Studies on Mendelian disorders of cornification R.G.L. Nellen STUDIES ON MENDELIAN DISORDERS OF CORNIFICATION Publicatie van dit proefschrift is mede mogelijk gemaakt door een financiële bijdrage van de Raad van Bestuur van het IJsselland Ziekenhuis, Capelle aan den IJssel. Cover design AdriaanTV Layout Renate Siebes | Proefschrift.nu Printed by Proefschriftmaken.nl ISBN 978-90-9030071-9 Copyright 2017 © R.G.L. Nellen, Rotterdam, The Netherlands All rights reserved. No part of this thesis may be reproduced, stored or transmitted in any form or by any means without prior permission of the author. STUDIES ON MENDELIAN DISORDERS OF CORNIFICATION PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit Maastricht, op gezag van de Rector Magnificus, prof. dr. Rianne M. Letschert volgens het besluit van het College van Decanen, in het openbaar te verdedigen op donderdag 19 januari 2017 om 14.00 uur door Ruud Gerard Leonard Nellen Geboren 12 juli 1980 te Roosendaal en Nispen Promotores Prof. dr. P.M. Steijlen Prof. dr. M.A.M. van Steensel Copromotores Dr. M. van Geel Prof. dr. J. Frank (Heinrich Heine Universität Dusseldorf, Duitsland) Beoordelingscommissie Prof. dr. C.T.R.M. Stumpel (voorzitter) Prof. dr. S.G.M.A. Pasmans (Erasmus MC, Rotterdam) Dr. A.M.G. Pasmooij (UMCG, Groningen) Prof. dr. H.J.M. Smeets Les études ça vous change, ça fait l’orgueil d’un homme. Il faut bien passer par là pour entrer dans le fond de la vie. Avant, on tourne autour seulement. On se prend pour un affranchi mais on bute dans des riens. On rêve de trop. On glisse sur tous les mots. Ça n’est pas ça. Ce n’est rien que des intentions, des apparences. Faut autre chose au résolu. Louis-Ferdinand Céline, Voyage au bout de la nuit. Aan Annieke Aan mijn ouders Contents Chapter I Introduction 9 Chapter II Mal de Meleda 15 Chapter III Epidermolytic Ichthyosis 51 Chapter IV Darier disease and Hailey-Hailey disease 67 Chapter V Conclusions, discussion and valorisation 125 Chapter VI Summary 152 Samenvatting 155 Appendix Curriculum vitae 164 List of publications 165 Dankwoord (Acknowledgements) 168 Chapter I Introduction CHAPTER 1 INTRODUCTION 1.1 Introduction The Mendelian disorders of cornification (MEDOC) encompass the hereditable mono­ genic skin diseases caused by mutations in genes responsible for homeostasis of the epidermis, in particular the development of the cornified envelope1,2. Disruption of keratinocyte physiology can yield strikingly different skin diseases. This is reflected in the most commonly used classification of MEDOC, in which syndromes are grouped according to clinical phenotype. The phenotypes distinguished are the ichthyoses1, palmoplantar keratodermas (PPK)3, Darier disease (DD) and Hailey­Hailey disease (HHD). A classification based on genotype or aetiology has also been proposed, which divides MEDOC into diseases of epidermal lipid metabolism, corneocyte physiology, cell­cell junctions and keratinocyte homeostasis1,2. Most PPKs are classified either according to the mode of inheritance or the occurrence of associated symptoms (syndromic and non­syndromic PPKs)3. In most MEDOC as well as other inherited disorders, genetic variants in the associated gene will cause a uniform phenotype, i.e. a phenotype that is more or less the same in each individual patient. This the case for homozygous or compound heterozygous mutations in SLURP1 in Mal de Meleda (MDM)4. However, this uniformity is not always present, as the phenotype of certain MEDOC can be highly variable. In some diseases, this variance is associated with a strong genotype­phenotype correlation, i.e. specific variations in the genomic sequence can be associated with a specific phenotype. For example, the severe phenotype of Epidermolytic Ichthyosis (EI) is associated with mutations in a relatively small area of the sequence of KRT1 or KRT105, in this case coding for the helix boundary motifs. The mild phenotype, on the other hand, is linked to mutations in the linker L12 domain of KRT16,7. Sometimes, an extensive phenotypic variation is observed with no apparent genotype­phenotype correlations. This variation includes differences in disease severity, as well as the presence or absence of specific symptoms. For example, in Darier disease (DD) and Hailey­Hailey disease (HHD), ATP2A2 and ATP2C1 mutations inherit with complete penetrance. However, clinical symptoms and disease severity may be variable, even within families affected by the same disease causing variant8­10. Variability in associated clinical features or severity may pose problems in identifying these syndromes. Unclear genotype­phenotype correlations make predicting disease course difficult. This ultimately interferes with patient care: without a diagnosis and 10 CHAPTER 1 INTRODUCTION prognosis, effective treatment and provision of adequate (genetic) counselling is impaired. There is therefore a dire need for studies that describe the clinical and genetic variation in MEDOC. This thesis addresses the problem of genotypic and phenotypic variation in four MEDOC with a relatively high prevalence and associated with impaired quality of life for patients: mal de Meleda (MDM), Epidermolytic Ichthyosis (EI), Darier disease (DD) and Hailey­Hailey disease (HHD). 1.2 Aims and outline The aims of this thesis can be formulated as follows: 1. What is the clinical and genetic variability in MDM, EI, DD and HHD? 2. Is it possible to assess genotype­phenotype correlations in MDM, EI, DD and HHD? To answer these questions, this thesis describes clinical and molecular studies in patients with MDM, EI, DD or HHD. Part I describes patients with MDM. We identified new mutations in the causative gene for MDM, SLURP1, in Dutch and Indian patients. Several mutations in SLURP1 recur in different populations. We investigated whether the p.(Trp15Arg) mutation recurred in the Western European population due to a founder effect. With regard to clinical variation in MDM, we discuss whether palmoplantar keratoderma of the Gamborg­Nielsen type (PPK­GN) should be considered as a separate disease entity. Part II considers the clinical variability of EI. We describe patients from a family with variable severity of symptoms due to mutation p.(Met339Lys) in the linker L12 domain KRT1. This observation shows that the genotype­phenotype correlations in KRT1­associated skin disease are not as strict as has been previously suggested. We provide clinical and functional evidence for the pathogenicity of variant p.(Met339Lys) in EI and add a novel variant to the mutation spectrum in EI. Part III describes two distinct clinical presentations of DD and a comprehensive review of all reported mutations in ATP2A2 and ATP2C1. To expand the clinical variability in DD, we report a patient with type II segmental distribution of DD and an unusually mild phenotype of DD in a Sinhalese patient with skin type V. In the former patient, we were able to provide molecular evidence for the loss of heterozygosity that 11 CHAPTER 1 INTRODUCTION underlies the type II segmental presentation. This evidence has so far only been provided for one instance11. Furthermore, we present data on a large cohort of patients with DD and HHD and report several new mutations in ATP2A2 and ATP2C1, respectively. We created a database for all mutations in ATP2A2 and ATP2C1 using the Leiden Open Variation Database (LOVD v3.0), for variants reported in the literature as well as to allow future inclusions. This enables us to fully quantify genetic variability in DD and HHD. It allows us to address the question of a genotype­phenotype correlation, which has not been noted unequivocally in DD and HHD. 12 CHAPTER 1 INTRODUCTION References 1 Oji, V., Tadini, G., Akiyama, M. et al. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Soreze 2009. J Am Acad Dermatol 2010; 63: p. 607­41. 2 Schmuth, M., Martinz, V., Janecke, A.R. et al. Inherited ichthyoses/generalized Mendelian disorders of cornification. Eur J Hum Genet 2013; 21: p. 123­33. 3 Itin, P.H., Fistarol, S.K. Palmoplantar keratodermas. Clin Dermatol 2005; 23: p. 15­22. 4 Fischer, J., Bouadjar, B., Heilig, R. et al. Mutations in the gene encoding SLURP­1 in Mal de Meleda. Hum Mol Genet 2001; 10: p. 875­80. 5 Arin, M.J., Oji, V., Emmert, S. et al. Expanding the keratin mutation database: novel and recurrent mutations and genotype­phenotype correlations in 28 patients with epidermolytic ichthyosis. Br J Dermatol 2011; 164: p. 442­7. 6 Bolling, M.C., Bladergroen, R.S., van Steensel, M.A. et al. A novel mutation in the L12 domain of keratin 1 is associated with mild epidermolytic ichthyosis. Br J Dermatol 2010; 162: p. 875­9. 7 Kremer, H., Lavrijsen, A.P., McLean, W.H. et al. An atypical form of bullous congenital ichthyosiform erythroderma is caused by a mutation in the L12 linker region of keratin 1. J Invest Dermatol 1998; 111: p. 1224­6. 8 Ikeda, S., Shigihara, T., Mayuzumi, N. et al. Mutations of ATP2C1 in Japanese patients with Hailey­Hailey disease: intrafamilial and interfamilial phenotype variations and lack of correlation with mutation patterns. J Invest Dermatol 2001; 117: p. 1654­6. 9 Ruiz­Perez, V.L., Carter, S.A., Healy, E. et al. ATP2A2 mutations in Darier’s disease: variant cutaneous phenotypes are associated with missense mutations, but neuropsychiatric features are independent of mutation class. Hum Mol Genet 1999; 8: p. 1621­30. 10 Wang, C.C., Chao, S.C., Tsai, T.H. Hailey­Hailey disease: a novel mutation of the ATP2C1 gene in a Taiwanese family with divergent clinical presentation. J Eur Acad Dermatol Venereol 2008; 22: p. 1145­6. 11 Poblete­Gutierrez, P., Wiederholt, T., Konig, A. et al. Allelic loss underlies type 2 segmental Hailey­Hailey disease, providing molecular confirmation of a novel genetic concept. J Clin Invest 2004; 114: p. 1467­74. 13 Chapter II Mal de Meleda Adapted from Compound heterozygosity for ARS Component B mutations in a Dutch patient with Mal de Meleda.