2. Academic Validation
  3. A homozygous loss-of-function mutation in FBXO43 causes human non-obstructive azoospermia

A homozygous loss-of-function mutation in FBXO43 causes human non-obstructive azoospermia

  • Clin Genet. 2022 Jan;101(1):55-64. doi: 10.1111/cge.14069.
Huan Wu 1 2 3,  Xin Zhang 4,  Qunshan Shen 1 5 6,  Yiyuan Liu 1,  Yang Gao 1 5 6,  Guanxiong Wang 1,  Mingrong Lv 1 5 6,  Rong Hua 4,  Yuping Xu 1 5 6,  Ping Zhou 1 5 6,  Zhaolian Wei 1 5 6,  Fangbiao Tao 2 3,  Xiaojin He 1 2 3,  Yunxia Cao 1 2 3,  Mingxi Liu 4
Affiliations

Affiliations

  • 1 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 2 NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China.
  • 3 Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, China.
  • 4 State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
  • 5 Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China.
  • 6 Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, China.
PMID: 34595750 DOI: 10.1111/cge.14069
Abstract

Non-obstructive azoospermia (NOA) represents one of the most serious forms of male infertility caused by spermatogenic failure. Despite multiple genes found to be associated with human NOA, the genetic basis of this idiopathic disease remains largely unknown. FBXO43 is a direct inhibitor of the anaphase-promoting complex/cyclosome (APC/C) E3 ligase and crucially important in mouse spermatogenesis. In this study, for the first time, we identified a homozygous nonsense mutation in FBXO43 c.1747C > T:p.Gln583X in two NOA brothers from a Chinese consanguineous family via whole-exome sequencing. FBXO43 was absent from testicular tissue of the proband, and FBXO43-immunostaining signals were invisible in the affected seminiferous tubules. Furthermore, in humans, FBXO43 defects cause meiotic arrest within early diplotene of prophase I. The results here demonstrate the pathogenicity of this loss-of-function mutation and confirmed that spermatocytes were unable to complete meiotic divisions without FBXO43 in humans. In mouse testicular protein extracts, three subunits of the APC/C, including ANAPC2, ANAPC8 and ANAPC10, were validated to interact directly with FBXO43, whereas no interactions were detected for FBXO43 and SKP1. This study furthers our understanding of the genetic basis of human NOA and provides insights into FBXO43 and male infertility.

Keywords

APC/C; FBXO43; non-obstructive azoospermia; spermatogenesis.

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