Tamio Suzuki

Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature

Adenosine deaminases acting on RNA (ADARs) catalyze the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) and thereby potentially alter the information content and structure of cellular RNAs. Notably, although the overwhelming majority of such editing events occur in transcripts derived from Alu repeat elements, the biological function of non-coding RNA editing remains uncertain. Here, we show that mutations in ADAR1 (also known as ADAR) cause the autoimmune disorder Aicardi-Goutières syndrome (AGS). As in Adar1-null mice, the human disease state is associated with upregulation of interferon-stimulated genes, indicating a possible role for ADAR1 as a suppressor of type I interferon signaling. Considering recent insights derived from the study of other AGS-related proteins, we speculate that ADAR1 may limit the cytoplasmic accumulation of the dsRNA generated from genomic repetitive elements.

Revised classification/nomenclature of vitiligo and related issues: the Vitiligo Global Issues Consensus Conference

During the 2011 International Pigment Cell Conference (IPCC), the Vitiligo European Taskforce (VETF) convened a consensus conference on issues of global importance for vitiligo clinical research. As suggested by an international panel of experts, the conference focused on four topics: classification and nomenclature; definition of stable disease; definition of Koebner’s phenomenon (KP); and ‘autoimmune vitiligo’. These topics were discussed in seven working groups representing different geographical regions. A consensus emerged that segmental vitiligo be classified separately from all other forms of vitiligo and that the term ‘vitiligo’ be used as an umbrella term for all non‐segmental forms of vitiligo, including ‘mixed vitiligo’ in which segmental and non‐segmental vitiligo are combined and which is considered a subgroup of vitiligo. Further, the conference recommends that disease stability be best assessed based on the stability of individual lesions rather than the overall stability of the disease as the latter is difficult to define precisely and reliably. The conference also endorsed the classification of KP for vitiligo as proposed by the VETF (history based, clinical observation based, or experimentally induced). Lastly, the conference agreed that ‘autoimmune vitiligo’ should not be used as a separate classification as published evidence indicates that the pathophysiology of all forms of vitiligo likely involves autoimmune or inflammatory mechanisms.

Genetics of pigmentary disorders

The genetic and molecular bases of various types of congenital pigmentary disorders have been classified in the past 10 years, as follows: (1) disorders of melanoblast migration in the embryo from the neural crest to the skin: piebaldism; Waardenburg syndrome 1–4 (WS1–WS4); dyschromatosis symmetrica hereditaria. (2) Disorders of melanosome formation in the melanocyte: Hermansky–Pudlak syndrome 1–7 (HPS1–7); Chediak–Higashi syndrome 1 (CHS1). (3) Disorders of melanin synthesis in the melanosome: oculocutaneous albinism 1–4 (OCA1–4). (4) Disorders of mature melanosome transfer to the tips of the dendrites Griscelli syndrome 1–3 (GS1–3). These disorders are presented and their gene mutations and pathogenesis are discussed.

The mouse organellar biogenesis mutant buff results from a mutation in Vps33a, a homologue of yeast vps33 and Drosophila carnation.

In the mouse, more than 16 loci are associated with mutant phenotypes that include defective pigmentation, aberrant targeting of lysosomal enzymes, prolonged bleeding, and immunodeficiency, the result of defective biogenesis of cytoplasmic organelles: melanosomes, lysosomes, and various storage granules. Many of these mouse mutants are homologous to the human Hermansky–Pudlak syndrome (HPS), Chediak–Higashi syndrome, and Griscelli syndrome. We have mapped and positionally cloned one of these mouse loci, buff (bf), which has a mutant phenotype similar to that of human HPS. Mouse bf results from a mutation in Vps33a and thus is homologous to the yeast vacuolar protein-sorting mutant vps33 and Drosophila carnation (car). This is the first found defect of the class C vacuole/prevacuole-associated target soluble N-ethylmaleimide-sensitive factor attachment protein receptor (t-SNARE) complex in mammals and the first mammalian mutant found that is directly homologous to a vps mutation of yeast. VPS33A thus is a good candidate gene for a previously uncharacterized form of human HPS.

Oculocutaneous Albinism Type 4 Is One of the Most Common Types of Albinism in Japan

Oculocutaneous albinism (OCA) is a complex genetic disease with great clinical heterogeneity. Four different types of OCA have been reported to date (OCA1, OCA2, OCA3, and OCA4). MATP was recently reported in a single Turkish OCA patient as the fourth pathological gene, but no other patients with OCA4 have been reported. Here, we report the mutational profile of OCA4, determined by genetic analysis of the MATP gene in a large Japanese population with OCA. Of 75 unrelated patients that were screened, 18 individuals (24%) were identified as having OCA4; they harbored seven novel mutations, including four missense mutations (P58S, D157N, G188V, and V507L) and three frameshift mutations (S90CGGCCA-->GC, V144insAAGT, and V469delG), showing that MATP is the most frequent locus for tyrosinase-positive OCA in Japanese patients. We discuss the functional melanogenic activity of each mutant allele, judging from the relationship between the phenotypes and genotypes of the patients. This is the first report on a large group of patients with OCA4.

Increasing the complexity: new genes and new types of albinism

Albinism is a rare genetic condition globally characterized by a number of specific deficits in the visual system, resulting in poor vision, in association with a variable hypopigmentation phenotype. This lack or reduction in pigment might affect the eyes, skin, and hair (oculocutaneous albinism, OCA), or only the eyes (ocular albinism, OA). In addition, there are several syndromic forms of albinism (e.g. Hermansky–Pudlak and Chediak–Higashi syndromes, HPS and CHS, respectively) in which the described hypopigmented and visual phenotypes coexist with more severe pathological alterations. Recently, a locus has been mapped to the 4q24 human chromosomal region and thus represents an additional genetic cause of OCA, termed OCA5, while the gene is eventually identified. In addition, two new genes have been identified as causing OCA when mutated: SLC24A5 and C10orf11, and hence designated as OCA6 and OCA7, respectively. This consensus review, involving all laboratories that have reported these new genes, aims to update and agree upon the current gene nomenclature and types of albinism, while providing additional insights from the function of these new genes in pigment cells.

Rhododendrol, a depigmentation‐inducing phenolic compound, exerts melanocyte cytotoxicity via a tyrosinase‐dependent mechanism

Rhododendrol, an inhibitor of melanin synthesis developed for lightening/whitening cosmetics, was recently reported to induce a depigmentary disorder principally at the sites of repeated chemical contact. Rhododendrol competitively inhibited mushroom tyrosinase and served as a good substrate, while it also showed cytotoxicity against cultured human melanocytes at high concentrations sufficient for inhibiting tyrosinase. The cytotoxicity was abolished by phenylthiourea, a chelator of the copper ions at the active site, and by specific knockdown of tyrosinase with siRNA. Hence, the cytotoxicity appeared to be triggered by the enzymatic conversion of rhododendrol to active product(s). No reactive oxygen species were detected in the treated melanocytes, but up‐regulation of the CCAAT‐enhancer‐binding protein homologous protein gene responsible for apoptosis and/or autophagy and caspase‐3 activation were found to be tyrosinase dependent. These results suggest that a tyrosinase‐dependent accumulation of ER stress and/or activation of the apoptotic pathway may contribute to the melanocyte cytotoxicity.

Recent advances in genetic analyses of oculocutaneous albinism types 2 and 4

Patients with OCA are characterized by reduced skin and hair pigmentation and consequent photosensitivity, actinic damage and risk of skin cancer, and by reduced visual acuity and nystagmus. Our survey of Japanese patients revealed that OCA1 was the most frequent type at 34%, while type 2 was present at less than 10%. OCA3 was absent. OCA4, which is a rare type worldwide, was the second most frequent type at 27%. Unexpectedly 10% of the patients turned out to be Hermansky-Pudlak syndrome type 1. Furthermore, the pathogenic p.A481T allele for OCA2, which has 70% melanogenesis activity, was found in approximately 12% of normally pigmented people, indicating that sub-clinical OCA2 might be more frequent in the Japanese than currently thought. And OCA4 is one of the most common types in Japanese patients, despite being rare worldwide.

Dystonia, mental deterioration, and dyschromatosis symmetrica hereditaria in a family with ADAR1 mutation

A family with dystonia associated with dyschromatosis symmetrica hereditaria (DSH), mental deterioration, and tissue calcification is described. The proband possessed an adenosine deaminase acting on the RNA 1 gene (ADAR1) mutation Gly1007Arg. This ADAR1 mutation could disturb RNA editing at Q/R sites of glutamate receptor in the brain and increase Ca2+ influx into neurons, which is thought to induce dystonia and mental deterioration. The observations in our family raise the possibility that the ADAR1 mutation might be a direct cause or a predisposing factor for heredodegenerative dystonia. Further investigation of ADAR1 mutations will shed light on the genotype–phenotype correlation in DSH.

Developing core outcome set for vitiligo clinical trials: international e‐Delphi consensus

1 Centre of Evidence Based Dermatology, University of Nottingham, Nottingham,UK 2 Department of Dermatology, Ghent University Hospital, Ghent, Belgium3 Department of Dermatology, Henry Ford Hospital, Detroit, MI, USA4 Department of Dermatology, Yamagata University School of Medicine,Yamagata, Japan 5 Department of Dermatology, Osaka University, Osaka, Japan6 Dermatology Department, Al-Minya University, Al-Minya, Egypt 7 Departmentof Dermatology and Venereology, Ain Shams University, Cairo, Egypt8 Department of Dermatology, Ibn Sina University Hospital, Rabat, Morocco9 Mohammed V Souissi University, Rabat, Morocco 10 Department ofDermatology, University of Bordeaux National Reference Centre for Rare SkinDiseases H^opital St-Andr e, Bordeaux, France 11 Department of Medicine,Division of Dermatology, University of Massachusetts Medical School,Worcester, MA, USA 12 Department of Dermatology, Pontifcia UniversidadeCatœlica do Paranffi, Curitiba, Brazil 13 Department of Dermatology, University ofTexas Southwestern Medical Center, Dallas, TX, USA 14 National Skin Centre,Singapore City, Singapore 15 Department of Dermatology, Kaohsiung MedicalUniversity, Kaohsiung City, Taiwan 16 Department of Dermatology, KinkiUniversity Faculty of Medicine, Osaka-Sayama, Japan 17 Vitiligo Light Clinic,Riyadh, Saudi Arabia 18 Department of Dermatology, Cairo University, Kasr AlAiny Hospital, Cairo, Egypt 19 Departments of Pathology, Microbiology andImmunology/Oncology Institute, Loyola University Chicago, Chicago, IL, USA20 Department of Dermatology, Dongguk University Ilsan Hospital, Gyeonggi-do,Korea 21 Department of Dermatology, PGIMER, Chandigarh, India 22 Departmentof Dermatology, San Gallicano Dermatologic Institute IRCCS, Roma, ItalyCORRESPONDENCE Khaled Ezzedine and Viktoria Eleftheriadou, e-mails: khaled.ezzedine@chu-bordeaux.fr; viktoria.eleftheriadou@nottingham.ac.uk