Dyschromatosis Symmetrica Hereditaria and Aicardi-Goutières Syndrome 6 Are Phenotypic Variants Caused by ADAR1 Mutations Michihiro Kono, Fumihiro Matsumoto,

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Dyschromatosis Symmetrica Hereditaria and Aicardi-Goutières Syndrome 6 Are Phenotypic Variants Caused by ADAR1 Mutations Michihiro Kono, Fumihiro Matsumoto, Yasuhiro Suzuki, Mutsumi Suganuma, Hirotomo Saitsu, Yasutomo Ito, Sakuhei Fujiwara, Shinichi Moriwaki, Kazuhiko Matsumoto, Naomichi Matsumoto, Yasushi Tomita, Kazumitsu Sugiura, Masashi Akiyama Journal of Investigative Dermatology Volume 136, Issue 4, Pages 875-878 (April 2016) DOI: 10.1016/j.jid.2015.12.034 Copyright © 2016 The Authors Terms and Conditions

Figure 1 Pedigree and clinical features of the proband with both dyschromatosis symmetrica hereditaria (DSH) and Aicardi-Goutières syndrome (AGS) and her mother with only DSH, and causative ADAR1 mutations. (a) The pedigree of the proband’s family. Closed circles and squares indicate individuals with DSH skin manifestations. The proband (arrow) has both DSH skin lesions and AGS neurological manifestations. The skin of her father was not examined (?). (b–e) Skin manifestations of the proband. A mixture of 5-mm hyper- and hypopigmented macules are visible on the (b) trunk, (c) arm, and (d) leg, and (e) frecklelike macules are observed on the face. (f) Skin lesions are recognized in the mother but are very faint. (g, h) Brain computed tomographic images of the proband at age (g) 4 months and (h) 17 months. (i) The mutation c.1600C>T was identified by sequence analysis of exons 2 of ADAR1. (j) The mutation c.3444-1G>A (IVS14-1G>A) was identified by sequence analysis of the boundary between intron 14 and exon 15 of ADAR1. (k) Agarose gel electrophoresis of reverse transcription polymerase chain reaction (RT-PCR) products derived from the boundary between exons 14 and 15 in ADAR1. The RT-PCR product from the patient’s father shows a 519-bp band (a normally spliced fragment) and a 555-bp band (an aberrantly spliced fragment), whereas the RT-PCR product from the patient shows only a 555-bp band (an aberrantly spliced fragment) derived from the paternal mutant allele with c.3444-1G>A (IVS14-1G>A). The RT-PCR product from the patient does not demonstrate a 519-bp band theoretically derived from the maternal mutant allele carrying the mutation c.1600C>T. Thus, it is thought that the allele with c.1600C>T underwent nonsense-mediated mRNA decay. The mother has only a 519-bp band derived from the wild-type allele. (l) Direct sequencing of RT-PCR products from the patient and her father reveals a 36-bp nucleotide insertion between exons 14 and 15. The paternal mutation c.3444-1G>A results in aberrant splicing and insertion of 36 bp between exon 14 and exon 15, that is, p.1148_1149insSQVNNECFCFSK in the deaminase domain. (m) The scheme of the domain structure of ADAR1 and two mutations found in the patient’s family. Journal of Investigative Dermatology 2016 136, 875-878DOI: (10.1016/j.jid.2015.12.034) Copyright © 2016 The Authors Terms and Conditions

Figure 2 RNA editing activity analysis of mutant ADAR1 p150 isoforms causative of dyschromatosis symmetrica hereditaria (DSH) and Aicardi-Goutières syndrome (AGS). (a) Structure of the RNA editing reporter construct. When the UAG at a double-stranded RNA site upstream of the luciferase gene is converted by ADAR1 into UIG by A-I editing, the stop is canceled and the luciferase gene is translated. Thereby, quantification of the editing efficiency is possible. (b) The A-I editing efficiency of cos7 cells transfected with DSH-causative or AGS-causative mutant p150 isoforms. For the three AGS-causative mutations, only mutant plasmids were transfected into cos7 cells, and the A-I editing efficiencies of the transfectants were evaluated. This system mimics the state of patients with homozygous ADAR1 mutations. As for the three DSH-causative mutations and pGly1007Arg (*) causative of DSH with neurological symptoms, both mutant plasmids and wild-type (WT) plasmids (half and half) were transfected into cos7 cells. This system mimics the state of patients with heterozygous ADAR1 mutations. Journal of Investigative Dermatology 2016 136, 875-878DOI: (10.1016/j.jid.2015.12.034) Copyright © 2016 The Authors Terms and Conditions