Skin disease‐associated <i>GJB4</i> variants differentially influence connexin stability, cell viability and channel function
Bibliographic record
Abstract
Abstract Here we characterize seven Cx30.3 gene variants (R22H, S26Y, P61R, C86S, E99K, T130M and M190L) clinically associated with the rare skin disorder erythrokeratodermia variabilis et progressiva (EKVP) in tissue‐relevant and differentiation‐competent rat epidermal keratinocytes (REKs). We found that all variants, when expressed alone or together with wildtype (WT) Cx30.3, had the capacity to traffic and form gap junctions with an efficiency like WT Cx30.3. Cx30.3 was found to have a slower relative turnover than Cx43. However, turnover was more rapid for the R22H and P61R variants relative to Cx30.3. Furthermore, REKs that expressed the P61R variant exhibited reduced viability and were more permeable to fluorescent dyes, indicative of leaky hemichannels and/or the loss of membrane integrity associated with cell death. In connexin‐null AD‐293 cells, dual patch clamp studies revealed that the variants had either reduced (C86S) or no (S26Y and T130M) gap junction channel function. The remaining variants formed functional gap junction channels with enhanced transjunctional voltage (Vj)‐dependent gating. Moreover, WT Cx30.3 and functional variant gap junction channels had similar unitary conductance of ∼34–42 pS, though variant channels appeared to have lower open probability than WT Cx30.3 channels at high Vjs. In conclusion, EKVP‐associated Cx30.3 variants each alter one or more Cx30.3 characteristics although the molecular changes identified for E99K were limited to enhanced Vj gating. The breadth of molecular changes identified may all be sufficient to cause EKVP, but this remains to be firmly established as more familial patients are genotyped for these variants. image Key points Here we characterize seven Cx30.3 variants (R22H, S26Y, P61R, C86S, E99K, T130M and M190L) that have been clinically associated with the rare skin disorder erythrokeratodermia variabilis et progressiva (EKVP). We discovered human Cx30.3 undergoes relatively slow turnover compared with Cx43 and exhibits kinetically slow and limited voltage gating. Wildtype Cx30.3 and all variants localized to intracellular compartments and gap junctions in rat epidermal keratinocytes. Each EKVP‐associated Cx30.3 variant altered one or more Cx30.3 characteristics related to protein stability, cell viability and/or channel function. The breadth of molecular changes identified for each Cx30.3 variant may independently be sufficient to cause EKVP, but this remains to be firmly established through additional genetic and molecular analysis.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".