Affinage

FAM161A

Protein FAM161A · UniProt Q3B820

Length
660 aa
Mass
76.8 kDa
Annotated
2026-06-09
26 papers in source corpus 9 papers cited in narrative 11 extracted findings
Cross-family judge faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FAM161A is a centrosomal and ciliary microtubule-associated protein that organizes the photoreceptor connecting cilium and basal body to support outer segment biogenesis and protein delivery (PMID:22940612, PMID:22791751, PMID:24833722). Through its evolutionarily conserved C-terminal UPF0564 domain it binds microtubules directly, promoting their acetylation and stabilization, and engages a network of ciliopathy-associated proteins including FAM161B, lebercilin, CEP290, OFD1, SDCCAG8, and C8orf37 (PMID:22791751, PMID:22940612, PMID:36233334). Beyond its ciliary role, FAM161A is a member of the Golgi-centrosomal interactome and tracks with the centrosome throughout mitosis, interacting with centrosomal and microtubule-network proteins such as AKAP9, NIN, PDE4DIP, KIFC3, and TRIP11 (PMID:25749990). In vivo loss of the C-terminal domain shortens the connecting cilium, splays ciliary microtubule doublets, mislocalizes lebercilin and Cep290, and misroutes outer segment cargo (opsin and peripherin-2), establishing this domain as essential for molecular delivery into the outer segment (PMID:24833722). Its retinal expression is transcriptionally driven by the photoreceptor factor CRX (PMID:20705278), and disease-associated nonsense alleles are eliminated by nonsense-mediated decay, indicating that pathology arises from protein deficiency (PMID:24651477); gene augmentation restoring both FAM161A isoforms at controlled dosage rescues connecting-cilium localization and retinal function in deficient mice (PMID:38504136).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2012 High

    Establishing where FAM161A acts and whether it is functionally required for cilia answered the first question of its cellular role.

    Evidence Immunofluorescence/immunohistochemistry across human, mouse and rat plus siRNA knockdown with a ciliary assembly readout in cultured cells

    PMID:22791751 PMID:22940612

    Open questions at the time
    • Does not define the molecular activity underlying ciliogenesis defect
    • Connecting-cilium versus basal-body specific functions not separated
  2. 2012 Medium

    Identifying direct microtubule binding via the UPF0564 domain provided a candidate biochemical mechanism for FAM161A's ciliary structural role.

    Evidence Overexpression in cultured cells with microtubule co-localization, tubulin acetylation assays, and domain-deletion mapping

    PMID:22791751

    Open questions at the time
    • No in vitro reconstitution with purified protein
    • Acetylation/stabilization shown in overexpression, not endogenous setting
  3. 2012 High

    Mapping UPF0564-mediated interactions placed FAM161A within a ciliopathy protein network at the connecting cilium.

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

    PMID:22791751 PMID:22940612

    Open questions at the time
    • Hierarchy and stoichiometry of the interaction network not resolved
    • Functional consequence of each interaction not tested
  4. 2012 Medium

    Demonstrating CRX control of FAM161A transcription connected its expression to the photoreceptor gene regulatory program.

    Evidence Chromatin immunoprecipitation and organotypic retinal explant reporter assays

    PMID:20705278

    Open questions at the time
    • Other regulators of FAM161A not addressed
    • Isoform-specific transcriptional control not examined
  5. 2014 High

    In vivo deletion of the C-terminal domain established that FAM161A is required for connecting-cilium architecture and for routing cargo into the outer segment.

    Evidence Gene-trap mouse model analyzed by electron microscopy, immunohistochemistry, western blot, and ERG

    PMID:24833722

    Open questions at the time
    • Mechanism by which cargo (opsin, peripherin-2) is sorted not defined
    • Distinguishes C-terminal requirement but not roles of other regions
  6. 2015 High

    A retinal interactome screen extended FAM161A beyond the cilium into a Golgi-centrosomal network.

    Evidence Yeast two-hybrid cDNA library screen validated by co-immunoprecipitation and proximity ligation assay

    PMID:25749990

    Open questions at the time
    • Functional significance of Golgi-centrosomal partners untested
    • Validated only a subset of 53 candidate interactors
  7. 2015 Medium

    Tracking FAM161A with the centrosome through mitosis raised the possibility of a cell-cycle role distinct from its G0 ciliary function.

    Evidence Cell-cycle staged immunofluorescence relative to centrosomal markers

    PMID:25749990

    Open questions at the time
    • No functional perturbation to test mitotic consequence
    • Single method without orthogonal validation
  8. 2015 Medium

    Showing NMD degradation of nonsense alleles clarified that disease results from protein loss rather than a dominant truncated product.

    Evidence FAM161A mRNA level analysis in patient-derived lymphoblasts

    PMID:24651477

    Open questions at the time
    • No NMD-inhibitor control reported
    • Limited to nonsense mutations, not other allele classes
  9. 2020 Low

    A structural-homology prediction proposed that FAM161A binds microtubules in a TPX2-like manner, offering a mechanistic hypothesis for its tubulin interaction.

    Evidence Computational profile-profile homology search and multiple sequence alignment

    PMID:33093951

    Open questions at the time
    • Purely computational with no experimental validation
    • Predicted nucleation activity not tested biochemically
  10. 2022 Medium

    Identifying C8orf37 as a UPF0564-domain partner co-localized at the ciliary base extended FAM161A's ciliopathy interaction map.

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

    PMID:36233334

    Open questions at the time
    • Functional consequence of the C8orf37 interaction not established
    • Single lab without reciprocal in vivo validation
  11. 2024 Medium

    Gene-augmentation rescue defined that restoring both FAM161A isoforms at controlled dosage is necessary for functional recovery, addressing therapeutic requirements.

    Evidence Subretinal AAV delivery in Fam161a KO mice with ERG, OCT, IHC across multiple vector/promoter/isoform combinations

    PMID:38504136

    Open questions at the time
    • Distinct functional roles of long versus short isoforms not mechanistically resolved
    • Single-lab demonstration in mouse only

Open questions

Synthesis pass · forward-looking unresolved questions
  • The biochemical mechanism by which FAM161A engages microtubules and directs outer-segment cargo trafficking remains undefined.
  • No reconstituted in vitro microtubule-binding/nucleation assay with purified FAM161A
  • Mechanism linking the interaction network to cargo sorting not established
  • Isoform-specific molecular functions unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005815 microtubule organizing center 3 GO:0005856 cytoskeleton 2 GO:0005929 cilium 2 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-9709957 Sensory Perception 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 base of the photoreceptor connecting cilium in human, mouse and rat, and to the ciliary basal body in ciliated mammalian cells. siRNA-mediated depletion of FAM161A in cultured cells causes reduction in assembled primary cilia, establishing a functional role in ciliogenesis. Immunofluorescence, immunohistochemistry, siRNA knockdown with ciliary assembly readout Human molecular genetics High 22791751 22940612
2012 FAM161A directly binds microtubules; overexpressed FAM161A associates with microtubules during interphase and mitosis and increases microtubule acetylation and stabilization. The evolutionarily conserved C-terminal UPF0564 domain mediates microtubule binding. Overexpression in cultured cells, immunofluorescence for microtubule co-localization, tubulin acetylation assay, domain deletion analysis Human molecular genetics Medium 22791751
2012 The UPF0564 domain of FAM161A mediates homo- and heterotypic interaction with FAM161B, as well as binding to ciliopathy-associated proteins lebercilin, CEP290, OFD1, and SDCCAG8, as demonstrated by yeast two-hybrid and pull-down experiments in cultured cells and bovine retinal extracts. Yeast two-hybrid, pull-down assays in cultured cells and bovine retinal extracts Human molecular genetics High 22791751 22940612
2014 In Fam161a gene-trap mice lacking the C-terminal domain, the connecting cilium is significantly shortened, ciliary microtubule doublets are spread, and outer segment disk organization is disturbed. Interactors lebercilin and Cep290 are mislocalized to the basal body/proximal connecting cilium, and outer segment cargo proteins opsin and rds/peripherin 2 are misrouted, indicating the C-terminal domain is required for molecular delivery into the outer segment cilium. Gene-trap mouse model, electron microscopy, immunohistochemistry, western blot, ERG Human molecular genetics High 24833722
2015 Yeast two-hybrid screening of human and bovine retinal cDNA libraries using FAM161A fragments as bait identified 53 interactors enriched in ciliary, Golgi apparatus, centrosomal, and microtubule network proteins, including AKAP9, FIP3, GOLGA3, KIFC3, KLC2, PDE4DIP, NIN, and TRIP11. Key interactions were validated by co-immunoprecipitation and proximity ligation assay, placing FAM161A as a member of the Golgi-centrosomal interactome. Yeast two-hybrid (cDNA library screen), co-immunoprecipitation, proximity ligation assay Human molecular genetics High 25749990
2015 FAM161A localization follows the centrosome during all stages of mitosis, suggesting compartmentalization related to centrosomal function during cell cycle progression as well as ciliary basal body function in G0. Cell cycle staging with immunofluorescence localization of FAM161A relative to centrosomal markers Human molecular genetics Medium 25749990
2015 Mutant FAM161A transcripts harboring nonsense mutations are actively degraded by nonsense-mediated mRNA decay (NMD) in patient-derived lymphoblasts, indicating that the disease mechanism involves FAM161A protein deficiency rather than production of a truncated protein. Analysis of FAM161A mRNA levels in cultured lymphoblasts from patients with nonsense mutations PloS one Medium 24651477
2020 Structural bioinformatics analysis predicts FAM161A is a homologue of the microtubule nucleation factor TPX2, with three copies of the extended loop element and one short helix homologous to the TPX2 microtubule-nucleating elements, suggesting FAM161A binds microtubules in the same way as TPX2. Computational profile-profile homology search (PSI-BLAST, HHblits, HHpred), multiple sequence alignment F1000Research Low 33093951
2022 C8orf37 physically interacts with FAM161A; the N-terminal region of C8orf37 binds to residues 341–517 within the UPF0564 domain of FAM161A. Both proteins co-localize at the ciliary base of photoreceptors in marmoset retina. Yeast two-hybrid screen, co-immunofluorescence, proximity ligation assay (PLA) in marmoset retinal sections and HEK293 cells, interaction domain mapping International journal of molecular sciences Medium 36233334
2012 FAM161A expression in the retina is transcriptionally regulated by the photoreceptor transcription factor CRX, as demonstrated by chromatin immunoprecipitation showing CRX binding to the Fam161a promoter and organotypic reporter assays in explanted retinas. Chromatin immunoprecipitation (ChIP), organotypic retinal explant reporter assays American journal of human genetics Medium 20705278
2024 In Fam161a-deficient mice, gene augmentation using AAV vectors expressing both the long (exon 4-containing) and short isoforms of human FAM161A under a weak promoter (FCBR1-F0.4) restored FAM161A localization to the connecting cilium and improved retinal function, whereas strong-promoter vectors or single-isoform delivery did not enhance retinal function despite improving cell survival, establishing that precise dosing and delivery of both isoforms is required for functional rescue. Subretinal AAV injection in Fam161a KO mice, ERG, OCT, immunohistochemistry, comparison of multiple vector/promoter/isoform 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 75 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 20 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 14 38504136
2014 Molecular genetics of FAM161A in North American patients with early-onset retinitis pigmentosa. PloS one 14 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

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