Mutations in POGLUT1, Encoding Protein O-Glucosyltransferase 1, Cause Autosomal-Dominant Dowling-Degos Disease

Abstract

Dowling-Degos disease (DDD) is an autosomal-dominant genodermatosis characterized by progressive and disfiguring reticulate hyperpigmentation. We previously identified loss-of-function mutations in KRT5 but were only able to detect pathogenic mutations in fewer than half of our subjects. To identify additional causes of DDD, we performed exome sequencing in five unrelated affected individuals without mutations in KRT5. Data analysis identified three heterozygous mutations from these individuals, all within the same gene. These mutations, namely c.11G>A (p.Trp4*), c.652C>T (p.Arg218*), and c.798-2A>C, are within POGLUT1, which encodes protein O-glucosyltransferase 1. Further screening of unexplained cases for POGLUT1 identified six additional mutations, as well as two of the above described mutations. Immunohistochemistry of skin biopsies of affected individuals with POGLUT1 mutations showed significantly weaker POGLUT1 staining in comparison to healthy controls with strong localization of POGLUT1 in the upper parts of the epidermis. Immunoblot analysis revealed that translation of either wild-type (WT) POGLUT1 or of the protein carrying the p.Arg279Trp substitution led to the expected size of about 50 kDa, whereas the c.652C>T (p.Arg218*) mutation led to translation of a truncated protein of about 30 kDa. Immunofluorescence analysis identified a colocalization of the WT protein with the endoplasmic reticulum and a notable aggregating pattern for the truncated protein. Recently, mutations in POFUT1, which encodes protein O-fucosyltransferase 1, were also reported to be responsible for DDD. Interestingly, both POGLUT1 and POFUT1 are essential regulators of Notch activity. Our results furthermore emphasize the important role of the Notch pathway in pigmentation and keratinocyte morphology.

O-Glycosylation modulates the stability of epidermal growth factor-like repeats and thereby regulates Notch trafficking

“…All three enzymes modify multiple EGF repeats in the extracellular domain of the Notch receptor (12)(13)(14), and these modifications are essential for optimal Notch activity (15)(16)(17). Human diseases result from inactivating mutations in these enzymes and appear to be mediated by reduced Notch function (17)(18)(19)(20). O-Glucose can be elongated by xylosyltransferases (GXYLT1/2 and XXYLT1) to form the trisaccharide Xyl␣1-3Xyl␣1-3Glc, and O-fucose can be elongated by Fringe enzymes (LFNG, MFNG, and RFNG) to ultimately form the tetrasaccharide Sia␣2-6Gal␤1-4GlcNAc␤1-3Fuc (21)(22)(23)(24).…”

Membrane dynamics in mammalian embryogenesis: Implication in signal regulation

“…The loss of expression of Crumbs2 in plasma membrane leads to developmental arrest at the gastrulation stage, due to severe defects in epithelium-mesenchymal transition. The activity of POGLUT-1 is implicated in various disorders in humans, such as Dowling-Degos disease 4 (OMIM 61596), an autosomal dominant genetic disorder that exhibits hyperpigmentation in skin (Basmanav et al, 2014). Furthermore, its overexpression is often associated with carcinogenesis (Ma et al, 2011;Chu et al, 2013;Jin et al, 2014).…”

Dermatose en terre sèche : aspects anatomo-cliniques

“…Elle est liée à une mutation perte de fonction du gène de la kératine 5 [23] chez moins de la moitié des patients. D'autres gènes ont été mis en évidence, notamment POFUT1 [24] et POGLUT1 [25], impliqués dans la régulation de la pigmentation et la différentiation kératinocytaire.…”