{"gene":"FAM161A","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2012,"finding":"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.","method":"Immunohistochemistry, immunofluorescence, siRNA knockdown with cilia quantification, recombinant tagged protein expression","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (IHC, siRNA KD with functional readout, localization in multiple species), replicated across two independent labs in the same year","pmids":["22940612","22791751"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Yeast two-hybrid, pull-down assay in cultured cells and bovine retinal extracts","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal validation by both Y2H and pull-down in native tissue, replicated in two independent studies","pmids":["22940612"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Microtubule co-sedimentation/binding assay, immunofluorescence of overexpressed protein, domain deletion analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro microtubule binding assay plus domain mutagenesis, with functional validation of acetylation increase","pmids":["22791751"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Gene-trap mouse model, electron microscopy, co-immunolabeling, electroretinography","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with multiple orthogonal structural and functional readouts, clear epistatic placement of FAM161A upstream of ciliary cargo trafficking","pmids":["24833722"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Yeast two-hybrid screen, co-immunoprecipitation, proximity ligation assay","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — large-scale Y2H interactome with validation by reciprocal Co-IP and PLA, multiple orthogonal methods","pmids":["25749990"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Immunofluorescence cell-cycle analysis in cultured cells","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 — single localization experiment without functional perturbation, but in context of broader interactome study","pmids":["25749990"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Chromatin immunoprecipitation, organotypic reporter assay in explanted mouse retinas","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus functional reporter assay, single study","pmids":["20705278"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Computational profile-profile search (HHpred/HHsearch, PSI-BLAST) and multiple sequence alignment","journal":"F1000Research","confidence":"Low","confidence_rationale":"Tier 4 — computational prediction only, no experimental validation","pmids":["33093951"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Yeast two-hybrid, interaction domain mapping, co-immunofluorescence, proximity ligation assay in retinal sections and HEK293 cells","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 — Y2H plus PLA and co-localization, domain-level mapping, single study","pmids":["36233334"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Analysis of mRNA levels in patient-derived lymphoblast cultures (RT-PCR/NMD assay)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — direct molecular assay in patient cells confirming NMD as mechanism","pmids":["24651477"],"is_preprint":false},{"year":2024,"finding":"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.","method":"AAV subretinal injection in Fam161a KO mice, ERG, OCT, immunohistochemistry, comparison of vector/promoter combinations","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo rescue experiment with multiple readouts and systematic comparison of isoforms and promoter strengths, single study","pmids":["38504136"],"is_preprint":false}],"current_model":"FAM161A is a centrosomal-ciliary microtubule-associated protein that localizes to the connecting cilium and basal body of photoreceptors (regulated transcriptionally by CRX), where it directly binds microtubules via its conserved C-terminal UPF0564 domain, stabilizes and acetylates microtubules, interacts with ciliopathy proteins (lebercilin, CEP290, OFD1, SDCCAG8, C8orf37) and a Golgi-centrosomal interactome (including AKAP9, NIN, TRIP11), and is required for the structural integrity of the connecting cilium and vectorial transport of outer-segment cargo proteins; loss of FAM161A causes progressive photoreceptor degeneration consistent with a retinal ciliopathy."},"narrative":{"teleology":[{"year":2010,"claim":"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","pmids":["20705278"],"confidence":"Medium","gaps":["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"]},{"year":2012,"claim":"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","pmids":["22940612","22791751"],"confidence":"High","gaps":["siRNA experiments were in cultured cells, not photoreceptors","Whether FAM161A is required for cilia maintenance versus initiation was not resolved"]},{"year":2012,"claim":"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","pmids":["22791751"],"confidence":"High","gaps":["No structural model of the FAM161A–microtubule interface","Whether FAM161A directly recruits an acetyltransferase or indirectly promotes acetylation is unknown"]},{"year":2012,"claim":"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","pmids":["22940612"],"confidence":"High","gaps":["Stoichiometry and whether these form a single complex or represent distinct subcomplexes is unresolved","Functional consequence of disrupting individual interactions not tested"]},{"year":2014,"claim":"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","pmids":["24833722"],"confidence":"High","gaps":["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"]},{"year":2014,"claim":"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","pmids":["24651477"],"confidence":"Medium","gaps":["Only two mutations tested; generalizability to all RP28 alleles not confirmed","NMD efficiency in photoreceptors versus lymphoblasts may differ"]},{"year":2015,"claim":"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","pmids":["25749990"],"confidence":"High","gaps":["Functional significance of the Golgi–centrosomal interactions for photoreceptor biology not tested in vivo","Whether FAM161A travels with Golgi-derived vesicles is unknown"]},{"year":2022,"claim":"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","pmids":["36233334"],"confidence":"Medium","gaps":["Functional consequence of disrupting the FAM161A–C8orf37 interaction not assessed","Whether C8orf37 competes with other UPF0564-binding partners is unknown"]},{"year":2024,"claim":"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","pmids":["38504136"],"confidence":"Medium","gaps":["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"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"High","gaps":["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":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,3,7]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,4,5]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,3,8,10]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,3,10]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,4]}],"complexes":[],"partners":["CEP290","LCA5","OFD1","SDCCAG8","C8ORF37","AKAP9","NIN","FAM161B"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"Q3B820","full_name":"Protein FAM161A","aliases":[],"length_aa":660,"mass_kda":76.8,"function":"Involved in ciliogenesis","subcellular_location":"Cytoplasm, cytoskeleton, cilium basal body; Cell projection, cilium; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole","url":"https://www.uniprot.org/uniprotkb/Q3B820/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FAM161A","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FAM161A","total_profiled":1310},"omim":[{"mim_id":"614784","title":"POC1 CENTRIOLAR PROTEIN B; POC1B","url":"https://www.omim.org/entry/614784"},{"mim_id":"613596","title":"FAMILY WITH SEQUENCE SIMILARITY 161, MEMBER A; FAM161A","url":"https://www.omim.org/entry/613596"},{"mim_id":"606068","title":"RETINITIS PIGMENTOSA 28; RP28","url":"https://www.omim.org/entry/606068"},{"mim_id":"268000","title":"RETINITIS PIGMENTOSA; RP","url":"https://www.omim.org/entry/268000"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Centrosome","reliability":"Supported"},{"location":"Basal body","reliability":"Supported"},{"location":"Flagellar centriole","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"retina","ntpm":26.9}],"url":"https://www.proteinatlas.org/search/FAM161A"},"hgnc":{"alias_symbol":["FLJ13305"],"prev_symbol":["RP28"]},"alphafold":{"accession":"Q3B820","domains":[{"cath_id":"1.20.5","chopping":"522-553","consensus_level":"medium","plddt":91.4644,"start":522,"end":553},{"cath_id":"1.10.287","chopping":"554-593","consensus_level":"medium","plddt":88.889,"start":554,"end":593}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q3B820","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q3B820-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q3B820-F1-predicted_aligned_error_v6.png","plddt_mean":66.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FAM161A","jax_strain_url":"https://www.jax.org/strain/search?query=FAM161A"},"sequence":{"accession":"Q3B820","fasta_url":"https://rest.uniprot.org/uniprotkb/Q3B820.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q3B820/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q3B820"}},"corpus_meta":[{"pmid":"20705279","id":"PMC_20705279","title":"Homozygosity mapping reveals null mutations in FAM161A as a cause of autosomal-recessive retinitis pigmentosa.","date":"2010","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20705279","citation_count":91,"is_preprint":false},{"pmid":"20705278","id":"PMC_20705278","title":"Nonsense mutations in FAM161A cause RP28-associated recessive retinitis pigmentosa.","date":"2010","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20705278","citation_count":74,"is_preprint":false},{"pmid":"22940612","id":"PMC_22940612","title":"FAM161A, associated with retinitis pigmentosa, is a component of the cilia-basal body complex and interacts with proteins involved in ciliopathies.","date":"2012","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22940612","citation_count":52,"is_preprint":false},{"pmid":"22791751","id":"PMC_22791751","title":"The retinitis pigmentosa 28 protein FAM161A is a novel ciliary protein involved in intermolecular protein interaction and microtubule association.","date":"2012","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22791751","citation_count":49,"is_preprint":false},{"pmid":"24833722","id":"PMC_24833722","title":"Disruption of the retinitis pigmentosa 28 gene Fam161a in mice affects photoreceptor ciliary structure and leads to progressive retinal degeneration.","date":"2014","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24833722","citation_count":48,"is_preprint":false},{"pmid":"24705771","id":"PMC_24705771","title":"An Intronic SINE insertion in FAM161A that causes exon-skipping is associated with progressive retinal atrophy in Tibetan Spaniels and Tibetan Terriers.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24705771","citation_count":34,"is_preprint":false},{"pmid":"10507729","id":"PMC_10507729","title":"Autosomal recessive retinitis pigmentosa locus RP28 maps between D2S1337 and D2S286 on chromosome 2p11-p15 in an Indian family.","date":"1999","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10507729","citation_count":28,"is_preprint":false},{"pmid":"33479377","id":"PMC_33479377","title":"A new mouse model for retinal degeneration due to Fam161a deficiency.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33479377","citation_count":23,"is_preprint":false},{"pmid":"15215745","id":"PMC_15215745","title":"Confirmation of linkage and refinement of the RP28 locus for autosomal recessive retinitis pigmentosa on chromosome 2p14-p15 in an Indian family.","date":"2004","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/15215745","citation_count":19,"is_preprint":false},{"pmid":"32938956","id":"PMC_32938956","title":"Unique combination of clinical features in a large cohort of 100 patients with retinitis pigmentosa caused by FAM161A mutations.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32938956","citation_count":19,"is_preprint":false},{"pmid":"24520187","id":"PMC_24520187","title":"Homozygosity mapping reveals new nonsense mutation in the FAM161A gene causing autosomal recessive retinitis pigmentosa in a Palestinian family.","date":"2014","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/24520187","citation_count":18,"is_preprint":false},{"pmid":"24664697","id":"PMC_24664697","title":"FAM161A, a novel centrosomal-ciliary protein implicated in autosomal recessive retinitis pigmentosa.","date":"2014","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/24664697","citation_count":16,"is_preprint":false},{"pmid":"25749990","id":"PMC_25749990","title":"Interactome analysis reveals that FAM161A, deficient in recessive retinitis pigmentosa, is a component of the Golgi-centrosomal network.","date":"2015","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25749990","citation_count":16,"is_preprint":false},{"pmid":"38504136","id":"PMC_38504136","title":"Fine-tuning FAM161A gene augmentation therapy to restore retinal function.","date":"2024","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38504136","citation_count":13,"is_preprint":false},{"pmid":"24651477","id":"PMC_24651477","title":"Molecular genetics of FAM161A in North American patients with early-onset retinitis pigmentosa.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24651477","citation_count":13,"is_preprint":false},{"pmid":"25007332","id":"PMC_25007332","title":"Ocular Phenotype of a Family with FAM161A-associated Retinal Degeneration.","date":"2014","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25007332","citation_count":13,"is_preprint":false},{"pmid":"26246154","id":"PMC_26246154","title":"Whole-exome sequencing reveals a novel frameshift mutation in the FAM161A gene causing autosomal recessive retinitis pigmentosa in the Indian population.","date":"2015","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26246154","citation_count":12,"is_preprint":false},{"pmid":"26574802","id":"PMC_26574802","title":"A Nonsense Mutation in FAM161A Is a Recurrent Founder Allele in Dutch and Belgian Individuals With Autosomal Recessive Retinitis Pigmentosa.","date":"2015","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/26574802","citation_count":10,"is_preprint":false},{"pmid":"36420180","id":"PMC_36420180","title":"Retinal Structure and Function in a Knock-in Mouse Model for the FAM161A-p.Arg523∗ Human Nonsense Pathogenic Variant.","date":"2022","source":"Ophthalmology science","url":"https://pubmed.ncbi.nlm.nih.gov/36420180","citation_count":9,"is_preprint":false},{"pmid":"26113502","id":"PMC_26113502","title":"Diverse clinical phenotypes associated with a nonsense mutation in FAM161A.","date":"2015","source":"Eye (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/26113502","citation_count":8,"is_preprint":false},{"pmid":"37580905","id":"PMC_37580905","title":"Gene augmentation therapy attenuates retinal degeneration in a knockout mouse model of Fam161a retinitis pigmentosa.","date":"2023","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37580905","citation_count":6,"is_preprint":false},{"pmid":"33093951","id":"PMC_33093951","title":"Structural bioinformatics predicts that the Retinitis Pigmentosa-28 protein of unknown function FAM161A is a homologue of the microtubule nucleation factor Tpx2.","date":"2020","source":"F1000Research","url":"https://pubmed.ncbi.nlm.nih.gov/33093951","citation_count":6,"is_preprint":false},{"pmid":"20011630","id":"PMC_20011630","title":"Ultra high throughput sequencing excludes MDH1 as candidate gene for RP28-linked retinitis pigmentosa.","date":"2009","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/20011630","citation_count":3,"is_preprint":false},{"pmid":"36233334","id":"PMC_36233334","title":"Interactions between C8orf37 and FAM161A, Two Ciliary Proteins Essential for Photoreceptor Survival.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36233334","citation_count":1,"is_preprint":false},{"pmid":"39062732","id":"PMC_39062732","title":"Exonic Short Interspersed Nuclear Element Insertion in FAM161A Is Associated with Autosomal Recessive Progressive Retinal Atrophy in the English Shepherd.","date":"2024","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/39062732","citation_count":1,"is_preprint":false},{"pmid":"26427412","id":"PMC_26427412","title":"FAM161A and TTC8 are Differentially Expressed in Non-Allelelic Early Onset Retinal Degeneration.","date":"2016","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/26427412","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14420,"output_tokens":2566,"usd":0.040875},"stage2":{"model":"claude-opus-4-6","input_tokens":5900,"output_tokens":2499,"usd":0.137962},"total_usd":0.178837,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Immunohistochemistry, immunofluorescence, siRNA knockdown with cilia quantification, recombinant tagged protein expression\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (IHC, siRNA KD with functional readout, localization in multiple species), replicated across two independent labs in the same year\",\n      \"pmids\": [\"22940612\", \"22791751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, pull-down assay in cultured cells and bovine retinal extracts\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal validation by both Y2H and pull-down in native tissue, replicated in two independent studies\",\n      \"pmids\": [\"22940612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Microtubule co-sedimentation/binding assay, immunofluorescence of overexpressed protein, domain deletion analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro microtubule binding assay plus domain mutagenesis, with functional validation of acetylation increase\",\n      \"pmids\": [\"22791751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Gene-trap mouse model, electron microscopy, co-immunolabeling, electroretinography\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with multiple orthogonal structural and functional readouts, clear epistatic placement of FAM161A upstream of ciliary cargo trafficking\",\n      \"pmids\": [\"24833722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, proximity ligation assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large-scale Y2H interactome with validation by reciprocal Co-IP and PLA, multiple orthogonal methods\",\n      \"pmids\": [\"25749990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Immunofluorescence cell-cycle analysis in cultured cells\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single localization experiment without functional perturbation, but in context of broader interactome study\",\n      \"pmids\": [\"25749990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Chromatin immunoprecipitation, organotypic reporter assay in explanted mouse retinas\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus functional reporter assay, single study\",\n      \"pmids\": [\"20705278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Computational profile-profile search (HHpred/HHsearch, PSI-BLAST) and multiple sequence alignment\",\n      \"journal\": \"F1000Research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational prediction only, no experimental validation\",\n      \"pmids\": [\"33093951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, interaction domain mapping, co-immunofluorescence, proximity ligation assay in retinal sections and HEK293 cells\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Y2H plus PLA and co-localization, domain-level mapping, single study\",\n      \"pmids\": [\"36233334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Analysis of mRNA levels in patient-derived lymphoblast cultures (RT-PCR/NMD assay)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct molecular assay in patient cells confirming NMD as mechanism\",\n      \"pmids\": [\"24651477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"AAV subretinal injection in Fam161a KO mice, ERG, OCT, immunohistochemistry, comparison of vector/promoter combinations\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo rescue experiment with multiple readouts and systematic comparison of isoforms and promoter strengths, single study\",\n      \"pmids\": [\"38504136\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FAM161A is a centrosomal-ciliary microtubule-associated protein that localizes to the connecting cilium and basal body of photoreceptors (regulated transcriptionally by CRX), where it directly binds microtubules via its conserved C-terminal UPF0564 domain, stabilizes and acetylates microtubules, interacts with ciliopathy proteins (lebercilin, CEP290, OFD1, SDCCAG8, C8orf37) and a Golgi-centrosomal interactome (including AKAP9, NIN, TRIP11), and is required for the structural integrity of the connecting cilium and vectorial transport of outer-segment cargo proteins; loss of FAM161A causes progressive photoreceptor degeneration consistent with a retinal ciliopathy.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"ChIP and organotypic reporter assay in explanted mouse retinas\",\n      \"pmids\": [\"20705278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct evidence that CRX is strictly necessary for all FAM161A expression (no CRX-KO retinal analysis of FAM161A levels)\",\n        \"Other transcription factors regulating FAM161A are unknown\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"Immunohistochemistry in human/mouse/rat retina, siRNA knockdown with cilia quantification in cultured cells\",\n      \"pmids\": [\"22940612\", \"22791751\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"siRNA experiments were in cultured cells, not photoreceptors\",\n        \"Whether FAM161A is required for cilia maintenance versus initiation was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro microtubule co-sedimentation, domain deletion analysis, immunofluorescence of overexpressed protein\",\n      \"pmids\": [\"22791751\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of the FAM161A–microtubule interface\",\n        \"Whether FAM161A directly recruits an acetyltransferase or indirectly promotes acetylation is unknown\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast two-hybrid and pull-down assays in cultured cells and bovine retinal extracts\",\n      \"pmids\": [\"22940612\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and whether these form a single complex or represent distinct subcomplexes is unresolved\",\n        \"Functional consequence of disrupting individual interactions not tested\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"Gene-trap KO mouse, electron microscopy, co-immunolabeling, electroretinography\",\n      \"pmids\": [\"24833722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether mislocalization of cargo is due to microtubule disorganization, gate defect, or IFT disruption was not distinguished\",\n        \"Temporal sequence of degeneration events not fully resolved\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"RT-PCR/NMD assay in patient-derived lymphoblast cultures\",\n      \"pmids\": [\"24651477\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Only two mutations tested; generalizability to all RP28 alleles not confirmed\",\n        \"NMD efficiency in photoreceptors versus lymphoblasts may differ\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast two-hybrid screen of retinal cDNA libraries, co-immunoprecipitation, proximity ligation assay\",\n      \"pmids\": [\"25749990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional significance of the Golgi–centrosomal interactions for photoreceptor biology not tested in vivo\",\n        \"Whether FAM161A travels with Golgi-derived vesicles is unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast two-hybrid with domain mapping, PLA in marmoset retina and HEK293 cells\",\n      \"pmids\": [\"36233334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of disrupting the FAM161A–C8orf37 interaction not assessed\",\n        \"Whether C8orf37 competes with other UPF0564-binding partners is unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"AAV subretinal injection in Fam161a KO mice with ERG, OCT, and immunohistochemistry comparison of vector/promoter combinations\",\n      \"pmids\": [\"38504136\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which the two isoforms cooperate is unknown\",\n        \"Long-term durability of rescue not established\",\n        \"Whether findings translate to human photoreceptors remains to be tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of FAM161A or the UPF0564 domain bound to microtubules\",\n        \"Whether FAM161A directly participates in IFT or acts solely as a structural scaffold is not established\",\n        \"Distinct functions of the long versus short isoform are undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 3, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 3, 8, 10]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 3, 10]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CEP290\",\n      \"LCA5\",\n      \"OFD1\",\n      \"SDCCAG8\",\n      \"C8orf37\",\n      \"AKAP9\",\n      \"NIN\",\n      \"FAM161B\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}