2. Academic Validation
  3. Bi-allelic variants in DNHD1 cause flagellar axoneme defects and asthenoteratozoospermia in humans and mice

Bi-allelic variants in DNHD1 cause flagellar axoneme defects and asthenoteratozoospermia in humans and mice

  • Am J Hum Genet. 2022 Jan 6;109(1):157-171. doi: 10.1016/j.ajhg.2021.11.022.
Chen Tan 1,  Lanlan Meng 2,  Mingrong Lv 3,  Xiaojin He 3,  Yanwei Sha 4,  Dongdong Tang 3,  Yaqi Tan 5,  Tongyao Hu 1,  Wenbin He 2,  Chaofeng Tu 6,  Hongchuan Nie 6,  Huan Zhang 2,  Juan Du 2,  Guangxiu Lu 6,  Li-Qing Fan 2,  Yunxia Cao 3,  Ge Lin 7,  Yue-Qiu Tan 8
Affiliations

Affiliations

  • 1 Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, People's Republic of China.
  • 2 Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, People's Republic of China; Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, Hunan 410078, People's Republic of China; Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha, Hunan 410013, People's Republic of China; NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Changsha, Hunan 410013, People's Republic of China.
  • 3 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, China; Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People's Republic of China, Hefei 230032, China.
  • 4 School of Public Health & Women and Children's Hospital, Xiamen University, Xiamen Fujian 361005, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen 361102, China.
  • 5 College of Life Science, Hunan Normal University, Changsha, Hunan 410081, People's Republic of China.
  • 6 Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, Hunan 410078, People's Republic of China; Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha, Hunan 410013, People's Republic of China; NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Changsha, Hunan 410013, People's Republic of China.
  • 7 Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, People's Republic of China; Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, Hunan 410078, People's Republic of China; Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha, Hunan 410013, People's Republic of China; NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Changsha, Hunan 410013, People's Republic of China; College of Life Science, Hunan Normal University, Changsha, Hunan 410081, People's Republic of China. Electronic address: linggf36@hotmail.com.
  • 8 Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, People's Republic of China; Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, Hunan 410078, People's Republic of China; Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha, Hunan 410013, People's Republic of China; NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Changsha, Hunan 410013, People's Republic of China; College of Life Science, Hunan Normal University, Changsha, Hunan 410081, People's Republic of China. Electronic address: tanyueqiu@csu.edu.cn.
PMID: 34932939 DOI: 10.1016/j.ajhg.2021.11.022
Abstract

Asthenoteratozoospermia, defined as reduced sperm motility and abnormal sperm morphology, is a disorder with considerable genetic heterogeneity. Although previous studies have identified several asthenoteratozoospermia-associated genes, the etiology remains unknown for the majority of affected men. Here, we performed whole-exome Sequencing on 497 unrelated men with asthenoteratozoospermia and identified DNHD1 bi-allelic variants from eight families (1.6%). All detected variants were predicted to be deleterious via multiple bioinformatics tools. Hematoxylin and eosin (H&E) staining revealed that individuals with bi-allelic DNHD1 variants presented striking abnormalities of the flagella; transmission electron microscopy (TEM) further showed flagellar axoneme defects, including central pair microtubule (CP) deficiency and mitochondrial sheath (MS) malformations. In sperm from fertile men, DNHD1 was localized to the entire flagella of the normal sperm; however, it was nearly absent in the flagella of men with bi-allelic DNHD1 variants. Moreover, abundance of the CP markers SPAG6 and SPEF2 was significantly reduced in spermatozoa from men harboring bi-allelic DNHD1 variants. In addition, Dnhd1 knockout male mice (Dnhd1‒/‒) exhibited asthenoteratozoospermia and infertility, a finding consistent with the sperm phenotypes present in human subjects with DNHD1 variants. The female partners of four out of seven men who underwent intracytoplasmic sperm injection therapy subsequently became pregnant. In conclusion, our study showed that bi-allelic DNHD1 variants cause asthenoteratozoospermia, a finding that provides crucial insights into the biological underpinnings of this disorder and should assist with counseling of affected individuals.

Keywords

DNHD1; male infertility; mitochondrial sheath; sperm flagella; whole-exome sequencing.

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