PMC5324688_01
Clinical findings. (a, b) Reticulate hyperpigmented scaling plaques on the proximal legs of the proband of family 1. (c) Light microscopy of three punch biopsies from the proband of family 1 revealed similar findings of filiform digitate downgrowth of the epidermal rete ridges, presence of small horn cysts, epidermal acanthosis, hypergranulosis, and hyperkeratosis with parakeratosis and suprabasilar acantholysis. (d) Small red-brown macules and crusted papules widely distributed over the trunk, neck, back, abdomen and limbs of the proband of family 2. The large body folds, hands and feet, and face were spared. (e) The father of the proband of family 2 had similar clinical features, limited to the neck region without involvement of the large flexures. (f) Light microscopy shows some apical acantholysis and parakeratosis with a moderate dermal inflammatory infiltrate. (g-j) The proband of family 3 with multiple small (approximately 5-mm-diameter) red-brown scaly papules, present predominantly on the legs but also on the forearms with some postinflammatory change from previous lesions. (k) Light microscopy from the proband of family 3, a medium-power view showing elongation of the rete ridge and modest inflammatory infiltrate. (l) A medium-power view of a second biopsy from the right anterior thigh. There is an intraepidermal vesicle, as a result of acantholysis of the keratinocytes, some of which show dyskeratosis. Note the elongation of the rete ridges immediately below the vesicle.
BJD-176-270-g001.jpg
PMC5324688_02_BJD-176-270-g001.jpg
bjd14914-fig-0001
These started on her legs then spread onto her forearms with a few lesions on her trunk (Fig. 1g-j). Light microscopy of different skin biopsies variably showed focal hyperkeratosis, focal parakeratosis, acantholysis and elongation of rete ridges with a mild patchy chronic inflammatory infiltrate in the upper dermis (Fig. 1k). One biopsy showed acantholysis, (Fig. 1l).
Mutation analysis and protein modelling. (a) Wild-type POGLUT1 sequence of exon 5 showing nucleotides c.502-516. (b) Equivalent region as in (a) from the proband of family 2, showing the heterozygous mutation c.509G>A leading to missense mutation p.Gly170Glu. (c) Wild-type POGLUT1 sequence showing nucleotides c.850-864 of exon 9. (d) Equivalent region as in (c) from the proband of family 3, showing the heterozygous mutation c.857G>A resulting in missense mutation p.Cys286Tyr. (e) The protein model of human POGLUT1. The enzyme structure is shown in cartoon format with cylinders (cyan) to represent alpha-helices, and arrows (purple) beta-strands that are linked by coils (brown). The residues Gly170, Cys263 and Cys286 are depicted in CPK representation coloured N blue, S yellow, O red and C green. The N-terminal domain consists of residues 1-180. The modelling predicts that each missense mutation, p.Gly170Glu and p.Cys286Tyr, would compromise enzyme activity due to a reduction in stability of the protein fold near the active site.
BJD-176-270-g002.jpg
PMC5324688_02_BJD-176-270-g002.jpg
bjd14914-fig-0002
POGLUT1, p.Cys286Tyr; c.857G>A, in both affected individuals (Fig. 2c, d). PolyPhen-2 and MutationTaster predict this previously unreported variant as disease causing; it is not in the dbSNP, NHLBI Exome Variant Server or ExAC databases. p.Cys286 is highly conserved across a number of species. Using homology modelling, we investigated the effects of the two missense mutations (Fig. 2e).
PMC5324688_02
Clinical findings. (a, b) Reticulate hyperpigmented scaling plaques on the proximal legs of the proband of family 1. (c) Light microscopy of three punch biopsies from the proband of family 1 revealed similar findings of filiform digitate downgrowth of the epidermal rete ridges, presence of small horn cysts, epidermal acanthosis, hypergranulosis, and hyperkeratosis with parakeratosis and suprabasilar acantholysis. (d) Small red-brown macules and crusted papules widely distributed over the trunk, neck, back, abdomen and limbs of the proband of family 2. The large body folds, hands and feet, and face were spared. (e) The father of the proband of family 2 had similar clinical features, limited to the neck region without involvement of the large flexures. (f) Light microscopy shows some apical acantholysis and parakeratosis with a moderate dermal inflammatory infiltrate. (g-j) The proband of family 3 with multiple small (approximately 5-mm-diameter) red-brown scaly papules, present predominantly on the legs but also on the forearms with some postinflammatory change from previous lesions. (k) Light microscopy from the proband of family 3, a medium-power view showing elongation of the rete ridge and modest inflammatory infiltrate. (l) A medium-power view of a second biopsy from the right anterior thigh. There is an intraepidermal vesicle, as a result of acantholysis of the keratinocytes, some of which show dyskeratosis. Note the elongation of the rete ridges immediately below the vesicle.
BJD-176-270-g001.jpg
PMC5324688_02_BJD-176-270-g001.jpg
bjd14914-fig-0001
These started on her legs then spread onto her forearms with a few lesions on her trunk (Fig. 1g-j). Light microscopy of different skin biopsies variably showed focal hyperkeratosis, focal parakeratosis, acantholysis and elongation of rete ridges with a mild patchy chronic inflammatory infiltrate in the upper dermis (Fig. 1k). One biopsy showed acantholysis, (Fig. 1l).
Mutation analysis and protein modelling. (a) Wild-type POGLUT1 sequence of exon 5 showing nucleotides c.502-516. (b) Equivalent region as in (a) from the proband of family 2, showing the heterozygous mutation c.509G>A leading to missense mutation p.Gly170Glu. (c) Wild-type POGLUT1 sequence showing nucleotides c.850-864 of exon 9. (d) Equivalent region as in (c) from the proband of family 3, showing the heterozygous mutation c.857G>A resulting in missense mutation p.Cys286Tyr. (e) The protein model of human POGLUT1. The enzyme structure is shown in cartoon format with cylinders (cyan) to represent alpha-helices, and arrows (purple) beta-strands that are linked by coils (brown). The residues Gly170, Cys263 and Cys286 are depicted in CPK representation coloured N blue, S yellow, O red and C green. The N-terminal domain consists of residues 1-180. The modelling predicts that each missense mutation, p.Gly170Glu and p.Cys286Tyr, would compromise enzyme activity due to a reduction in stability of the protein fold near the active site.
BJD-176-270-g002.jpg
PMC5324688_02_BJD-176-270-g002.jpg
bjd14914-fig-0002
POGLUT1, p.Cys286Tyr; c.857G>A, in both affected individuals (Fig. 2c, d). PolyPhen-2 and MutationTaster predict this previously unreported variant as disease causing; it is not in the dbSNP, NHLBI Exome Variant Server or ExAC databases. p.Cys286 is highly conserved across a number of species. Using homology modelling, we investigated the effects of the two missense mutations (Fig. 2e).