LRRC46

LRRC46 is a leucine-rich repeat protein with two experimentally established roles: it is essential for sperm flagellum biogenesis and it promotes collagen synthesis in connective and reproductive tissues (PMID:35955660, PMID:38874710). In the male germ line, LRRC46 localizes throughout the sperm flagellum with concentration at the midpiece, and its loss in mice produces multiple morphological abnormalities of the flagella (MMAF) — short, coiled, irregular flagella with axonemal and mitochondrial sheath defects, reduced sperm counts, impaired motility, and complete male infertility (PMID:35955660). Its correct positioning within the flagellum depends on CCDC181, which physically interacts with LRRC46 and acts upstream of it, since loss of CCDC181 mislocalizes LRRC46 and phenocopies MMAF (PMID:39245650). Independently, LRRC46 supports extracellular matrix output: a loss-of-function mutation reduces LRRC46 protein in human corneal epithelial cells, and knockout mice display a myopia phenotype with corneal and scleral thinning and downregulated collagen synthesis, with LRRC46 specifically required for collagen VIII (Col8a1) formation (PMID:38874710). In bovine granulosa cells, LRRC46 drives proliferation, steroidogenesis, and anti-apoptotic responses by upregulating COL8A1, which promotes EGFR phosphorylation and activates PI3K/AKT signaling, an effect abolished by EGFR inhibition (PMID:42224836). How the same protein links flagellar structural assembly to collagen biogenesis at the molecular level has not been characterized in the available corpus.

1. 2022 High

   Established the first functional role of LRRC46 by showing it is required for sperm flagellum biogenesis, defining where it acts and the consequence of its loss.

   Evidence Lrrc46 knockout mice with immunofluorescence localization, SEM/Papanicolaou morphology, TEM ultrastructure, and motility assays

   PMID:35955660

   Open questions at the time

   • Molecular activity of LRRC46 within the flagellum not defined
   • No direct binding partners identified in this study
   • Mechanism linking LRRC46 to axonemal/mitochondrial sheath assembly unresolved
2. 2024 Medium

   Placed LRRC46 in a flagellar assembly hierarchy by identifying CCDC181 as a direct interactor that controls LRRC46 positioning.

   Evidence Co-immunoprecipitation between CCDC181 and LRRC46 plus Ccdc181 knockout mice scored for LRRC46 localization

   PMID:39245650

   Open questions at the time

   • Interaction not validated reciprocally or structurally
   • Binding interface and stoichiometry unknown
   • Whether CCDC181 directly recruits or indirectly stabilizes LRRC46 not distinguished
3. 2024 Medium

   Revealed a distinct collagen-related function by linking LRRC46 loss-of-function to myopia and impaired collagen VIII synthesis in ocular tissue.

   Evidence Human LRRC46 mutation study in HCE-T cells, Lrrc46 knockout mouse phenotyping, RNA-seq of corneal/scleral tissue, and in vitro collagen formation assay

   PMID:38874710

   Open questions at the time

   • Direct molecular mechanism by which LRRC46 controls collagen VIII output unknown
   • Connection between the flagellar role and the collagen role not established
   • Single-lab finding
4. 2026 Medium

   Defined a downstream signaling axis for the collagen function, showing LRRC46 acts through COL8A1 to engage EGFR and PI3K/AKT signaling controlling proliferation and steroidogenesis.

   Evidence Overexpression in bovine granulosa cells with proliferation, apoptosis, and steroidogenesis readouts and Afatinib EGFR-inhibitor rescue

   PMID:42224836

   Open questions at the time

   • Gain-of-function only; no loss-of-function validation in this system
   • Mechanism by which LRRC46 upregulates COL8A1 unknown
   • Whether axis operates in non-bovine or in vivo contexts untested

• It remains unknown what biochemical activity LRRC46 carries out and how a single LRR protein reconciles its flagellar structural role with its collagen-biogenesis role.
• No molecular activity assigned
• No structural model of LRRC46 or its complexes
• Mechanistic link between flagellar and ECM functions absent