, P., et al., 2017. PLCzeta is the physiological trigger of the Ca(2+) oscillations that induce embryogenesis in mammals but conception can occur in its absence. Development. 144, 2914-2924.

He, X., Li, W., Wu, H., Lv, M., Liu, W., Liu, C., Zhu, F., Li, C., Fang, Y., Yang, C., et al., 2019. Novel homozygous CFAP69 mutations in humans and mice cause severe asthenoteratospermia with multiple morphological abnormalities of the sperm flagella. J. Med. Genet. 56, 96-103.

He, X., Liu, C., Yang, X., Lv, M., Ni, X., Li, Q., Cheng, H., Liu, W., Tian, S., Wu, H., et al., 2020. 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. 107, 514-526.

Hirose, M., Honda, A., Fulka, H., Tamura-Nakano, M., Matoba, S., Tomishima, T., Mochida, K., Hasegawa, A., Nagashima, K., Inoue, K., et al., 2020. Acrosin is essential for sperm penetration through the zona pellucida in hamsters. Proc. Natl. Acad. Sci. U. S. A. 117, 2513-2518.

Hu, T., Meng, L., Tan, C., Luo, C., He, W.B., Tu, C., Zhang, H., Du, J., Nie, H., Lu, G.X., et al., 2023. Biallelic CFAP61 variants cause male infertility in humans and mice with severe oligoasthenoteratozoospermia. J. Med. Genet. 60, 144-153.

Hua, R., Xue, R., Liu, Y., Li, Y., Sha, X., Li, K., Gao, Y., Shen, Q., Lv, M., Xu, Y., et al., 2023. ACROSIN deficiency causes total fertilization failure in humans by preventing the sperm from penetrating the zona pellucida. Hum. Reprod. 38, 1213-1223.

Jiao, S.Y., Yang, Y.H., Chen, S.R., 2021. Molecular genetics of infertility: loss-of-function mutations in humans and corresponding knockout/mutated mice. Hum. Reprod. Update. 27, 154-189.

Jin, H.J., Wang, J.L., Geng, X.Y., Wang, C.Y., Wang, B.B., Chen, S.R., 2023. CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men. EBioMedicine. 93, 104675.

Jin, M., Fujiwara, E., Kakiuchi, Y., Okabe, M., Satouh, Y., Baba, S.A., Chiba, K., Hirohashi, N., 2011. Most fertilizing mouse spermatozoa begin their acrosome reaction before contact with the zona pellucida during in vitro fertilization. Proc. Natl. Acad. Sci. U. S. A. 108, 4892-4896.

Kanemori, Y., Koga, Y., Sudo, M., Kang, W., Kashiwabara, S.-i., Ikawa, M., Hasuwa, H., Nagashima, K., Ishikawa, Y., Ogonuki, N., et al., 2016. Biogenesis of sperm acrosome is regulated by pre-mRNA alternative splicing of Acrbp in the mouse. Proc. Natl. Acad. Sci. U. S. A. 113, E3696-E3705.

Kang, J.Y., Wen, Z., Pan, D., Zhang, Y., Li, Q., Zhong, A., Yu, X., Wu, Y.C., Chen, Y., Zhang, X., et al., 2022. LLPS of FXR1 drives spermiogenesis by activating translation of stored mRNAs. Science. 377, eabj6647.

Khawar, M.B., Gao, H., Li, W., 2019. Mechanism of acrosome biogenesis in mammals. Front. Cell Dev. Biol. 7, 195.

Li, W., Wu, H., Li, F., Tian, S., Kherraf, Z.E., Zhang, J., Ni, X., Lv, M., Liu, C., Tan, Q., et al., 2020. Biallelic mutations in CFAP65 cause male infertility with multiple morphological abnormalities of the sperm flagella in humans and mice. J. Med. Genet. 57, 89-95.

Li, W.Y., He, X.J., Yang, S.M., Liu, C.Y., Wu, H., Liu, W.J., Lv, M.R., Tang, D.D., Tan, J., Tang, S.Y., et al., 2019. Biallelic mutations of CFAP251 cause sperm flagellar defects and human male infertility. J. Hum. Genet. 64, 49-54.

Liu, C., He, X., Liu, W., Yang, S., Wang, L., Li, W., Wu, H., Tang, S., Ni, X., Wang, J., et al., 2019a. Bi-allelic mutations in TTC29 cause male subfertility with asthenoteratospermia in humans and mice. Am. J. Hum. Genet. 105, 1168-1181.

Liu, C., Miyata, H., Gao, Y., Sha, Y., Tang, S., Xu, Z., Whitfield, M., Patrat, C., Wu, H., Dulioust, E., et al., 2020. Bi-Allelic DNAH8 variants lead to multiple morphological abnormalities of the sperm flagella and primary male infertility. Am. J. Hum. Genet. 107, 330-341.

Liu, C., Shen, Y., Tang, S., Wang, J., Zhou, Y., Tian, S., Wu, H., Cong, J., He, X., Jin, L., et al., 2023a. Homozygous variants in AKAP3 induce asthenoteratozoospermia and male infertility. J. Med. Genet. 60, 137-143.

Liu, C., Si, W., Tu, C., Tian, S., He, X., Wang, S., Yang, X., Yao, C., Li, C., Kherraf, Z.E., et al., 2023b. Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile men and cynomolgus monkey and tree shrew models. Am. J. Hum. Genet. 110, 516-530.

Liu, C., Tu, C., Wang, L., Wu, H., Houston, B.J., Mastrorosa, F.K., Zhang, W., Shen, Y., Wang, J., Tian, S., et al., 2021. Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility. Am. J. Hum. Genet. 108, 309-323.

Liu, W.J., Wu, H., Wang, L., Yang, X.Y., Liu, C.Y., He, X.J., Li, W.Y., Wang, J.J., Chen, Y.J., Wang, H.Y., et al., 2019b. Homozygous loss-of-function mutations in FSIP2 cause male infertility with asthenoteratospermia. J. Genet. Genomics 46, 53-56.

Lu, Y.G., Shimada, K., Tang, S.G., Zhang, J.J., Ogawa, Y., Noda, T., Shibuya, H., Ikawa, M., 2023. 1700029I15Rik orchestrates the biosynthesis of acrosomal membrane proteins required for sperm-egg interaction. Proc. Natl. Acad. Sci. U. S. A. 120, e2207263120.

Ma, A., Zhou, J., Ali, H., Abbas, T., Ali, I., Muhammad, Z., Dil, S., Chen, J., Huang, X., Ma, H., et al., 2023. Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice. JCI Insight 8, e166869.

Morohoshi, A., Miyata, H., Oyama, Y., Oura, S., Noda, T., Ikawa, M., 2021. FAM71F1 binds to RAB2A and RAB2B and is essential for acrosome formation and male fertility in mice. Development. 148, dev199644.

Neto, F.T.L., Bach, P.V., Najari, B.B., Li, P.S., Goldstein, M., 2016. Spermatogenesis in humans and its affecting factors. Semin. Cell Dev. Biol. 59, 10-26.

Perland, E., Bagchi, S., Klaesson, A., Fredriksson, R., 2017. Characteristics of 29 novel atypical solute carriers of major facilitator superfamily type: evolutionary conservation, predicted structure and neuronal co-expression. Open Biol. 7, 170142.

Pierre, V., Martinez, G., Coutton, C., Delaroche, J., Yassine, S., Novella, C., Pernet-Gallay, K., Hennebicq, S., Ray, P.F., Arnoult, C., 2012. Absence of Dpy19l2, a new inner nuclear membrane protein, causes globozoospermia in mice by preventing the anchoring of the acrosome to the nucleus. Development. 139, 2955-2965.

Shen, C., Xiong, W., Li, C., Ge, H., Shen, Y., Tang, L., Zhang, H., Lu, S., Fei, J., Wang, Z., 2022. Testis-specific serine protease PRSS54 regulates acrosomal granule localization and sperm head morphogenesis in mice. Biol. Reprod. 107, 1139-1154.

Song, B., Liu, C., Gao, Y., Marley, J.L., Li, W., Ni, X., Liu, W., Chen, Y., Wang, J., Wang, C., et al., 2020. Novel compound heterozygous variants in dynein axonemal heavy chain 17 cause asthenoteratospermia with sperm flagellar defects. J. Genet. Genomics 47, 713-717.

Sosnik, J., Buffone, M.G., Visconti, P.E., 2010. Analysis of CAPZA3 localization reveals temporally discrete events during the acrosome reaction. J. Cell. Physiol. 224, 575-580.

Tang, S., Wang, X., Li, W., Yang, X., Li, Z., Liu, W., Li, C., Zhu, Z., Wang, L., Wang, J., et al., 2017. Biallelic mutations in CFAP43 and CFAP44 cause male infertility with multiple morphological abnormalities of the sperm flagella. Am. J. Hum. Genet. 100, 854-864.

Teves, M., Roldan, E., Krapf, D., Strauss Iii, J., Bhagat, V., Sapao, P., 2020. Sperm differentiation: the role of trafficking of proteins. Int. J. Mol. Sci. 21, 3702.

Tian, S., Tu, C., He, X., Meng, L., Wang, J., Tang, S., Gao, Y., Liu, C., Wu, H., Zhou, Y., et al., 2023. Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA. J. Med. Genet. 60, 827-834.

Tu, C., Cong, J., Zhang, Q., He, X., Zheng, R., Yang, X., Gao, Y., Wu, H., Lv, M., Gu, Y., et al., 2021. Bi-allelic mutations of DNAH10 cause primary male infertility with asthenoteratozoospermia in humans and mice. Am. J. Hum. Genet. 108, 1466-1477.

Wang, J., Zhang, J.T., Sun, X.P., Lin, Y.T., Cai, L.B., Cui, Y.G., Liu, J.Y., Liu, M.X., Yang, X.Y., 2021. Novel bi-allelic variants in ACTL7A are associated with male infertility and total fertilization failure. Hum. Reprod. 36, 3161-3169.

Wang, L.B., Li, M.Y., Qu, C., Miao, W.Y., Yin, Q., Liao, J.Y., Cao, H.T., Huang, M., Wang, K., Zuo, E.W., et al., 2017a. CRISPR-Cas9-mediated genome editing in one blastomere of two-cell embryos reveals a novel Tet3 function in regulating neocortical development. Cell Res. 27, 815-829.

Wang, X., Jin, H., Han, F., Cui, Y., Chen, J., Yang, C., Zhu, P., Wang, W., Jiao, G., Wang, W., et al., 2017b. Homozygous DNAH1 frameshift mutation causes multiple morphological anomalies of the sperm flagella in Chinese. Clin. Genet. 91, 313-321.

Wang, Y., Huang, X., Sun, G., Chen, J., Wu, B., Luo, J., Tang, S., Dai, P., Zhang, F., Li, J., et al., 2023. Coiled-coil domain-containing 38 is required for acrosome biogenesis and fibrous sheath assembly in mice. J. Genet. Genomics 51, 407-418.

Wang, Y.L., Chen, J.W., Huang, X.Y., Wu, B.G., Dai, P., Zhang, F., Li, J.S., Wang, L.B., 2024. Gene-knockout by iSTOP enables rapid reproductive disease modeling and phenotyping in germ cells of the founder generation. Sci. China Life Sci. 67, 1035-1050.

Wei, Y.Q., Wang, J.X., Qu, R., Zhang, W.Q., Tan, Y.L., Sha, Y.W., Li, L., Yin, T.L., 2023. Genetic mechanisms of fertilization failure and early embryonic arrest: a comprehensive review. Hum. Reprod. Update. 30, 48-80.

Wu, N., Ming, X., Xiao, J., Wu, Z., Chen, X., Shinawi, M., Shen, Y., Yu, G., Liu, J., Xie, H., et al., 2015. Null variants and a common hypomorphic allele in congenital scoliosis. N. Engl. J. Med. 372, 341-350.

Xiao, N., Kam, C., Shen, C., Jin, W.Y., Wang, J.Q., Lee, K.M., Jiang, L.W., Xia, J., 2009. PICK1 deficiency causes male infertility in mice by disrupting acrosome formation. J. Clin. Invest. 119, 802-812.

Xiong, W.F., Shen, C.L., Wang, Z.G., 2021. The molecular mechanisms underlying acrosome biogenesis elucidated by gene-manipulated mice. Biol. Reprod. 105, 789-807.

Xu, K., Su, X., Fang, K., Lv, Y., Huang, T., Li, M., Wang, Z., Yin, Y., Muhammad, T., Liu, S., et al., 2023. The Slingshot phosphatase 2 is required for acrosome biogenesis during spermatogenesis in mice. Elife. 12, e83129.

Yassine, S., Escoffier, J., Martinez, G., Coutton, C., Karaouzene, T., Zouari, R., Ravanat, J.L., Metzler-Guillemain, C., Lee, H.C., Fissore, R., et al., 2015. Dpy19l2-deficient globozoospermic sperm display altered genome packaging and DNA damage that compromises the initiation of embryo development. Mol. Hum. Reprod. 21, 169-185.

Zhang, B.B., Ma, H., Khan, T., Ma, A., Li, T., Zhang, H., Gao, J.N., Zhou, J.T., Li, Y., Yu, C.P., et al., 2020. A DNAH17 missense variant causes flagella destabilization and asthenozoospermia. J. Exp. Med. 217, e20182365.

Zhang, X.Z., Wei, L.L., Jin, H.J., Zhang, X.H., Chen, S.R., 2022. The perinuclear theca protein Calicin helps shape the sperm head and maintain the nuclear structure in mice. Cell Rep. 40, 111049.

Zhao, S., Cui, Y., Guo, S.L., Liu, B.Y., Bian, Y.H., Zhao, S.G., Chen, Z.J., Zhao, H., 2023. Novel variants in ACTL7A and PLCZ1 are associated with male infertility and total fertilization failure. Clin. Genet. 103, 603-608.

Zhou, Y., Wang, Y., Chen, J., Wu, B., Tang, S., Zhang, F., Liu, C., Wang, L., 2023. Dnali1 is required for sperm motility and male fertility in mice. Basic Clin. Androl. 33, 32.

Relative Articles

Supplements(0)

Cited By

Proportional views