DNAJB13

DNAJB13 is an HSP40/DnaJ co-chaperone that localizes to the radial spokes of the 9+2 axoneme in motile cilia and sperm flagella, where it is essential for axonemal assembly and motility (PMID:19919626, PMID:18247331). Loss-of-function mutations in DNAJB13—including missense variants that trigger proteasomal degradation and splice-site mutations that ablate transcript integrity—cause primary ciliary dyskinesia with central complex defects and male infertility due to sperm immotility (PMID:27486783, PMID:31342671). DNAJB13 functions at the radial spoke head in a pathway with RSPH1, RSPH9, and the inner dynein arm component DNAH12 to maintain central pair stability (PMID:27486783).

1. 2008 High

   Establishing that DNAJB13 is an axoneme-specific protein rather than a general cytoplasmic chaperone answered the fundamental question of where this co-chaperone acts, placing it within the flagellar motility apparatus.

   Evidence Fractionation of mouse sperm tail structures combined with immunolocalization showing axoneme-specific association

   PMID:18247331

   Open questions at the time

   • Exact sub-structural position within the axoneme not resolved
   • No functional consequence of DNAJB13 loss yet established
2. 2010 High

   Pinpointing DNAJB13 to the radial spokes by immunoelectron microscopy refined its localization from 'axoneme-associated' to a specific structural element, implicating it in radial spoke function and central pair signaling.

   Evidence Immunoelectron microscopy of mouse sperm flagella

   PMID:19919626

   Open questions at the time

   • Direct binding partners at the radial spoke not identified
   • No genetic evidence linking DNAJB13 to motility defects
3. 2016 High

   Identification of biallelic DNAJB13 mutations in primary ciliary dyskinesia families, coupled with demonstration that missense and splice-site variants abolish protein stability via proteasomal degradation, established DNAJB13 as a disease gene and linked its loss to central complex defects in motile cilia.

   Evidence In vitro protein stability and proteasomal degradation assays; RT-PCR of patient airway cell transcripts; ultrastructural analysis of patient cilia

   PMID:27486783

   Open questions at the time

   • Mechanism by which DNAJB13 loss leads specifically to central pair disassembly is unclear
   • Client proteins of DNAJB13's chaperone activity not defined
4. 2019 Medium

   Showing that a DNAJB13 missense variant reduces protein levels in sperm and produces flagellar ultrastructural defects with immotility extended the gene's disease relevance from ciliary dyskinesia to isolated male infertility (asthenozoospermia).

   Evidence Multiple reaction monitoring mass spectrometry, immunoelectron microscopy, and TEM of patient sperm

   PMID:31342671

   Open questions at the time

   • Single-lab study; independent replication in additional cohorts not reported
   • Unclear whether reduced DNAJB13 level or altered function drives the phenotype
5. 2024 Medium

   Demonstrating that DNAJB13 interacts with the inner dynein arm heavy chain DNAH12 at the radial spoke head and that DNAH12 knockout disrupts central pair stability placed DNAJB13 within a defined molecular pathway (DNAH12–DNAJB13–RSPH1/RSPH9) linking radial spokes to central pair integrity.

   Evidence Co-immunoprecipitation and DNAH12 knockout mouse model with TEM analysis (preprint)

   PMID:bio_10.1101_2024.06.20.599934

   Open questions at the time

   • Preprint; not yet peer-reviewed
   • Whether DNAJB13 chaperone activity is required for the interaction with DNAH12 is untested
   • Directionality of the pathway (whether DNAJB13 recruits DNAH12 or vice versa) not resolved

• The client specificity and enzymatic chaperone mechanism of DNAJB13 within the radial spoke remain undefined—it is unknown whether DNAJB13 folds radial spoke structural proteins, stabilizes the central pair through direct chaperoning, or acts as a scaffold independent of its J-domain activity.
• No reconstituted chaperone activity assay for DNAJB13
• HSP70 partner for DNAJB13 in the axoneme not identified
• Structural basis of DNAJB13 integration into the radial spoke unknown