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10.4103/aja202577
Biallelic variants in TBC1D8 are potentially associated with male infertility due to non-obstructive azoospermia or cryptozoospermia
Sang, Yi-Lin1,*; Peng, Yao2,3,*; Tu, Chao-Feng4,5; Lin, Ge2,3,4,5; Lu, Guang-Xiu2,3,4,5; Du, Juan2,4,5; Wang, Fu-Yan1; Tan, Yue-Qiu2,3,4,5; Liu, Lv-Jun6; He, Wen-Bin2,3,5
1Department of Immunology, Xiangya School of Basic Medical Sciences, Central South University, Changsha 410013, China
2Hunan Guangxiu Hospital Affiliated with Hunan Normal University, Hunan Normal University Health Science Center, Changsha 410017, China
3Changsha Gene Editing Technique Innovation Center, Hunan Normal University Health Science Center, Changsha 410017, China
4Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Xiangya School of Basic Medical Sciences, Central South University, Changsha 410078, China
5Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410078, China
6Hunan Provincial Key Laboratory of Regional Hereditary Birth Defects Prevention and Control, Changsha Hospital for Maternal and Child Health Care Affiliated to Hunan Normal University, Changsha 410007, China
Correspondence: Dr. WB He (hewenbin@hunnu.edu.cn) or Dr. LJ Liu (lljunius@foxmail.com)
Received: 20 February 2025; Accepted: 09 September 2025; published online: 20 January 2026
| Abstract |
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Non-obstructive azoospermia (NOA) and cryptozoospermia are two significant conditions contributing to male infertility. However, the underlying genetic factors in most cases remain unknown. In our study, whole exome sequencing identified novel biallelic variants in TBC1 domain family member 8 (TBC1D8) in two patients. Patient P1 with NOA harbored c.890C>T (p.A297V) and c.2461G>A (p.V821I), and patient P2 with cryptozoospermia carried c.854C>T (p.P285L) and c.1912G>A (p.D638N). Bioinformatic analyses predicted that all identified TBC1D8 variants were likely pathogenic. Compared with a normal control, patient P1 showed reduced expression of TBC1D8 in testicular tissue. Subsequently, hematoxylin-eosin staining and immunofluorescence analysis of testicular sections showed defective acrosome formation and the absence of elongated spermatids in patient P1, resulting from abnormal autophagy. Additionally, intracytoplasmic sperm injection treatment was beneficial for patient P2 with cryptozoospermia. In conclusion, our results suggest that TBC1D8 is a potentially novel candidate gene for male infertility associated with NOA or cryptozoospermia in humans.
Keywords: cryptozoospermia; male infertility; non-obstructive azoospermia; spermatogenesis; TBC1D8
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