Over the past 15 years, our research has focused on the identification of novel sterility-related genes in male infertility and the investigation of their clinical significance and molecular functions during spermatogenesis. Using genomic, proteomic, and gene-editing approaches, we have established several disease models to elucidate the mechanisms underlying male infertility. First, we identified ten novel genes associated with human spermatogenesis through cDNA microarray analysis of testicular tissues (Ref 1). We further demonstrated that mutations in SEPTIN12 are linked to teratozoospermia, and Septin12 knockout models exhibit teratozoospermia-like phenotypes (Ref 2–4). In addition, we characterized TBC1D21 as a critical regulator localized to the post-acrosomal region during spermiogenesis; Tbc1d21 knockout mice display severe sperm defects, and reduced TBC1D21 expression is observed in patients with teratozoospermia (Ref 5–7). More recently, we identified pathogenic mutations in AGTPBP1 in teratozoospermia cases and generated both knockout and knock-in mouse models, demonstrating its essential role in sperm head and tail formation (Ref 8). In parallel, our research has expanded into neuromuscular disorders, particularly muscular dystrophy. We identified a novel five-nucleotide microdeletion in the DYSFERLIN (DYSF) gene in Taiwanese patients with Limb-Girdle Muscular Dystrophy (LGMD-R2), which is predicted to produce a truncated dysferlin protein (Ref 9). To investigate its pathogenic mechanisms, we generated a patient-derived Dysf microdeletion knock-in mouse model, which recapitulates key features of muscular dystrophy, including muscle degeneration, adipocyte infiltration, inflammation, and metabolic remodeling (Ref 10). Collectively, our studies integrate reproductive biology and genetic disease modeling to uncover molecular mechanisms underlying human infertility and muscular disorders, providing translational insights into disease pathogenesis and potential therapeutic strategies. 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. 9. Chen YL, Wu WB, Wang P, Yip PK, Wu YN, Lin YH, Lin WN. Novel five nucleotide deletion in dysferlin leads to autosomal recessive limb-girdle muscular dystrophy. Physiol Rep. 2023 Dec;11(24):e15887. 10. Chen YL, Lin WN, Pan PY, Ku WC, Wang P, Yip PK, Tsui KC, Wu YN, Lin YH. Generation of a novel Dysferlin microdeletion knock-in mouse model mimicking muscular dystrophy-like pathology. Sci Rep. 2026 Apr 1.