View metadata, citation and similar papers at core.ac.uk brought to you by CORE providedCA by Elsevier Scott - Publisheret al. Connector Sequence Capture in Molecular Diagnosis of Skin Diseases Immunohistochemical staining indi- 1The Wellcome Trust Center for Human cause of Olmsted syndrome. Am J Hum cated that MBTPS2 is mainly expressed Genetics, Nuffield Department of Clinical Genet 90:558–64 Medicine, University of Oxford, Oxford, UK; Mevorah B, Goldberg I, Sprecher E et al. (2005) in the upper granular layer in normal 2 Centre for Cutaneous Research, The Blizard Olmsted syndrome: mutilating palmo- skin, as previously shown (Aten et al., Institute, Barts & The London School of plantar keratoderma with periorificial 2010); however, in OS skin, MBTPS2 Medicine and Dentistry, Queen Mary keratotic plaques. J Am Acad Dermatol 53: University of London, London, UK; S266–72 was expressed throughout the epi- 3 dermis (Figure 2c). There was no Department of Dermatology, Jundishapur Naiki M, Mizuno S, Yamada K et al. (2012) University of Medical Sciences, Ahvaz, Iran; MBTPS2 mutation causes BRESEK/BRESHECK 4 apparent difference in MBTPS2 locali- Genetic Department, Kerman University of syndrome. Am J Med Genet A 158A:97–102 zation in the skin of a KFSD patient with 5 Medical Sciences, Kerman, Iran and Darwin Oeffner F, Fischer G, Happle R et al. (2009) IFAP the p.N508S mutation (Aten et al., Building, University College London Genetics syndrome is caused by deficiency in MBTPS2, 2010). It is unclear why this is but it Institute, University College London, London, an intramembrane zinc metalloprotease essen- may be because of differences in UK tial for cholesterol homeostasis and ER stress E-mail: [email protected] response. Am J Hum Genet 84:459–67 processing of the mutants in the two 6These authors contributed equally to this work Olmsted HC (1927) Keratodermia palmaris et diseases. and should be considered joint first author. plantaris congenitalis. Am J Dis Child In summary, we demonstrate a novel 33:757–64 association between an MBTPS2 muta- Sakai J, Nohturfft A, Goldstein JL et al. (1998) tion and an X-linked form of OS. This SUPPLEMENTARY MATERIAL Cleavage of sterol regulatory element- expands the number of disorders linked Supplementary material is linked to the online binding proteins (SREBPs) at site-1 requires version of the paper at http://www.nature.com/jid interaction with SREBP cleavage-activating to MBTPS2 mutations and reveals clin- protein. Evidence from in vivo competition ical heterogeneity associated with dif- studies. J Biol Chem 273:5785–93 REFERENCES ferent MBTPS2 mutations. Tang L, Liang J, Wang W et al. (2011) A novel Written, informed consent was Aten E, Brasz LC, Bornholdt D et al. (2010) mutation in MBTPS2 causes a broad pheno- Keratosis follicularis spinulosa decalvans is obtained from all family members or typic spectrum of ichthyosis follicularis, caused by mutations in MBTPS2. Hum Mut atrichia, and photophobia syndrome in a their legal guardians. This study was 31:1125–33 large Chinese family. J Am Acad Dermatol approved by the South East NHS Bergonse FN, Rabello SM, Barreto RL et al. (2003) 64:716–22 Research Ethics Committee and was Olmsted syndrome: the clinical spectrum of Tang L, Zhang L, Ding H et al. (2012) Olmsted mutilating palmoplantar keratoderma. Pediatr syndrome: a new case complicated with performed according to the Declaration Dermatol 20:323–6 of Helsinki Principles. easily broken hair and treated with oral Cambiaghi S, Tadini G, Barbareschi M et al. retinoid. J Dermatol 39:1–2 (1995) Olmsted syndrome in twins. Arch Yaghoobi R, Omidian M, Sina N et al. (2007) CONFLICT OF INTEREST Dermatol 131:738–9 Olmsted syndrome in an Iranian family: report The authors state no conflict of interest. Ding YG, Wang JY, Qiao JJ et al. (2010) A novel of two new cases. Arch Iran Med 10:246–9 mutation in MBTPS2 causes ichthyosis folli- Ye J, Rawson RB, Komuro R et al. (2000) ER stress ACKNOWLEDGMENTS cularis, alopecia and photophobia (IFAP) induces cleavage of membrane-bound ATF6 We thank Barts and The London Charity for its syndrome in a Chinese family. Br J Dermatol by the same proteases that process SREBPs. financial support (to DPK). 163:886–9 Mol Cell 6:1355–64 1,6 2,6 Larregue M, Callot V, Kanitakis J et al. (2000) Zelenski NG, Rawson RB, Brown MS et al. Alireza Haghighi , Claire A. Scott , Olmsted syndrome: report of two new cases 2 3 (1999) Membrane topology of S2P, a Daniel S. Poon , Reza Yaghoobi , and literature review. J Dermatol 27:557–68 4 protein required for intramembranous Nasrollah Saleh-Gohari , Lin Z, Chen Q, Lee M et al. (2012) Exome cleavage of sterol regulatory element-bind- Vincent Plagnol5 and David P. Kelsell2 sequencing reveals mutations in TRPV3 as a ing proteins. JBiolChem274:21973–80 Targeted Sequence Capture and High-Throughput Sequencing in the Molecular Diagnosis of Ichthyosis and Other Skin Diseases Journal of Investigative Dermatology (2013) 133, 573–576; doi:10.1038/jid.2012.332; published online 20 September 2012 TO THE EDITOR Mendelian disorders of cornification, integument (Oji et al., 2010). The two The inherited ichthyoses are a large and characterized by scaling and/or hyper- main nonsyndromic ichthyosis groups genetically heterogeneous group of keratosis over the majority of the are autosomal recessive congenital ichthyosis (ARCI), encompassing lamel- lar ichthyosis (LI), congenital ichthyosi- Abbreviations: ARCI, autosomal recessive congenital ichthyosis; CIE, congenital ichthyosiform erythroderma; HI, harlequin ichthyosis; KPI, keratinopathic ichthyosis; LI, lamellar ichthyosis; NGS, next- form erythroderma (CIE), and harlequin generation sequencing; SPPK, striate palmoplantar keratoderma; SNP, single-nucleotide polymorphism ichthyosis (HI), in which patients are www.jidonline.org 573 CA Scott et al. Sequence Capture in Molecular Diagnosis of Skin Diseases usually born as collodion babies; and Table 1. Genes implicated in ichthyosis and other skin diseases on the keratinopathic ichthyoses (KPI), the two custom capture microarray main groups of which are epidermolytic Cytogenetic Disease(s) with ichthyosis (EI) and superficial epider- Gene OMIM location (hg19) skin phenotype molytic ichthyosis (SEI) (Oji et al., 2010). KPI are linked to mutations in Exons captured keratin genes. Mutations in ABCA12 are ABHD5 *604780 3p21.33 CDS associated with HI, the most deva- AP1S1 *603531 7q22.1 MEDNIK stating and frequently lethal form of ALOXE3 *607206 17p13.1 ARCI (CIE) ichthyosis (Akiyama et al., 2005; Kelsell et al., 2005). However, mutations in ALOX12B *603741 17p13.1 ARCI (CIE) multiple genes (Table 1), including CDSN *602593 6p21.33 Hypotrichosis, PSS ABCA12, are linked to LI and CIE, CSTA *184600 3q21.1 AREI which display clinical overlap (Akiya- CYP4F22 *611495 19p13.12 ARCI (LI) ma et al., 2003). DSG1 *125670 18q12.1 SPPK1 As mutations in multiple genes are linked to nonsyndromic and syndromic DSP *125647 6p24.3 DCWHK, LAEB, SFWHS, SPPK2 ichthyosis, undertaking genetic screen- GJB2 *121011 13q12.11 BPS, HID, KID, PPK with deafness ing by PCR and Sanger sequencing in a GJB3 +603324 1p34.3 EKV gene-by-gene approach is labor-inten- GJB4 *605425 1p34.3 EKV sive and expensive. Screening known ichthyosis genes simultaneously in a KRT1 *139350 12q13.13 AEI, EI, EPPK, ICM, NEPPK, SPPK3 patient (or multiple patients) could en- KRT2 *600194 12q13.13 SEI able a swifter identification of gene LOR *152445 1q21.3 LK mutations in patients and facilitate pre- NIPAL4 *609383 5q33.3 ARCI (CIE) natal diagnosis and genetic counseling. Next-generation sequencing (NGS) POMP *613386 13q12.3 KLICK has proven effective in the discovery of SLC27A4 *604194 9q34.11 IPS mutations in novel disease-associated SLURP1 *606119 8q24.3 MDM genes, for example, by exome sequen- SPINK5 *605010 5q32 Atopy, NS cing (Ng et al., 2009) or by targeted STS #308100 Xp22.31 XLI sequence capture of chromosomal re- gions previously linked to a condition TGM1 *190195 14q12 ARCI (CIE, LI) (Blaydon et al., 2011, 2012). For con- TGM5 *603805 15q15.2 APSS ditions associated with mutations in Exons, introns multiple known genes, targeted gene ABCA12 *607800 2q35 ARCI (CIE, LI, HI) capture coupled with NGS has shown promise in the molecular diagnosis of Abbreviations: AEI, annular epidermolytic ichthyosis; APSS, acral peeling skin syndrome; ARCI, autosomal recessive congenital ichthyosis; AREI, autosomal recessive exfoliative ichthyosis; BPS, Bart- disease (Berg et al., 2011; Artuso et al., Pumphrey syndrome; CDS, Chanarin-Dorfman syndrome; CIE, congenital ichthyosiform erythroder- 2012). Here, we designed a custom ma; DCWHK, dilated cardiomyopathy with woolly hair and keratoderma; EI, epidermolytic ichthyosis; NimbleGen microarray for sequence EKV, erythrokeratoderma variabilis; EPPK, epidermolytic palmoplantar keratoderma; HI, harlequin ichthyosis; HID, hystrix-like ichthyosis with deafness; ICM, ichthyosis histrix, Curth-Macklin type; IPS, capture and NGS of the ABCA12 gene ichthyosis prematurity syndrome; KID, keratitis–ichthyosis–deafness syndrome; KLICK, keratosis locus, as well as the exons of 23 other linearis–ichthyosis congenital–keratoderma; LAEB, lethal acantholytic epidermolysis bullosa; LI, genes linked to nonsyndromic and lamellar ichthyosis; LK, loricrin keratoderma; MDM, mal de Meleda; MEDNIK, mental retardation, syndromic forms of ichthyosis, acral enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratodermia; NEPPK, nonepidermo- lytic palmoplantar keratoderma; NS, Netherton syndrome;