TZMP1 (transition zone microprotein 1; formerly SMIM27, C9orf133, TOPORS-AS1) is a 55-amino-acid vertebrate microprotein with a single predicted transmembrane helix, encoded on chromosome 9 by a transcript antisense to and partially overlapping TOPORS that was previously annotated as a long non-coding RNA. The protein localizes to the ciliary transition zone, just distal to FAM92A and the distal-appendage protein CEP164, and co-purifies with components of the MKS (Meckel syndrome) transition-zone module, including MKS1, B9D1/2, TCTN1/2/3, TMEM231, TMEM17 and CC2D2A. Its transition-zone localization depends on TMEM67, whereas FAM92A, MKS1 and TCTN1 remain at the transition zone without it, placing TZMP1 downstream in the MKS module hierarchy. In human RPE1 cells TZMP1 is required for primary cilium assembly at a late step: mother-centriole uncapping, intraflagellar transport recruitment and ciliary vesicle formation occur, but ciliary membrane growth and axoneme extension fail. Loss of the mouse orthologue impairs ciliogenesis in fibroblasts, and depletion of the Xenopus tropicalis orthologue reduces and immobilizes motile cilia of epidermal multiciliated cells and disrupts left-right patterning. No molecular activity has been defined.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0035869 ciliary transition zone | IMP PMID:41270742 A microscopy-based CRISPR screening platform enables organel... | ACCEPT | Summary: A rescue-validated, epitope-tagged TZMP1 transgene localizes to the base of the cilium and, by expansion microscopy, to the transition zone just distal to FAM92A and CEP164. The localization requires TMEM67. Reason: The term is correct and is the core location of TZMP1. The evidence is direct imaging of a functional tagged protein, so IDA would describe it better than IMP, but the assertion itself is sound. All MKS-module comparators checked (TMEM67, MKS1, CEP290, TCTN1, TMEM231, B9D1) carry the same term. Supporting Evidence: PMID:41270742 we found that SMIM27 localizes at the transition zone, just distal to transition zone protein FAM92A and centriolar distal appendage protein CEP164 PMID:41270742 knockout of TMEM67, an MKS gene not strictly required for ciliogenesis (Figure 4D–E), led to loss of SMIM27-2xMyc localization at the transition zone |
| GO:0060170 ciliary membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping (cilium membrane), based on the transition-zone localization in PMID:41270742 together with a predicted single transmembrane helix. Reason: The transition zone membrane is a specialized domain of the ciliary membrane, and TZMP1 is a predicted single-pass membrane protein that co-purifies with membrane-anchored MKS-module proteins (TMEM231, TMEM17, TCTN1-3). The mapping is consistent, and comparators TMEM67 and TMEM231 carry the same term. The membrane topology itself is predicted, not tested, and the transition zone term is the more precise location. Supporting Evidence: PMID:41270742 recently shown to encode a 55 amino acid protein with a single predicted transmembrane domain |
| GO:0060271 cilium assembly | IMP PMID:41270742 A microscopy-based CRISPR screening platform enables organel... | ACCEPT | Summary: TZMP1 knockout in RPE1 cells (sgRNAs in exon 2, not overlapping TOPORS) causes a severe loss of cilia that is fully rescued by an sgRNA-resistant transgene. The block is at a late step: ciliary vesicle formation, CP110 removal and IFT recruitment proceed, but ciliary membrane growth and axoneme extension fail. Mouse fibroblast knockout and Xenopus morphants confirm a conserved requirement. Reason: Clean knockout/rescue evidence that excludes the overlapping TOPORS gene. On participation: TZMP1 is a structural component of the transition-zone MKS module at the site where the ciliary membrane grows, the same role in which MKS1, TMEM67, TCTN1, TMEM231, B9D1 and CEP290 all carry GO:0060271. So the annotation follows the established convention for transition-zone components and is not a downstream-necessity inference. Supporting Evidence: PMID:41270742 SMIM27 KO cells exhibited a severe loss of cilia labeled by Arl13b or polyglutamylated tubulin, and these defects were fully rescued by an sgRNA-resistant SMIM27-2xMyc transgene PMID:41270742 Thus, the ciliary vesicle can likely form in the absence of TZMP1, but ciliary membrane growth and axoneme extension fail to occur. PMID:41270742 we knocked out Smim27 in mouse NIH-3T3 cells and observed impaired ciliogenesis, although to a lesser degree than in RPE1 cells |
| GO:0036038 MKS complex | IDA PMID:41270742 A microscopy-based CRISPR screening platform enables organel... | NEW | Summary: Affinity purification and mass spectrometry of tagged TZMP1 from knockout-rescued RPE1 cells recovered many MKS-complex components (MKS1, B9D1/2, TCTN1/2/3, TMEM231, TMEM17, CC2D2A), scored as specific when found in two replicate TZMP1 purifications but not in a negative control purification. TZMP1 co-localizes with these proteins at the transition zone and depends on TMEM67 for its localization. Reason: The basis is direct evidence for TZMP1 itself. Tagged TZMP1 co-purified MKS1, B9D1/2, TCTN1-3, TMEM231, TMEM17 and CC2D2A by mass spectrometry, it localizes to the transition zone where the MKS module sits and needs TMEM67 to get there, and UniProt records the subunit relationship (SUBUNIT, ECO:0000269 PubMed:41270742) without a corresponding GO row. The evidence is co-purification plus transition-zone localization rather than reconstitution or a structure, so confidence is moderate. It is the authors' explicit conclusion and the same kind of evidence on which other MKS-module members were assigned. As a consistency check, TMEM67, MKS1, CEP290, TCTN1, TMEM231 and B9D1 all carry part_of GO:0036038. Supporting Evidence: PMID:41270742 mass spectrometry of proteins co-purifying with SMIM27-HRV3C-2xMyc revealed many components of the MKS protein complex PMID:41270742 Specific interactors of SMIM27 were defined as proteins found in two replicate purifications of SMIM27 but not in a negative control purification PMID:41270742 Thus, SMIM27 is a transition zone microprotein component of the MKS complex, and we propose the revised name TZMP1. |
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Download this section (compressed HTML)Q: Does TZMP1 bind the MKS module directly, and through which partner (e.g. TMEM67, TMEM231 or TMEM17)? AP-MS cannot distinguish direct from indirect association, and the answer would support or replace the MKS complex assignment.
Q: Is TZMP1 a Meckel-Gruber, Joubert or related ciliopathy gene? The authors name it a candidate, but no patient variants have been reported, and the small antisense locus is easily missed by exome pipelines.
Q: Is the TOPORS-AS1 RNA function reported in ovarian cancer cells separable from the encoded peptide, or do those overexpression results partly reflect TZMP1 protein?
Experiment: Determine membrane topology and test whether the transmembrane helix is required for transition-zone targeting and ciliogenesis rescue (helix-swap or deletion mutants in TZMP1 knockout RPE1 cells).
Experiment: Map direct partners within the MKS module by pairwise co-immunoprecipitation in cells lacking individual MKS genes, or by crosslinking mass spectrometry.
Experiment: Generate a Tzmp1 knockout mouse to test for ciliopathy phenotypes (cystic kidney, polydactyly, CNS malformation, laterality defects).
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