Mutations in POGLUT1 in Galli–Galli/Dowling–Degos disease

DEAR EDITOR, The group of reticulate pigmentary disorders includes the rare autosomal dominant Dowling–Degos disease (DDD) and Galli–Galli disease (GGD; OMIM 179850, 615327 and 615696). 1 In light of substantial clinical, histological and mutational overlap between GGD and DDD, they are considered to belong to the same entity. 2,3 Mutations in KRT5 (encoding keratin 5) have been associated with GGD/DDD since 2006. With the development of whole-exome sequencing, mutations in POFUT1 (encoding protein O-fucosyltransferase 1) 6,7 and POGLUT1 (encoding protein O-glucosyltransferase 1) 8 have been shown to underlie some cases of GGD/DDD. We report mutations in POGLUT1 in three families of European ancestry. In family 1 the mother presented, aged 75 years, with a 40-year history of reticulate hyperpigmented scaling plaques on the neck, lateral proximal arms, proximal legs and popliteal fossae (Fig. 1a, b). Light microscopy revealed epidermal acan-thosis, hypergranulosis and hyperkeratosis with parakeratosis and suprabasilar acantholysis (Fig. 1c). Direct DNA sequencing of KRT5 was negative for mutations. A whole-exome sequenc-ing approach was taken using DNA from the affected mother (Appendix S1 and Table S1; see Supporting Information). During this time mutations were reported in POFUT1 and POGLUT1. A previously reported heterozygous nonsense mutation was identified in POGLUT1, p.Arg218*; c.652C>T, and confirmed by Sanger sequencing. The mutation was identified in her affected son but not in two unaffected daughters. A second family with GGD/DDD, present in two generations, was also negative for KRT5 mutation. The proband was a 40-year-old man who progressively developed, starting from adolescence , small red-brown macular and papular crusted lesions (Fig. 1d). His father had similar clinical features (Fig. 1e). Light microscopy showed filiform digitate downgrowth of epidermal rete ridges, presence of small horn cysts, apical acantholysis and parakeratosis with a moderate dermal inflammatory infiltrate (Fig. 1f). POFUT1 and POGLUT1 were screened by Sanger sequencing (Appendix S1). A previously unreported heterozy-gous missense mutation was identified in POGLUT1, p.Gly170-Glu; c.509G>A, in the affected father and affected son, but not in the unaffected mother or unaffected brother (Fig. 2a, b). p.Gly170 is highly conserved in the encoded enzyme across species. In silico prediction tools, MutationTaster A 52-year-old woman, in family 3, presented at age 50 years with a 10-year history of multiple, sometimes itchy, small red-brown scaly lesions. These started on her legs then spread onto her forearms with a few lesions on her trunk (Fig. 1g–j). Her mother had similar lesions. Light microscopy of different skin …