SEC61A1

SEC61A1 encodes the α-subunit of the Sec61 translocon, the ER-membrane channel through which nascent polypeptides are translocated cotranslationally, and disease-associated variants converge on loss of this translocation function with downstream ER calcium dysregulation (PMID:28782633). Heterozygous missense variants cause distinct molecular fates: p.Thr185Ala and p.Val67Gly mislocalize the protein to the Golgi rather than the ER (PMID:27392076), whereas p.Arg236Cys is retained in the ER but undergoes increased proteasomal degradation, lowering SEC61A1 levels and impairing biosynthesis of the client protein polycystin-2 (PMID:36478640). Functionally, the p.V85D variant is deficient in cotranslational translocation, perturbs cellular calcium homeostasis, and drives the terminal unfolded protein response in plasma-cell models (PMID:28782633), and the R236C variant produces ER-to-cytoplasm calcium leakiness together with reduced autophagy, cAMP synthesis, and secretion and increased cell death under oxidative stress (PMID:38664472). Independently of inherited disease, SEC61A1 is the essential host channel through which the toxin mycolactone triggers eIF2α phosphorylation and caspase-dependent apoptosis (PMID:35939511). These findings establish ADTKD and polycystic liver/kidney phenotypes as direct consequences of translocon dysfunction (PMID:27392076, PMID:36478640).

1. 2016 High

   Established that SEC61A1 missense variants are pathogenic by demonstrating they disrupt the protein's normal ER residence, pointing to defective translocation across the ER membrane as the disease mechanism.

   Evidence Transient expression of mutant constructs with subcellular localization, patient renal biopsy immunostaining, and zebrafish loss-of-function with human mRNA rescue

   PMID:27392076

   Open questions at the time

   • Does not directly measure translocation defect for the Golgi-mislocalized variants
   • Mechanism linking mislocalization to specific client failures not defined
2. 2017 High

   Connected a specific variant to a measurable loss of translocon function, showing impaired cotranslational translocation, disturbed calcium homeostasis, and terminal UPR as the basis of plasma-cell deficiency.

   Evidence In vitro cotranslational translocation assay, calcium measurement in HeLa cells, and UPR reporter assays in multiple myeloma lines

   PMID:28782633

   Open questions at the time

   • Single-lab study
   • Does not establish whether calcium dysregulation is cause or consequence of UPR activation
3. 2022 Medium

   Revealed an alternative molecular fate—proteasomal degradation rather than mislocalization—linking reduced SEC61A1 abundance to decreased polycystin-2 biosynthesis and polycystic liver/kidney disease.

   Evidence Immunoblot of immortalized patient urine cells, proteasomal degradation assay, and ER localization analysis

   PMID:36478640

   Open questions at the time

   • Single lab, not independently replicated
   • Direct mechanism by which reduced SEC61A1 selectively limits PC2 biosynthesis not resolved
4. 2022 High

   Identified SEC61A1 as the essential host channel mediating mycolactone toxicity, extending its role beyond inherited disease to toxin-induced ER stress and apoptosis.

   Evidence Genome-scale lenti-CRISPR screen and targeted CRISPR/Cas9 knockout in THP-1 cells with eIF2α phosphorylation and apoptosis readouts

   PMID:35939511

   Open questions at the time

   • Does not resolve the direct biochemical interaction between mycolactone and Sec61
   • Generality across other cell types not established here
5. 2024 Medium

   Defined the broad cellular consequences of a single variant across two patient-derived platforms, tying ER calcium leakiness to downstream defects in autophagy, cAMP, secretion, and stress-induced cell death.

   Evidence Immortalized patient urine cells and iPSC-derived cholangiocyte progenitor-like cells with calcium, autophagy, cAMP, secretion, and apoptosis/necrosis assays

   PMID:38664472

   Open questions at the time

   • Single lab
   • Causal ordering among calcium leak, autophagy reduction, and apoptosis not established

• How distinct variants produce divergent molecular fates (Golgi mislocalization vs. ER-retained degradation) yet converge on overlapping calcium and translocation phenotypes remains unresolved.
• No structural model relating variant position to channel dysfunction in the corpus
• Mechanism dictating which clients are preferentially affected not defined