Mutations in POFUT1, Encoding Protein O-fucosyltransferase 1, Cause Generalized Dowling-Degos Disease

Abstract

Dowling-Degos disease (DDD), or reticular pigmented anomaly of the flexures, is a type of rare autosomal-dominant genodermatosis characterized by reticular hyperpigmentation and hypopigmentation of the flexures, such as the neck, axilla, and areas below the breasts and groin, and shows considerable heterogeneity. Loss-of-function mutations of keratin 5 (KRT5) have been identified in DDD individuals. In this study, we collected DNA samples from a large Chinese family affected by generalized DDD and found no mutation of KRT5. We performed a genome-wide linkage analysis of this family and mapped generalized DDD to a region between rs1293713 and rs244123 on chromosome 20 [corrected]. By exome sequencing, we identified nonsense mutation c.430G>T (p.Glu144(∗)) in POFUT1, which encodes protein O-fucosyltransferase 1, in the family. Study of an additional generalized DDD individual revealed the heterozygous deletion mutation c.482delA (p.Lys161Serfs(∗)42) in POFUT1. Knockdown of POFUT1 reduces the expression of NOTCH1, NOTCH2, HES1, and KRT5 in HaCaT cells. Using zebrafish, we showed that pofut1 is expressed in the skin and other organs. Morpholino knockdown of pofut1 in zebrafish produced a phenotype characteristic of hypopigmentation at 48 hr postfertilization (hpf) and abnormal melanin distribution at 72 hpf, replicating the clinical phenotype observed in our DDD individuals. At 48 and 72 hpf, tyrosinase activities decreased by 33% and 45%, respectively, and melanin protein contents decreased by 20% and 25%, respectively. Our findings demonstrate that POFUT1 mutations cause generalized DDD. These results strongly suggest that the protein product of POFUT1 plays a significant and conserved role in melanin synthesis and transport.

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

“…12 Additionally, recent studies of two Chinese families with DDD led to the identification of mutations in POFUT1 (MIM 607491), which encodes protein O-fucosyltransferase 1 from the Notch pathway. 13 Here, we describe the identification of nine different mutations in POGLUT1 (RefSeq accession number NM_152305.2) from 13 unrelated individuals with DDD. POGLUT1 encodes protein O-glucosyltransferase 1 and is a part of the Notch signaling pathway.…”

Familial Disseminated Comedones without Dyskeratosis: Report of an Affected Family and Review of the Literature

“…Patients with Dowling-Degos disease are characterized by the typical reticulated hyper- and/or hypopigmentation in the flexural regions [16], which were not seen in our patients. Further genetic studies on the reported POFUT1 mutations encoding protein O-fucosyltransferase 1 can further exclude the diagnosis [17]. The absence of contact history to dioxins and of atrophy of the sebaceous gland in histology makes the diagnosis of MADISH unlikely [18].…”

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).…”