Affinage

FAM161A

Protein FAM161A · UniProt Q3B820

Length
660 aa
Mass
76.8 kDa
Annotated
2026-04-28
26 papers in source corpus 9 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FAM161A is a centrosomal and ciliary microtubule-associated protein essential for photoreceptor connecting-cilium integrity and outer-segment cargo trafficking. Its conserved C-terminal UPF0564 domain directly binds and stabilizes microtubules, promotes microtubule acetylation, and mediates interactions with ciliopathy-associated proteins (lebercilin, CEP290, OFD1, SDCCAG8, C8orf37) and Golgi–centrosome network components (AKAP9, NIN, TRIP11), linking it to both ciliary gate assembly and vesicular transport to the cilium (PMID:22791751, PMID:22940612, PMID:25749990, PMID:36233334). Loss of Fam161a in mice causes connecting-cilium shortening, splayed microtubule doublets, mislocalization of ciliary and outer-segment proteins, and progressive photoreceptor degeneration, establishing FAM161A deficiency as the mechanism underlying RP28-linked autosomal recessive retinitis pigmentosa (PMID:24833722, PMID:24651477). Functional rescue in Fam161a-deficient mice requires co-delivery of both retinal isoforms at tightly controlled expression levels to restore proper connecting-cilium localization and retinal function (PMID:38504136).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2010 Medium

    Identifying transcriptional control of Fam161a by CRX established that its expression is photoreceptor-specific and developmentally regulated, linking it to the gene-regulatory network governing photoreceptor differentiation.

    Evidence ChIP and organotypic reporter assay in explanted mouse retinas

    PMID:20705278

    Open questions at the time
    • No direct evidence that CRX is strictly necessary for all FAM161A expression (no CRX-KO retinal analysis of FAM161A levels)
    • Other transcription factors regulating FAM161A are unknown
  2. 2012 High

    Demonstrating that FAM161A localizes to the photoreceptor connecting cilium and basal body, and that its depletion impairs ciliogenesis, established it as a functional ciliary protein rather than merely a centrosomal marker.

    Evidence Immunohistochemistry in human/mouse/rat retina, siRNA knockdown with cilia quantification in cultured cells

    PMID:22791751 PMID:22940612

    Open questions at the time
    • siRNA experiments were in cultured cells, not photoreceptors
    • Whether FAM161A is required for cilia maintenance versus initiation was not resolved
  3. 2012 High

    Showing that the UPF0564 domain mediates direct microtubule binding, promotes acetylation/stabilization, and enables homo-/heterotypic interaction with FAM161B defined the molecular activity of FAM161A as a microtubule-stabilizing scaffold.

    Evidence In vitro microtubule co-sedimentation, domain deletion analysis, immunofluorescence of overexpressed protein

    PMID:22791751

    Open questions at the time
    • No structural model of the FAM161A–microtubule interface
    • Whether FAM161A directly recruits an acetyltransferase or indirectly promotes acetylation is unknown
  4. 2012 High

    Identifying physical interactions between FAM161A and ciliopathy proteins lebercilin, CEP290, OFD1, and SDCCAG8 placed FAM161A in a shared ciliary-disease network and suggested a common pathogenic mechanism.

    Evidence Yeast two-hybrid and pull-down assays in cultured cells and bovine retinal extracts

    PMID:22940612

    Open questions at the time
    • Stoichiometry and whether these form a single complex or represent distinct subcomplexes is unresolved
    • Functional consequence of disrupting individual interactions not tested
  5. 2014 High

    The Fam161a gene-trap mouse revealed that FAM161A is required for connecting-cilium structural integrity and vectorial transport of outer-segment cargo (opsin, peripherin-2), providing the first in vivo epistatic placement of FAM161A upstream of ciliary trafficking.

    Evidence Gene-trap KO mouse, electron microscopy, co-immunolabeling, electroretinography

    PMID:24833722

    Open questions at the time
    • Whether mislocalization of cargo is due to microtubule disorganization, gate defect, or IFT disruption was not distinguished
    • Temporal sequence of degeneration events not fully resolved
  6. 2014 Medium

    Demonstrating nonsense-mediated mRNA decay of mutant FAM161A transcripts in patient lymphoblasts established that RP28 disease results from protein deficiency (loss of function) rather than a dominant-negative mechanism.

    Evidence RT-PCR/NMD assay in patient-derived lymphoblast cultures

    PMID:24651477

    Open questions at the time
    • Only two mutations tested; generalizability to all RP28 alleles not confirmed
    • NMD efficiency in photoreceptors versus lymphoblasts may differ
  7. 2015 High

    A comprehensive interactome screen expanded FAM161A's network to 53 partners enriched in Golgi, centrosome, and microtubule functions, connecting it to a Golgi–centrosomal transport axis via validated interactions with AKAP9, NIN, and TRIP11.

    Evidence Yeast two-hybrid screen of retinal cDNA libraries, co-immunoprecipitation, proximity ligation assay

    PMID:25749990

    Open questions at the time
    • Functional significance of the Golgi–centrosomal interactions for photoreceptor biology not tested in vivo
    • Whether FAM161A travels with Golgi-derived vesicles is unknown
  8. 2022 Medium

    Mapping the FAM161A–C8orf37 interaction to the UPF0564 domain and confirming their co-localization at the photoreceptor ciliary base added another retinal-disease gene to the FAM161A hub, reinforcing its role as a ciliary gate scaffold.

    Evidence Yeast two-hybrid with domain mapping, PLA in marmoset retina and HEK293 cells

    PMID:36233334

    Open questions at the time
    • Functional consequence of disrupting the FAM161A–C8orf37 interaction not assessed
    • Whether C8orf37 competes with other UPF0564-binding partners is unknown
  9. 2024 Medium

    Gene therapy rescue experiments showed that both FAM161A isoforms at tightly controlled expression levels are needed for correct connecting-cilium localization and functional restoration, revealing isoform cooperativity and dose sensitivity critical for therapeutic design.

    Evidence AAV subretinal injection in Fam161a KO mice with ERG, OCT, and immunohistochemistry comparison of vector/promoter combinations

    PMID:38504136

    Open questions at the time
    • Mechanism by which the two isoforms cooperate is unknown
    • Long-term durability of rescue not established
    • Whether findings translate to human photoreceptors remains to be tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of FAM161A's microtubule binding, the mechanism by which it coordinates ciliary gate assembly with cargo trafficking, and how its two isoforms functionally differ remain unresolved.
  • No high-resolution structure of FAM161A or the UPF0564 domain bound to microtubules
  • Whether FAM161A directly participates in IFT or acts solely as a structural scaffold is not established
  • Distinct functions of the long versus short isoform are undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3
Localization
GO:0005929 cilium 4 GO:0005815 microtubule organizing center 3 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-9609507 Protein localization 2
Partners
AKAP9C8ORF37CEP290FAM161BLCA5NINOFD1SDCCAG8

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 FAM161A localizes to the connecting cilium (ciliary basal body and adjacent centriole) in photoreceptors of human, mouse, and rat retinas, and at the ciliary basal body of ciliated mammalian cells. siRNA-mediated depletion of FAM161A in cultured cells reduces the number of assembled primary cilia, demonstrating a functional role in ciliogenesis. Immunohistochemistry, immunofluorescence, siRNA knockdown with cilia quantification, recombinant tagged protein expression Human molecular genetics High 22791751 22940612
2012 FAM161A directly interacts with ciliopathy-associated proteins lebercilin, CEP290, OFD1, and SDCCAG8 via its C-terminal domain, as demonstrated by yeast two-hybrid and pull-down experiments in cultured cells and bovine retinal extracts. Yeast two-hybrid, pull-down assay in cultured cells and bovine retinal extracts Human molecular genetics High 22940612
2012 FAM161A binds directly to microtubules and increases microtubule acetylation and stabilization. The evolutionarily conserved C-terminal UPF0564 domain mediates microtubule association, as well as homo- and heterotypic interaction with FAM161B. Microtubule co-sedimentation/binding assay, immunofluorescence of overexpressed protein, domain deletion analysis Human molecular genetics High 22791751
2014 In Fam161a gene-trap mice lacking the C-terminal domain, the connecting cilium is significantly shortened, ciliary microtubule doublets are spread, and photoreceptor disk organization is disturbed. Ciliary proteins centrin-3, lebercilin, and CEP290 are mislocalized, and outer-segment cargo proteins opsin and rds/peripherin-2 are misrouted, demonstrating that Fam161a is required for molecular delivery into the outer segment cilium. Gene-trap mouse model, electron microscopy, co-immunolabeling, electroretinography Human molecular genetics High 24833722
2015 Yeast two-hybrid screening of human and bovine retinal cDNA libraries using FAM161A fragments as baits identified 53 interactors enriched in ciliary, Golgi, centrosomal, and microtubule-network proteins. Key interactions with AKAP9, FIP3, GOLGA3, KIFC3, KLC2, PDE4DIP, NIN, and TRIP11 were validated by co-immunoprecipitation and proximity ligation assay, placing FAM161A in the Golgi-centrosomal interactome. Yeast two-hybrid screen, co-immunoprecipitation, proximity ligation assay Human molecular genetics High 25749990
2015 FAM161A follows the centrosome through all stages of mitosis, indicating cell-cycle-dependent compartmentalization consistent with its role at the ciliary basal body during G0 phase. Immunofluorescence cell-cycle analysis in cultured cells Human molecular genetics Medium 25749990
2010 Fam161a expression in the mouse retina is developmentally regulated and controlled by the photoreceptor transcription factor CRX, as demonstrated by chromatin immunoprecipitation and organotypic reporter assays on explanted retinas. Chromatin immunoprecipitation, organotypic reporter assay in explanted mouse retinas American journal of human genetics Medium 20705278
2020 Structural bioinformatics predicts that FAM161A is a homologue of the microtubule nucleation factor TPX2, with sequence profile homology spanning >200 residues including the microtubule-nucleating loop and helix elements; FAM161A contains three copies of the loop element and one helix, suggesting it binds microtubules similarly to TPX2. Computational profile-profile search (HHpred/HHsearch, PSI-BLAST) and multiple sequence alignment F1000Research Low 33093951
2022 C8orf37 interacts with FAM161A; yeast two-hybrid identified the interaction, and domain mapping showed the N-terminal region of C8orf37 binds amino acid residues 341–517 within the UPF0564 domain of FAM161A. The two proteins co-localize at the photoreceptor ciliary base in marmoset retina and in HEK293 cells, as confirmed by proximity ligation assay. Yeast two-hybrid, interaction domain mapping, co-immunofluorescence, proximity ligation assay in retinal sections and HEK293 cells International journal of molecular sciences Medium 36233334
2014 Mutant FAM161A transcripts carrying nonsense mutations are actively degraded by nonsense-mediated mRNA decay in patient-derived lymphoblasts, establishing that the disease mechanism involves FAM161A protein deficiency. Analysis of mRNA levels in patient-derived lymphoblast cultures (RT-PCR/NMD assay) PloS one Medium 24651477
2024 FAM161A has two isoforms in human retina (long with exon 4, short without). Gene therapy rescue experiments in Fam161a-deficient mice showed that delivery of both isoforms together under a weak photoreceptor promoter (FCBR1-F0.4) was required to achieve precise FAM161A expression in the connecting cilium and restore retinal function, whereas single-isoform or high-expression vectors improved cell survival but not ciliary structure or function. AAV subretinal injection in Fam161a KO mice, ERG, OCT, immunohistochemistry, comparison of vector/promoter combinations EMBO molecular medicine Medium 38504136

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Homozygosity mapping reveals null mutations in FAM161A as a cause of autosomal-recessive retinitis pigmentosa. American journal of human genetics 91 20705279
2010 Nonsense mutations in FAM161A cause RP28-associated recessive retinitis pigmentosa. American journal of human genetics 74 20705278
2012 FAM161A, associated with retinitis pigmentosa, is a component of the cilia-basal body complex and interacts with proteins involved in ciliopathies. Human molecular genetics 52 22940612
2012 The retinitis pigmentosa 28 protein FAM161A is a novel ciliary protein involved in intermolecular protein interaction and microtubule association. Human molecular genetics 49 22791751
2014 Disruption of the retinitis pigmentosa 28 gene Fam161a in mice affects photoreceptor ciliary structure and leads to progressive retinal degeneration. Human molecular genetics 48 24833722
2014 An Intronic SINE insertion in FAM161A that causes exon-skipping is associated with progressive retinal atrophy in Tibetan Spaniels and Tibetan Terriers. PloS one 34 24705771
1999 Autosomal recessive retinitis pigmentosa locus RP28 maps between D2S1337 and D2S286 on chromosome 2p11-p15 in an Indian family. Journal of medical genetics 28 10507729
2021 A new mouse model for retinal degeneration due to Fam161a deficiency. Scientific reports 23 33479377
2020 Unique combination of clinical features in a large cohort of 100 patients with retinitis pigmentosa caused by FAM161A mutations. Scientific reports 19 32938956
2004 Confirmation of linkage and refinement of the RP28 locus for autosomal recessive retinitis pigmentosa on chromosome 2p14-p15 in an Indian family. Molecular vision 19 15215745
2014 Homozygosity mapping reveals new nonsense mutation in the FAM161A gene causing autosomal recessive retinitis pigmentosa in a Palestinian family. Molecular vision 18 24520187
2015 Interactome analysis reveals that FAM161A, deficient in recessive retinitis pigmentosa, is a component of the Golgi-centrosomal network. Human molecular genetics 16 25749990
2014 FAM161A, a novel centrosomal-ciliary protein implicated in autosomal recessive retinitis pigmentosa. Advances in experimental medicine and biology 16 24664697
2024 Fine-tuning FAM161A gene augmentation therapy to restore retinal function. EMBO molecular medicine 13 38504136
2014 Molecular genetics of FAM161A in North American patients with early-onset retinitis pigmentosa. PloS one 13 24651477
2014 Ocular Phenotype of a Family with FAM161A-associated Retinal Degeneration. Ophthalmic genetics 13 25007332
2015 Whole-exome sequencing reveals a novel frameshift mutation in the FAM161A gene causing autosomal recessive retinitis pigmentosa in the Indian population. Journal of human genetics 12 26246154
2015 A Nonsense Mutation in FAM161A Is a Recurrent Founder Allele in Dutch and Belgian Individuals With Autosomal Recessive Retinitis Pigmentosa. Investigative ophthalmology & visual science 10 26574802
2022 Retinal Structure and Function in a Knock-in Mouse Model for the FAM161A-p.Arg523∗ Human Nonsense Pathogenic Variant. Ophthalmology science 9 36420180
2015 Diverse clinical phenotypes associated with a nonsense mutation in FAM161A. Eye (London, England) 8 26113502
2023 Gene augmentation therapy attenuates retinal degeneration in a knockout mouse model of Fam161a retinitis pigmentosa. Molecular therapy : the journal of the American Society of Gene Therapy 6 37580905
2020 Structural bioinformatics predicts that the Retinitis Pigmentosa-28 protein of unknown function FAM161A is a homologue of the microtubule nucleation factor Tpx2. F1000Research 6 33093951
2009 Ultra high throughput sequencing excludes MDH1 as candidate gene for RP28-linked retinitis pigmentosa. Molecular vision 3 20011630
2024 Exonic Short Interspersed Nuclear Element Insertion in FAM161A Is Associated with Autosomal Recessive Progressive Retinal Atrophy in the English Shepherd. Genes 1 39062732
2022 Interactions between C8orf37 and FAM161A, Two Ciliary Proteins Essential for Photoreceptor Survival. International journal of molecular sciences 1 36233334
2016 FAM161A and TTC8 are Differentially Expressed in Non-Allelelic Early Onset Retinal Degeneration. Advances in experimental medicine and biology 1 26427412