| Gene / protein | DDD subtype / MIM (if supported) | Variant / mechanism | Typical phenotype distribution | Evidence / model | Key source / date / PMID or DOI |
|---|---|---|---|---|---|
| **KRT5 / keratin 5** | Established causal gene; classic DDD included under **MIM 179850** | Loss-of-function / haploinsufficiency; landmark variants **c.418dupA (p.Ile140Asnfs*39)** and **c.14C>A (p.Ser5*)**. 2024 founder study showed recurrent **c.418dup** on a shared haplotype in multiple apparently unrelated families. Mechanistically linked to epithelial remodeling, melanosome mistargeting, and altered perinuclear keratin organization. | Typically **large body folds / flexures**, plus **trunk, neck, face**; postpubertal progressive reticulate hyperpigmentation with hyperkeratotic papules, sometimes pruritus. | Human pedigrees + histopathology + electron microscopy + transfected cell studies; founder haplotype analysis in >120 unrelated DDD cases/families. | Betz **2006**, *Am J Hum Genet*; DOI: https://doi.org/10.1086/500850; PMID **16465624** (pqac-00000004, pqac-00000005, pqac-00000016). Kumar et al. **2024**, *J Invest Dermatol*; DOI: https://doi.org/10.1016/j.jid.2023.04.036 (pqac-00000012, pqac-00000013) |
| **POFUT1 / protein O-fucosyltransferase 1** | Established causal gene; DDD subtype listed in 2024 synthesis among **MIM 615327 / 615696 / 613736** disease spectrum, but exact subtype-to-gene mapping not fully resolved in available context | Loss-of-function / presumed haploinsufficiency affecting **O-fucosylation of Notch receptors** and downstream Notch signaling. Referenced prior knockdown studies in **zebrafish larvae** and **keratinocyte-origin cells** showing differential expression of Notch-pathway genes. | Often reported with **acro-genital involvement**; generalized reticulate hyperpigmentation may occur. | Human genetic association from prior primary studies summarized in 2024 dissertation; comparative functional evidence from zebrafish and keratinocyte knockdown literature. | Kumar **2024** dissertation summary; DOI: https://doi.org/10.48565/bonndoc-397 (pqac-00000010, pqac-00000014). Open Targets disease-target evidence citing PMIDs **23684010**, **25229252**, **25639155** (pqac-00000000) |
| **POGLUT1 / protein O-glucosyltransferase 1** | Established causal gene; DDD subtype listed in 2024 synthesis within **MIM 179850 / 615327 / 615696 / 613736** spectrum; exact mapping not fully explicit in available context | Loss-of-function / presumed haploinsufficiency affecting **O-glucosylation of Notch receptors**. Representative founder / recurrent variants from 2024 haplotype study: **c.652C>T (p.Arg218*)**, **c.798-2A>C**, **c.835C>T (p.Arg279Trp)**, **c.1051C>T (p.Gln351*)**, **c.205C>T (p.Arg69*)**, **c.1080_1081insG (p.Asn361Glufs*5)**, **c.11G>A (p.Trp4*)**. 2023 transcriptomic mechanism: POGLUT1 knockdown in melanocyte-derived cells altered Notch-pathway gene expression and reduced cleaved Notch1 activity. | Often reported with **extremity-predominant hyperpigmentation**; face/trunk may also be involved. | Human founder haplotype analysis; **MZ7-mel melanocyte** and **HaCaT keratinocyte** siRNA knockdown with RNA-seq / pathway analysis / cleaved Notch1 ELISA. | Kumar et al. **2024**, *J Invest Dermatol*; DOI: https://doi.org/10.1016/j.jid.2023.04.036 (pqac-00000012, pqac-00000013). Kumar et al. **2023** transcriptomic study summarized in 2024 dissertation; DOI: https://doi.org/10.48565/bonndoc-397 (pqac-00000001, pqac-00000011, pqac-00000012, pqac-00000014, pqac-00000015) |
| **PSENEN / PEN-2, gamma-secretase subunit** | Established causal gene; DDD subtype listed in 2024 synthesis within **MIM 179850 / 615327 / 615696 / 613736** spectrum; exact subtype mapping not explicit in available context | Loss-of-function / presumed haploinsufficiency impairing **gamma-secretase-mediated Notch receptor cleavage**. Also linked to **DDD with hidradenitis suppurativa (acne inversa)** in susceptible individuals. 2023 transcriptomic mechanism: PSENEN knockdown in melanocyte-derived cells reduced Notch signaling, with enrichment of **Notch**, **ESR**, **RTK signaling**, and **membrane trafficking** pathways. | DDD pigmentation phenotype with potential **HS overlap**, especially in intertriginous sites; classic DDD may involve face, trunk, flexures. | Human clinical genetics + overlap phenotype reports; melanocyte / keratinocyte siRNA knockdown transcriptomics and functional Notch assay. | Ralser et al. / summarized in Kumar **2024** dissertation; DOI: https://doi.org/10.48565/bonndoc-397 (pqac-00000010, pqac-00000011, pqac-00000014, pqac-00000015). Open Targets cites PMID **28287404** for PSENEN-DDD association (pqac-00000000) |
| **NCSTN / nicastrin** | **Not established** as canonical DDD gene in available disease-level resources; **emerging HS-DDD overlap report** | Reported **loss-of-function NCSTN mutation** in a familial phenotype combining **hidradenitis suppurativa and DDD**, supporting shared **Notch/gamma-secretase pathway** biology rather than established isolated DDD causation. | Overlap phenotype with **HS in intertriginous regions** plus clinical / histologic DDD features; not enough evidence in current context to define a standalone DDD distribution pattern. | Case-report / familial overlap evidence only; should be interpreted as **emerging** and not equivalent to the four established DDD genes. | Garcovich et al. **2020**, *Br J Dermatol*; DOI: https://doi.org/10.1111/bjd.19121 (pqac-00000007). Additional 2023 NCSTN-HS-DDD overlap paper listed in search results but unobtainable in full context (pqac-00000001) |
| **Shared 2023 molecular mechanism across Notch-pathway DDD genes** | Not a subtype entry; cross-gene mechanism most directly tested for **POGLUT1** and **PSENEN** | In **melanocyte-derived MZ7-mel cells**, siRNA knockdown caused differential expression of multiple **Notch signaling** genes, significant pathway enrichment, and **reduced cleaved Notch1**; downstream candidate pathways: **estrogen receptor signaling**, **receptor tyrosine kinase signaling**, and **membrane trafficking**. HaCaT keratinocytes showed altered expression but no clear Notch pathway enrichment. | Provides a mechanistic explanation for **hyperpigmentation**, pointing to melanocyte-centered dysregulation rather than a purely keratinocyte-intrinsic pigment defect. | In vitro transcriptomics / pathway analysis / ELISA; not yet a validated clinical biomarker or therapy target. | Kumar et al. **2023** research letter summarized in dissertation **2024**; DOI: https://doi.org/10.48565/bonndoc-397 (pqac-00000001, pqac-00000011, pqac-00000012, pqac-00000014, pqac-00000015, pqac-00000022) |


*Table: This compact table summarizes the core gene-level knowledge base for Dowling-Degos disease, including established causal genes, representative variants, phenotype patterns, and the recent Notch-centered mechanistic evidence. It also separates NCSTN as an emerging hidradenitis suppurativa–DDD overlap finding rather than a fully established canonical DDD gene.*