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LRRC23 truncation impairs radial spoke 3 head assembly and sperm motility underlying male infertility

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Hwang, Jae Yeon, Chai, Pengxin, Nawaz, Shoaib, Choi, Jungmin, Lopez-Giraldez, Francesc, Hussain, Shabir, Bilguvar, Kaya, Mane, Shrikant, Lifton, Richard P, Ahmad, Wasim, Zhang, Kai, Chung, Jean-Ju·2023·eLife
DOI 10.7554/elife.90095.3

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Abstract

Radial spokes (RS) are T-shaped multiprotein complexes on the axonemal microtubules. Repeated RS1, RS2, and RS3 couple the central pair to modulate ciliary and flagellar motility. Despite the cell type specificity of RS3 substructures, their molecular components remain largely unknown. Here, we report that a leucine-rich repeat-containing protein, LRRC23, is an RS3 head component essential for its head assembly and flagellar motility in mammalian spermatozoa. From infertile male patients with defective sperm motility, we identified a splice site variant of LRRC23 . A mutant mouse model mimicking this variant produces a truncated LRRC23 at the C-terminus that fails to localize to the sperm tail, causing male infertility due to defective sperm motility. LRRC23 was previously proposed to be an ortholog of the RS stalk protein RSP15. However, we found that purified recombinant LRRC23 interacts with an RS head protein RSPH9, which is abolished by the C-terminal truncation. Evolutionary and structural comparison also shows that LRRC34, not LRRC23, is the RSP15 ortholog. Cryo-electron tomography clearly revealed that the absence of the RS3 head and the sperm-specific RS2-RS3 bridge structure in LRRC23 mutant spermatozoa. Our study provides new insights into the structure and function of RS3 in mammalian spermatozoa and the molecular pathogenicity of LRRC23 underlying reduced sperm motility in infertile human males.

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Metadata

Authors
Hwang, J. Y., Chai, P., Nawaz, S., Choi, J., Lopez-Giraldez, F., Hussain, S., Bilguvar, K., Mane, S., Lifton, R. P., Ahmad, W., Zhang, K., & Chung, J.-J.
Affiliations
  • Yale University (US)
  • Quaid-i-Azam University (PK)
  • Korea University (KR)
  • Yale Center forGenome Analysis, Yale University
  • Department of Genetics, YaleSchool of Medicine, Yale University
  • Rockefeller University (US)
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2023-12-13
Volume
12
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.90095.3
OpenAlex
W4389664003
Cited by
9
References
2
Citations by year
2026: 1 · 2025: 6 · 2024: 2
FWCI
2.16
Type
journal article
Language
en
Open access
Licence
Locations
eLife (publishedVersion, cc-by)
Funders
  • Yale University (Start-up funds)
  • National Institutes of Health (R01HD096745, R35GM142959)
  • Pakistan Academy of Sciences (PAS-171)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
Keywords
sperm motility, male infertility, axoneme, flagellar motility, splice site mutation, C-terminal truncation, cryo-electron tomography, axonemal microtubules, central pair

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