LRRC23

LRRC23 is a leucine-rich repeat-containing protein that functions as a structural component of the radial spoke 3 (RS3) head in mammalian sperm flagella, where it is essential for RS3 head assembly and formation of the sperm-specific RS2–RS3 bridge (PMID:38091523). LRRC23 physically interacts with radial spoke head proteins RSPH9 and RSPH3A/B through its C-terminus, and loss of this interaction—by truncation or nonsense mutation—abolishes its flagellar localization and disrupts radial spoke integrity (PMID:34585727, PMID:38091523, PMID:37804054). Loss-of-function mutations in LRRC23 cause asthenozoospermia and male infertility in both mice and humans without affecting somatic cilia motility, establishing a sperm-specific requirement (PMID:34585727, PMID:37804054, PMID:39054792).

1. 2005 Low

   Initial characterization placed LRRC23 in ocular tissues with nuclear and cytoplasmic localization and partial co-localization with mimecan, but provided no functional insight into its mechanism of action.

   Evidence RT-PCR, immunohistochemistry, and confocal co-localization in human ocular tissues and MG-63 cells

   PMID:16030496

   Open questions at the time

   • No functional assay was performed; co-localization with mimecan does not establish a direct interaction or functional role
   • No connection to ciliary or flagellar biology was made
   • Findings have not been replicated or extended by independent studies
2. 2021 High

   A knockout mouse model resolved that LRRC23 is a testis-enriched, flagellum-localized radial spoke protein whose loss causes male infertility through RS disorganization and impaired sperm motility, without affecting somatic cilia—establishing it as a sperm-specific axonemal component.

   Evidence Lrrc23 knockout mice with fertility and motility phenotyping, Co-IP with RSPH3A/RSPH3B, immunofluorescence, and transmission EM of sperm axonemes

   PMID:34585727

   Open questions at the time

   • Whether LRRC23 belongs to the RS2 stalk (as proposed by homology to Chlamydomonas RSP15) or a different RS sub-complex was unresolved
   • The precise binding interface and domain requirements for RSPH3A/B interaction were not defined
   • Human disease relevance was not yet established
3. 2023 High

   Cryo-electron tomography and human genetic data redefined LRRC23 as an RS3 head component (not an RS2 stalk protein), showed that its C-terminus is required for RSPH9 binding and flagellar localization, and demonstrated that its loss specifically eliminates the RS3 head and the sperm-specific RS2–RS3 bridge.

   Evidence Human splice-site variant in infertile males, cryo-ET of mutant sperm axonemes, recombinant pulldown of LRRC23–RSPH9 with truncation controls, evolutionary analysis reassigning LRRC34 as the true RSP15 ortholog

   PMID:38091523

   Open questions at the time

   • Full atomic-resolution structure of the RS3 head complex with LRRC23 is lacking
   • The complete set of RS3 head subunits that LRRC23 organizes is not fully defined
   • How LRRC23 is trafficked to the flagellum and its assembly timing during spermiogenesis are unknown
4. 2023 Medium

   Identification of a homozygous nonsense mutation in human LRRC23 confirmed its requirement for radial spoke integrity and sperm motility in humans and validated the LRRC23–RSPH3 interaction in human cells.

   Evidence Human genetics in a consanguineous family, Co-IP of LRRC23–RSPH3 in human cells, TEM of patient sperm axoneme

   PMID:37804054

   Open questions at the time

   • Single family; additional kindreds needed to establish LRRC23 as a recurrently mutated asthenozoospermia gene
   • Genotype–phenotype correlation across different mutation types is incomplete
5. 2024 Medium

   Compound heterozygous LRRC23 mutations in a non-consanguineous family independently confirmed RS3 loss as the ultrastructural basis of LRRC23-associated asthenozoospermia, broadening the allelic spectrum.

   Evidence Human genetics, Western blot and immunofluorescence confirming protein loss, TEM showing RS3 absence in patient sperm

   PMID:39054792

   Open questions at the time

   • Functional rescue experiments in patient-derived or model systems have not been performed
   • Whether partial LRRC23 loss produces an intermediate motility phenotype is unknown

• Key open questions include the high-resolution structure of the LRRC23-containing RS3 head complex, the mechanism by which LRRC23 is selectively required in sperm but dispensable in somatic cilia, and whether LRRC23 plays any non-flagellar role consistent with its reported ocular expression.
• No atomic-resolution structure of LRRC23 within the RS3 head complex
• Molecular basis of sperm-specific versus somatic cilia dispensability is unexplained
• Any functional significance of LRRC23 expression outside the testis remains uncharacterized