| Evidence type | System | Perturbation | Readouts | Key quantitative results (n, resolution, kDa, patient counts) | Interpretation for EMC9 function | Source (with URL) |
|---|---|---|---|---|---|---|
| Biochemical/structural | Recombinant human proteins; native human EMC cryo-EM map | Reconstitution of EMC2 with EMC9; EMC8 added to pre-formed EMC2·EMC9 complex | SEC-MALS complex formation; cryo-EM docking of EMC2·EMC9 into EMC density; substrate-binding vestibule placement | EMC2·EMC9 formed a stable 1:1 complex at expected ~59 kDa; EMC8 monomer ~23 kDa; no ternary EMC2·EMC9·EMC8 complex detected; full EMC map used for positioning at 6.4 Å (pqac-00000006, pqac-00000015, pqac-00000020) | EMC9 is a cytosolic EMC subunit that binds EMC2 directly and likely occupies the EMC8/9 slot in a mutually exclusive manner, contributing to the cytosolic vestibule that engages client TMDs (pqac-00000006, pqac-00000015, pqac-00000020) | O'Donnell et al., 2020, eLife, https://doi.org/10.7554/eLife.57887 (pqac-00000006, pqac-00000015, pqac-00000020) |
| Biochemical/client-binding | Recombinant EMC2·EMC8 and EMC2·EMC9 complexes | In vitro substrate-binding assays with EMC2·EMC8 or EMC2·EMC9 | Ability of complexes to bind client transmembrane domains and protect them from aggregation | Both EMC2·EMC8 and EMC2·EMC9 were reported to bind substrate TMDs; EMC8 and EMC9 are ~44% identical in mammals (pqac-00000020) | EMC9 is functionally competent in the cytosolic client-engagement module and can substitute for EMC8 in early TMD handling at least in vitro (pqac-00000020) | O'Donnell et al., 2020, eLife, https://doi.org/10.7554/eLife.57887 (pqac-00000020) |
| Structural/mechanistic context for EMC8/9 module | Human EMC bound to CaV1.2–CaVβ3 | Cryo-EM structure of EMC-client complex | Identification of TM dock and Cyto dock; client interaction through cytosolic domain | EMC–CaV complex ~0.6 MDa; structures solved at 3.4 Å and 3.3 Å; Cyto dock involves EMC2 and EMC8 regions (pqac-00000023, pqac-00000024) | Although EMC9 was not directly visualized, the structure demonstrates that the EMC2–EMC8/9 cytosolic module can participate directly in client binding and channel assembly, supporting functional annotation of EMC9 by paralogy and alternative complex occupancy (pqac-00000023, pqac-00000024) | Chen et al., 2023, Nature, https://doi.org/10.1038/s41586-023-06175-5 (pqac-00000023, pqac-00000024) |
| Human genetic/clinical | Human patients/families compiled from literature | Putatively damaging EMC9 and EMC10 variants associated with congenital anomalies | Clinical phenotype aggregation | Table summarized mutations in EMC9/EMC10 in 18 individuals from 10 families; reported phenotypes included congenital heart disease, neurodevelopmental delay, and craniofacial dysmorphology (pqac-00000013, pqac-00000022) | Human genetic evidence supports EMC9 as disease-relevant and non-dispensable in development, consistent with a role in membrane-protein topogenesis rather than a redundant accessory factor (pqac-00000013, pqac-00000022) | Marquez et al., 2023, genesis, https://doi.org/10.1002/dvg.23520 (pqac-00000013, pqac-00000022) |
| Model organism developmental genetics | Xenopus tropicalis embryos/tadpoles | CRISPR/Cas9 F0 emc9 loss of function targeting exon 2 | sox10 whole-mount in situ hybridization; craniofacial cartilage staining; motility assay; neuromuscular AChR labeling | sox10 assay n=60/condition over 3 replicates; cartilage assay n=60/condition over 3 replicates; motility control n=30 and emc9-depleted n=30 over 3 replicates; sparse nAChR signal in n=30 animals (pqac-00000013, pqac-00000019) | emc9 depletion disrupts neural crest development, craniofacial morphogenesis, and neuromuscular organization, indicating EMC9 is required for developmental programs dependent on proper membrane protein biogenesis (pqac-00000013, pqac-00000019) | Marquez et al., 2023, genesis, https://doi.org/10.1002/dvg.23520 (pqac-00000013, pqac-00000019) |
| Model organism mechanistic signaling evidence | Xenopus tropicalis tadpoles | CRISPR/Cas9 emc9 depletion | Immunoblotting for Fzd7 and nuclear β-catenin | Pooled immunoblots used n=30 per stage per condition; emc9 depletion decreased Fzd7 and markedly reduced nuclear β-catenin (pqac-00000013, pqac-00000019, pqac-00000022) | Supports a mechanism in which EMC9 loss impairs biogenesis/stability of transmembrane signaling proteins, with downstream reduction in WNT signaling output (pqac-00000013, pqac-00000019, pqac-00000022) | Marquez et al., 2023, genesis, https://doi.org/10.1002/dvg.23520 (pqac-00000013, pqac-00000019, pqac-00000022) |
| Review-backed localization/family evidence | Mammalian/human EMC literature synthesis | None (review synthesis) | Sequence/topology and complex-organization summaries | EMC9 reported as ~208 aa or ~23 kDa; EMC8 and EMC9 share ~40% sequence identity; cytosolic/peripheral localization with EMC2 at the cytoplasmic face of ER-resident EMC (pqac-00000002, pqac-00000004, pqac-00000007) | Supports the core functional annotation that EMC9 is not an enzyme or transporter but a soluble EMC subunit contributing to ER membrane protein insertion/biogenesis machinery (pqac-00000002, pqac-00000004, pqac-00000007) | Volkmar & Christianson, 2020, https://doi.org/10.1242/jcs.243519; Chitwood & Hegde, 2019, https://doi.org/10.1016/j.tcb.2019.01.007 (pqac-00000002, pqac-00000004, pqac-00000007) |
| Database curation status | Open Targets | None | Disease-target evidence coverage | One generic “genetic disorder” association row with score 0 and no supporting evidence rows (pqac-00000000) | Curated target-disease annotation for EMC9 remains sparse despite emerging primary literature, so disease interpretation currently depends more on individual genetic/developmental studies than on mature target databases (pqac-00000000) | Open Targets Platform, https://platform.opentargets.org/target/ENSG00000100908 (pqac-00000000) |


*Table: This table compiles supported EMC9-specific experimental and disease evidence across biochemical, structural, genetic, and developmental studies. It helps distinguish directly demonstrated EMC9 findings from broader EMC or EMC8/9-module inferences.*