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10.4103/aja2025109
Novel mutations in ZMYND15 expand the phenotypic spectrum to acephalic spermatozoa: abnormal sperm head–tail connection mediated by SUN5
Qian-Jun Zhang1,2,3,*
Hao Lin3,*
Rui-Long Hao3
Yun-Fei Zhang4
Yu-Ping Lin3
Si-Cong Zeng3,5
Huan Zhang1,2
Wei-Na Li1,2,6,
1Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Central South University, Changsha 410013, China
2Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410008, China
3Clinical Laboratory, Hunan Guangxiu Hospital, Hunan Normal University, Changsha 410013, China
4Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha 410013, China
5Scientific Research Department, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410008, China
6Department of Urology (Andrology), Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410008, China
Correspondence: Dr. WN Li (liweinaking@126.com)
Received: 14 April 2025; Accepted: 24 December 2025; published online: 28 July 2026
| Abstract |
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Acephalic spermatozoa syndrome (ASS) is a rare cause of male infertility characterized by sperm tails lacking heads. Although zinc finger MYND-type containing 15 (ZMYND15) mutations are linked to male infertility, their role in ASS is unknown. In this study, whole-exome sequencing identified novel homozygous truncating mutations, c.292C>T (p.Arg98Ter) and c.337G>T (p.Glu113Ter), in ZMYND15 from two infertile patients. These mutations caused protein truncation and impaired function, leading to extremely low sperm counts, poor motility, and numerous acephalic spermatozoa. Electron microscopy and sperm immunofluorescence revealed abnormal sperm neck structures, missing mitochondrial sheaths, failure of acrosome formation, and a lack of central microtubules. Experiments showed reduced mutant protein expression and high rates of degradation. Coimmunoprecipitation experiments indicated a direct interaction between ZMYND15 and Sad1 and UNC84 domain containing 5 (SUN5), crucial for forming the sperm head–tail connection. One patient achieved a live birth via intracytoplasmic sperm injection (ICSI), whereas the other had an early miscarriage. This study links ZMYND15 mutations directly to ASS, highlighting its role in spermatogenesis and offering insights for clinical diagnosis and treatment.
Keywords: acephalic spermatozoa syndrome; male infertility; sperm morphology; SUN5; ZMYND15
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