Affinage

FAM149B1

Primary cilium assembly protein FAM149B1 · UniProt Q96BN6

Length
582 aa
Mass
64.6 kDa
Annotated
2026-06-09
5 papers in source corpus 3 papers cited in narrative 3 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FAM149B1 (JBTS36) is a ciliary regulatory protein that controls intraflagellar transport (IFT) turnaround at the ciliary tip and thereby sets primary cilium length and Sonic hedgehog signaling output (PMID:30905400, PMID:35609210). It physically associates with BROMI/TBC1D32 and the kinase CCRK/CDK20, placing it within a complex that governs IFT machinery dynamics at the distal cilium (PMID:35609210). FAM149B1 acts upstream in the CCRK–ICK/MAK kinase cascade: its homolog XBX-4 in C. elegans promotes CCRK (DYF-18) function to control the localization and activity of the downstream kinase MAK (DYF-5), regulating axonemal microtubule stability (PMID:34731674). Loss of FAM149B1 leaves ciliogenesis intact but causes abnormally elongated cilia with accumulation of IFT complexes and the kinase ICK/CILK1 at the ciliary tip, phenocopying BROMI- and CCRK-knockout cells (PMID:30905400, PMID:35609210). Joubert syndrome-associated mutations map to its conserved DUF3719 domain and recapitulate cilia elongation in vivo, establishing FAM149B1 loss of function as a cause of this ciliopathy (PMID:30905400, PMID:34731674).

Mechanistic history

Synthesis pass · year-by-year structured walk · 3 steps
  1. 2019 Medium

    Establishing whether FAM149B1 has a ciliary function, this work showed that patient loss-of-function mutations disrupt IFT distribution rather than cilium formation, defining the gene as a regulator of IFT turnaround and cilium length.

    Evidence Immunofluorescence, cilia length measurement, and SHH signaling assays in patient-derived mutant fibroblasts

    PMID:30905400

    Open questions at the time
    • Single-lab cellular phenotype without molecular partners identified
    • Mechanism linking IFT tip accumulation to SHH dysregulation not resolved
    • No direct demonstration of the affected kinase pathway
  2. 2021 High

    To place FAM149B1 in a defined signaling hierarchy, genetic epistasis in C. elegans positioned the homolog XBX-4 upstream of the CCRK–MAK kinase cascade controlling cilia length and axonemal microtubule stability, and validated that disease-variant alleles are functionally pathogenic in vivo.

    Evidence C. elegans double-mutant epistasis with dyf-18/dyf-5, microtubule stability assays, and expression of human disease-variant alleles

    PMID:34731674

    Open questions at the time
    • How XBX-4/FAM149B1 promotes CCRK function biochemically is unknown
    • Conservation of the precise kinase regulatory step to mammals not directly shown in this work
  3. 2022 High

    To define the physical basis of FAM149B1's regulatory role, reciprocal Co-IP demonstrated direct interaction with BROMI/TBC1D32 and CCRK/CDK20, and knockout cells showed IFT and ICK/CILK1 accumulation at the tip, unifying FAM149B1 with the BROMI/CCRK complex controlling IFT turnaround.

    Evidence Reciprocal co-immunoprecipitation and knockout cell lines with IFT/ICK localization and cilia length analysis

    PMID:35609210

    Open questions at the time
    • Stoichiometry and architecture of the FAM149B1–BROMI–CCRK complex not resolved
    • Whether FAM149B1 directly modulates CCRK catalytic activity is not established
    • No structural model of the DUF3719 domain's interactions

Open questions

Synthesis pass · forward-looking unresolved questions
  • The biochemical mechanism by which FAM149B1 promotes CCRK activity and triggers IFT turnaround at the ciliary tip remains unresolved.
  • No enzymatic or molecular activity assigned to FAM149B1 itself
  • Mechanism converting tip-localized kinase signaling into IFT turnaround unknown
  • Structural basis of DUF3719-mediated complex assembly undetermined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2
Localization
GO:0005929 cilium 3
Pathway
GO:0140096 catalytic activity, acting on a protein 1
Partners
CDK20TBC1D32

Evidence

Reading pass · 3 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 Loss-of-function mutations in FAM149B1 in patient fibroblasts cause abnormal accumulation of IFT complex at distal ciliary tips (bulbous appearance), increased primary cilium length, and dysregulated SHH signaling, while ciliogenesis itself remains normal. Patient-derived mutant fibroblast analysis (immunofluorescence for IFT complex localization, cilia length measurement, SHH signaling assay) American journal of human genetics Medium 30905400
2022 FAM149B1 physically interacts with both BROMI/TBC1D32 and CCRK/CDK20, placing it in a complex that regulates IFT turnaround at the ciliary tip; FAM149B1-knockout cells display abnormally long cilia and accumulation of IFT machinery and ICK/CILK1 at the ciliary tip, phenocopying BROMI-KO and CCRK-KO cells. Co-immunoprecipitation (direct interaction with CCRK and BROMI), knockout cell line generation with ciliary phenotype analysis (immunofluorescence for IFT machinery and ICK localization, cilia length measurement) Molecular biology of the cell High 35609210
2021 XBX-4, the C. elegans FAM149B1 homolog (DUF3719 domain), acts upstream in the DYF-18 CCRK / DYF-5 MAK kinase pathway to regulate cilia length and axonemal microtubule stability; loss of xbx-4 elongates sensory neuron cilia with stabilized axonemal MTs, and XBX-4 promotes DYF-18 CCRK function to regulate localization and activity of DYF-5 MAK. Joubert syndrome-associated mutations in the DUF3719 domain also elongate cilia in C. elegans. C. elegans genetic epistasis (double mutants with dyf-18 and dyf-5), cilia length and MT stability assays, kinase localization/function analysis in xbx-4 mutant background, expression of human disease-variant alleles Current biology : CB High 34731674

Source papers

Stage 0 corpus · 5 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Bi-allelic Mutations in FAM149B1 Cause Abnormal Primary Cilium and a Range of Ciliopathy Phenotypes in Humans. American journal of human genetics 27 30905400
2022 BROMI/TBC1D32 together with CCRK/CDK20 and FAM149B1/JBTS36 contributes to intraflagellar transport turnaround involving ICK/CILK1. Molecular biology of the cell 12 35609210
2021 xbx-4, a homolog of the Joubert syndrome gene FAM149B1, acts via the CCRK and RCK kinase cascade to regulate cilia morphology. Current biology : CB 8 34731674
2026 Joubert syndrome gene fam149b1 homolog, xbx-4 , is required for multiple sensory behaviors. microPublication biology 0 42064743
2025 Comprehensive Proteomics and Machine Learning Analysis to Distinguish Follicular Adenoma and Follicular Thyroid Carcinoma from Indeterminate Thyroid Nodules. Endocrinology and metabolism (Seoul, Korea) 0 40205804

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