Ying-Hung Lin
Over the past 15 years, we have focused on the identification of novel sterility-related genes in male infertility cases and on the clinical roles and molecular functions of these candidate genes during spermatogenesis. (1) We identified ten novel sterility-related genes from the testicular tissues of patients with spermatogenic defects using a cDNA microarray (Ref 1). (2) We also identified SEPTIN12 mutations in teratozospermia, and we provided knockout Septin12 results in teratozospermia-like phenotypes (Ref 2-4), (3) Characterization of TBC1D21 is specifically expressed in the post-acrosomal region of sperm during tail formation in mammalian spermiogenesis. We also generated Tbc1d21 knockout mice, and their sperm exhibited severe defects. Additionally, TBC1D21 mRNA levels are significantly decreased in the sperm of patients with teratozoospermia (Ref 5-7). (4) Through whole-exon sequencing, we identified several AGTPBP1 mutations in teratozospermia cases, and knockout of the Agtpbp1 gene results in severe sperm head and tail defects (Ref 8). In this study, we specific generated an Agtpbp1 knock-in (KI) mouse model with a critical mutated site that results in teratozoospermia. The KI mice also exhibit mild sperm head and tail defects. Based on serial studies, we propose that AGTPBP1 mutation damages sperm formation and plays critical pathological roles of teratozoospermia cases. We believe that this will be attractive to readers, urologists, and OB-GYN specialists.
References:
1. Lin YH, Lin YM, Teng YN, Hsieh TY, Lin YS, Kuo PL. Identification of ten novel genes involved in human spermatogenesis by microarray analysis of testicular tissue. Fertil Steril. 2006 Dec;86(6):1650-8.
2. Lin YH, Lin YM, Wang YY, Yu IS, Lin YW, Wang YH, Wu CM, Pan HA, Chao SC, Yen PH, Lin SW, Kuo PL. The expression level of septin12 is critical for
spermiogenesis. Am J Pathol. 2009 May;174(5):1857-68.
3. Lin YH, Chou CK, Hung YC, Yu IS, Pan HA, Lin SW, Kuo PL. SEPT12 deficiency causes sperm nucleus damage and developmental arrest of preimplantation embryos. Fertil Steril. 2011 Jan;95(1):363-5.
4. Kuo YC, Lin YH, Chen HI, Wang YY, Chiou YW, Lin HH, Pan HA, Wu CM, Su SM, Hsu CC, Kuo PL. SEPT12 mutations cause male infertility with defective sperm annulus. Hum Mutat. 2012 Apr;33(4):710-9.
5. Lin YH, Lin YM, Kuo YC, Wang YY, Kuo PL. Identification and characterization of a novel Rab GTPase-activating protein in spermatids. Int J Androl. 2011 Oct;34(5 Pt 2):e358-67.
6. Wang YY, Ke CC, Chen YL, Lin YH, Yu IS, Ku WC, O'Bryan MK, Lin YH. Deficiency of the Tbc1d21 gene causes male infertility with morphological abnormalities of the sperm mitochondria and flagellum in mice. PLoS Genet. 2020 Sep 25;16(9):e1009020.
7. Pan PY, Ke CC, Wang YY, Lin YH, Ku WC, Au CF, Chan CC, Huang CY, Lin YH. Proteomic profiling of TBC1 domain family member 21-null sperms reveals the critical roles of TEKT 1 in their tail defects. Dev Dyn. 2024 Jun 1.
8. Lin YH, Wang YY, Lai TH, Teng JL, Lin CW, Ke CC, Yu IS, Lee HL, Chan CC, Tung CH, Conrad DF, O'Bryan MK, Lin YH. Deleterious genetic changes in AGTPBP1 result in teratozoospermia with sperm head and flagella defects. J Cell Mol Med. 2024 Jan;28(2):e18031.