BBS10

BBS10 is a vertebrate-specific chaperonin-like protein that functions at the basal body of the primary cilium to promote assembly of the BBSome, a multiprotein complex essential for ciliary trafficking. Together with BBS6 and BBS12, BBS10 forms a chaperone subcomplex that facilitates BBSome assembly; truncating mutations destabilize BBS10 via the ubiquitin–proteasome pathway, disrupt its interactions with BBS7 and BBS12, and shorten ciliary length (PMID:16582908, PMID:30312873, PMID:40914337). Loss of BBS10 in mice causes obesity, retinal degeneration, and renal dysfunction driven by systemic rather than renal-epithelial-cell-autonomous mechanisms, and BBS10-null renal cells exhibit increased proliferation and a metabolic shift toward aerobic glycolysis, indicating extraciliary roles in cellular metabolism (PMID:26273430, PMID:36012682). Biallelic mutations in BBS10 cause Bardet-Biedl syndrome, and a rare recessive missense variant independently confers risk for type 2 diabetes (PMID:16582908, PMID:25439097).

1. 2006 High

   Positional cloning identified BBS10 as a vertebrate-specific chaperonin-like gene whose disruption participates in a common genetic pathway with other BBS loci, establishing the molecular identity and epistatic context of BBS10.

   Evidence Positional cloning with sequence analysis and zebrafish morpholino epistasis testing across multiple BBS genes in a large multi-ethnic cohort

   PMID:16582908

   Open questions at the time

   • Direct biochemical demonstration of chaperonin activity was not provided
   • The specific protein partners and cargo of BBS10 were not identified
   • Whether BBS10 functions outside the cilium was unknown
2. 2014 Medium

   A recessive BBS10 missense variant was shown to confer type 2 diabetes risk independently of classical ciliopathy, broadening BBS10's functional scope to metabolic regulation.

   Evidence RAFT statistical genetics method followed by zebrafish in vivo pathogenicity assay of the p.Ile397Val variant

   PMID:25439097

   Open questions at the time

   • The cellular mechanism by which this variant alters glucose homeostasis was not determined
   • Replication in independent human cohorts was not shown
   • Whether the effect is cilium-dependent or cilium-independent was not resolved
3. 2015 High

   Complete versus tissue-specific knockout in mice established that BBS10 loss drives obesity, retinal degeneration, and renal dysfunction through systemic rather than renal-epithelial-cell-autonomous mechanisms, resolving whether kidney pathology is intrinsic to ciliary defects in renal tubules.

   Evidence Whole-body and Cdh16-Cre conditional Bbs10 knockout mice with ERG, renal histology, body weight, urine output, and serum AVP measurements

   PMID:26273430

   Open questions at the time

   • The non-renal tissues or systemic signals responsible for the renal phenotype were not identified
   • Neuronal or hypothalamic contributions to the obesity phenotype were not dissected
   • Whether BBS10 has functions beyond BBSome assembly in vivo was not tested
4. 2018 Medium

   Patient-derived iPSCs confirmed that BBS10, together with BBS6 and BBS12, forms a chaperonin subcomplex required for BBSome assembly, providing a human cellular system consistent with the chaperone model.

   Evidence iPSC derivation from a BBS10 patient carrying the c.271insT mutation, with reference to prior biochemical evidence of BBS6/10/12 chaperonin complex

   PMID:30312873

   Open questions at the time

   • Direct reconstitution of BBSome assembly dependent on the BBS6/10/12 complex was not performed in this study
   • Functional phenotyping of the iPSC-derived cells was not reported
5. 2022 Medium

   Proteomic and metabolic profiling of Bbs10-knockout renal cells revealed extraciliary functions including altered proliferation, increased ATP production, and upregulated aerobic glycolysis, answering whether BBS10 has roles beyond ciliary structure.

   Evidence Mass spectrometry interactomics and metabolic assays (ATP, glycolysis) in Bbs10-knockout IMCD3 cells, with urine metabolomics in BBS patients

   PMID:36012682

   Open questions at the time

   • The interactors identified by MS have not been validated by reciprocal co-IP or functional assays
   • Whether the metabolic shift is a direct consequence of BBS10 loss or secondary to disrupted BBSome trafficking is unresolved
   • In vivo relevance of the glycolytic shift to BBS pathophysiology was not demonstrated
6. 2025 Medium

   Biochemical dissection of disease-causing truncating mutations showed that C-terminal integrity is required for BBS10 protein stability (via protection from ubiquitin–proteasome degradation) and for interaction with BBS12 and BBS7, linking genotype to ciliogenesis defects.

   Evidence Overexpression of mutant BBS10 constructs in HEK293T and hTERT-RPE1 cells with co-immunoprecipitation, Western blot stability assays, proteasome inhibitor rescue, and ciliary length measurements

   PMID:40914337

   Open questions at the time

   • Experiments relied on overexpressed tagged constructs rather than endogenous protein
   • Whether reduced interaction with BBS7 is the proximate cause of shortened cilia was not tested directly
   • Structural basis for how the C-terminal domain stabilizes BBS10 and mediates partner binding is unknown

• The precise mechanism by which BBS10 chaperone activity promotes BBSome assembly, the structural basis of the BBS6/10/12 complex, and the molecular pathways linking BBS10 loss to metabolic reprogramming and systemic (non-cell-autonomous) organ pathology remain unresolved.
• No reconstituted in vitro BBSome assembly assay with purified BBS6/10/12 complex exists
• No high-resolution structure of BBS10 or the BBS6/10/12 chaperonin complex is available
• The systemic signals or cell types responsible for non-cell-autonomous renal and metabolic pathology have not been identified