POGLUT1 – Dowling-Degos disease

Dowling-Degos disease (DDD) is an autosomal-dominant reticulate hyperpigmentation disorder characterized by progressive pigmented macules in flexural areas. POGLUT1 encodes protein O-glucosyltransferase 1, a key enzyme for O-glucosylation of EGF repeats in Notch receptors, implicating Notch pathway dysregulation in DDD pathogenesis.

In a cohort study, exome sequencing of five unrelated DDD probands negative for KRT5 mutations identified three heterozygous POGLUT1 variants (c.11G>A (p.Trp4Ter), c.652C>T (p.Arg218Ter), c.798-2A>G) (PMID:24387993). Subsequent screening of additional unexplained DDD cases revealed six more loss-of-function or splice-site mutations, totaling at least 11 affected individuals (PMID:24387993). All variants were heterozygous, consistent with autosomal dominant inheritance and absence of biallelic hits.

The variant spectrum comprises nonsense, frameshift, and canonical splice-site alleles disrupting POGLUT1, with c.798-2A>G being a recurrent splice mutation. These variants are predicted to abolish enzymatic activity, leading to haploinsufficiency in epidermal keratinocytes.

Functional assays demonstrated significantly reduced POGLUT1 immunostaining in patient epidermis and truncated protein products from nonsense alleles; immunofluorescence revealed endoplasmic reticulum aggregation of mutant POGLUT1 (PMID:24387993). In Drosophila, loss of the Rumi enzyme (POGLUT1 ortholog) or individual O-glucose site mutations compromised Notch signaling at elevated temperatures, confirming that O-glucosylation is critical for robust Notch activity (PMID:21771811).

Several single-case reports describe DDD co-presenting with Darier disease and hidradenitis suppurativa, implicating POGLUT1 and related glycosyltransferases in overlapping cutaneous phenotypes, although molecular confirmation was not performed in those studies (PMID:26685052; PMID:33488918).

Integration of genetic and experimental data supports a strong gene–disease association via an autosomal-dominant haploinsufficiency mechanism. Key take-home: POGLUT1 loss-of-function variants reliably diagnose DDD and guide differential evaluation of reticulate hyperpigmentation disorders.

References

• American Journal of Human Genetics • 2014 • Mutations in POGLUT1, encoding protein O-glucosyltransferase 1, cause autosomal-dominant Dowling-Degos disease. PMID:24387993
• Development (Cambridge, England) • 2011 • Multiple O-glucosylation sites on Notch function as a buffer against temperature-dependent loss of signaling. PMID:21771811
• Clinical and Experimental Dermatology • 2016 • Dowling-Degos disease co-presenting with Darier disease. PMID:26685052
• The Journal of Clinical and Aesthetic Dermatology • 2020 • Hidradenitis Suppurativa Associated with Galli-Galli Disease: Extending the Link with Dowling-Degos Disease. PMID:33488918

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