Hiroyuki Takama

PNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis

Mutations in patatin-like phospholipase domain-containing 1 (PNPLA1) cause autosomal recessive congenital ichthyosis, but the mechanism involved remains unclear. Here we show that PNPLA1, an enzyme expressed in differentiated keratinocytes, plays a crucial role in the biosynthesis of ω-O-acylceramide, a lipid component essential for skin barrier. Global or keratinocyte-specific Pnpla1-deficient neonates die due to epidermal permeability barrier defects with severe transepidermal water loss, decreased intercellular lipid lamellae in the stratum corneum, and aberrant keratinocyte differentiation. In Pnpla1−/− epidermis, unique linoleate-containing lipids including acylceramides, acylglucosylceramides and (O-acyl)-ω-hydroxy fatty acids are almost absent with reciprocal increases in their putative precursors, indicating that PNPLA1 catalyses the ω-O-esterification with linoleic acid to form acylceramides. Moreover, acylceramide supplementation partially rescues the altered differentiation of Pnpla1−/− keratinocytes. Our findings provide valuable insight into the skin barrier formation and ichthyosis development, and may contribute to novel therapeutic strategies for treatment of epidermal barrier defects.

Prevalent founder mutation c.736T>A of LIPH in autosomal recessive woolly hair of Japanese leads to variable severity of hypotrichosis in adulthood.

Background  Mutations in LIPH are a cause of autosomal recessive woolly hair (ARWH). Homozygous c.736T>A (p.Cys246Ser), and compound heterozygous c.736T>A and c.742C>A (p.His248Asn) have been reported in 5 and 7 Japanese children with ARWH respectively. The severity of hypotrichosis is known to be able to change in the clinical course, and the mutation patterns of LIPH do not always correlate with the severity of hypotrichosis in ARWH caused by other mutation sites of LIPH. However, all 12 Japanese children previously reported to have ARWH have shown similar severity of hypotrichosis.

Dowling-Degos disease with mutations in POFUT1 is clinicopathologically distinct from reticulate acropigmentation of Kitamura.

DEAR EDITOR, Dowling–Degos disease (DDD) is a rare autosomal dominant genetic pigmentary disorder characterized by dot-like or reticulate, slightly depressed, sharply demarcated brown macules particularly affecting the flexures and other major skinfolds (Fig. 1a). There has long been controversy over whether DDD and reticulate acropigmentation of Kitamura (RAK; MIM #615537), which has similar skin manifestations but affects mainly the dorsa of the hands and the feet, are distinct clinical entities or variants of the same disease. Several reports have suggested that RAK and DDD are identical disorders with different spectra. The causative gene of DDD was clarified as KRT5 in 2006, and recently also POFUT1 (encoding protein O-fucosyltransferase 1) and POGLUT1 were identified. As for RAK, it was shown to be due to mutations in ADAM10 in 2013. In this study, to clarify the differences between genetically confirmed DDD and RAK, we performed genetic diagnoses of three DDD pedigrees and one RAK pedigree. We compared the detailed clinical and histological features between patients with DDD and patients with RAK, who were confirmed to have the causative POFUT1 and ADAM10 gene mutations, respectively, including previously reported cases. The mutation search for each gene was performed as previously described. Informed consent and blood samples of patients were obtained under protocols approved by the ethics review committee of Nagoya University School of Medicine. In addition, histopathological examinations of biopsy specimens from the skin lesions were performed. Four patients with DDD from three unrelated families, who had the known heterozygous mutation c.397C>T (p.Arg133X) (family D1) or the novel mutations c.460C>T (p.Gln154X) (family D2) or c.891G>A (p.Trp297X) (family D3) in POFUT1, were included in the present study (Figs S1 and S2a–c; see Supporting Information). Two patients with RAK from one family who had the novel heterozygous mutation c.1000G>A (p.Gly334Arg) (family R1) in ADAM10 were also included in the present study (Fig. S2d,e). In addition, we referred to nine cases of RAK previously reported by our group and two cases of DDD reported by Li et al. (Table S1; see Supporting Information). The histopathological features of the patients with DDD with the POFUT1 mutations were acanthosis of the epidermis, tight digitiform rete ridges with prominent hyperpigmentation at the tips, pigmentary incontinence and small cornified cysts (Fig. 1e). In contrast, histopathological investigation revealed that the epidermis of the patient with RAK with the ADAM10 mutation showed pigmentation at the tip of the rete ridges, slight elongation and thinning of the rete ridges, thinning of the epidermis and slight hyperkeratosis without parakeratosis or pigmentary incontinence (Fig. 1f). Both POFUT1 and POGLUT1 are involved in the Notch pathway. Keratinocyte-specific deletion of the Notch1 gene results in marked epidermal hyperplasia. These investigational results may support the idea of histopathological differences between DDD and RAK. Thus, DDD skin lesions show acanthosis with tight digitiform rete ridges, although Adam10-deficient mice show thinning of the spinous layers of the epidermis. Regarding melanocytes, although Adam10-deficient mice show no alteration of pigmentation, Adam10-deficient hairless mice show pigmented macules. Notch signalling may also affect the melanocyte lineage. Genetic ablation of Notch signalling in the mouse results in a dramatic reduction of embryonic melanoblasts and a dilution of initial hair pigmentation. However, it is still unknown how these research results relate to the pathogenesis of pigmentation diseases in humans. The age at onset and the distribution of the skin lesions also differ between DDD and RAK (Table S1). RAK has an earlier age of onset than DDD: the age of onset for DDD ranges from 18 to 56 years, averaging 28 8 13 9 years, whereas the onset age for RAK ranges from 5 to 12 years, averaging 9 2 2 2 years. Among all of the 11 patients with RAK in this study and in our previous report, 10 had the initial skin lesion on the dorsa of the hands. In contrast, four of the five patients with DDD with information available on the primary sites had the primary skin lesions at locations other than the dorsa of the hands. Comedo-like follicular papules were seen only in the patients with DDD (Fig. 1c) and not in any patient with RAK. Hyperpigmentation and papules on the perianal and genital regions were also seen only in patients with DDD (Fig. 1d) and not in RAK. All of the patients with DDD except D3-1 showed skin manifestations involving the limbs. Interestingly, all of their mutations were truncation mutations around the N-terminal third of POFUT-1, abolishing the C-terminal two-thirds of the amino acid sequence of the protein (Fig. 1g). In contrast, case D3-1 showed a clinically rare genital lesion; histopathologically, the acanthosis and digitiform rete ridges were relatively mild, although the hyperpigmentation at the tips still stood out. The POFUT1 truncation mutation in case D3-1 results in

Possible roles of barrier-to-autointegration factor 1 in regulation of keratinocyte differentiation and proliferation

BACKGROUND Barrier-to-autointegration factor 1 (BANF1) is an essential component of the nuclear lamina. Recent studies have clarified that BANF1 is a causative molecule of Nestor-Guillermo progeria syndrome. Despite recent progress in studies on BANF1, the role of BANF1 in keratinocytes has not been addressed at all. OBJECTIVE This study aims to determine the localization of BANF1 in psoriatic epidermal keratinocytes as well as in normal keratinocytes and to clarify its possible function in those keratinocytes. METHODS Immunohistochemistry of BANF1 was performed on 10 cases of psoriasis and 10 healthy control individuals. Expression of molecules associated with inflammation of the skin by HSC-1, a human skin squamous cell carcinoma cell line, stimulated by TPA and treated with siRNA to BANF1 were analyzed with quantitative PCR and Western blot. RESULTS Strong nuclear-dominant immunostaining of BANF1 was seen in the epidermal keratinocytes of psoriatic lesions, although in the normal epidermis, all the KCs in the upper epidermis showed cytoplasmic-dominant staining of BANF1. By BANF1 knockdown in TPA-stimulated HSC-1 cells, the mRNA levels of S100A9 were significantly elevated compared with those of control HSC-1 cells treated with siRNA to CD4. The protein expression level of S100A9 and phosphorylated c-Jun was elevated by BANF1 knockdown. CONCLUSION BANF1 is translocated onto the nuclear envelope in the psoriatic epidermal keratinocytes, suggesting that BANF1 is associated with upregulated proliferation of keratinocytes in psoriatic lesions. Activation of BANF1 possibly suppresses S100A9 expression and inactivates c-Jun, resulting in suppression of cutaneous inflammation.

Erythrokeratoderma Variabilis Caused by p.Gly45Glu in Connexin 31: Importance of the First Extracellular Loop Glycine Residue for Gap Junction Function.

© 2016 The Authors. doi: 10.2340/00015555-2307 Journal Compilation

Cytomegalovirus reactivation accompanied by varicella zoster virus reactivation or reinfection in an adult patient of multiple myeloma during bortezomib therapy

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Urticarial vasculitis and subcutaneous nodules in the extremities seen in a patient with mucopolysaccharidosis II after hematopoietic stem cell therapy

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Infant bald patch: ultrasonographic diagnosis of aplasia cutis congenita

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Leg ulcers associated with cutaneous vascular degeneration in a patient receiving pazopanib chemotherapy

Pazopanib is an oral multi-targeted tyrosine kinase inhibitor (TKI) used for the treatment of advanced renal cell carcinoma (RCC) and soft tissue sarcoma. Cutaneous adverse effects of pazopanib are very rare. We herein report a patient with advanced RCC who developed, during chemotherapy with pazopanib, multiple ulcers on both lower legs associated with cutaneous vascular degeneration. A 66-year-old man was diagnosed with metastatic RCC (of clear cell type) and underwent left nephrectomy. Thereafter, [...]

Eosinophilic annular erythema localized on the neck

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