University of Groningen

Epidermolysis bullosa simplexBolling, Maria Caroline

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Epidermolysis bullosa simplex

New insights in desmosomal cardiocutaneous syndrome

Marieke Bolling, 2010

Copyright © 2010 by M.C. Bolling, Groningen, The Netherlands

Cover design: Marten Faber, www.bens.nl

Page lay-out: Proefschriftmaken.nl

Printed by: Boxpress BV, Oisterwijk

Financial support for the publication of this thesis was provided by:

ABBOTT BV; Afdeling Dermatologie Groningen; Astellas Pharma Inc; Fagron BV; Galderma;

GlaxoSmithKline; Graduate School of Medicine Groningen; Janssen-Cilag BV; LEO Pharma

BV; Louis Widmer Nederland; Medeco; Medizorg; Mölnycke Healthcare BV; Novartis Pharma

BV; Roche; Schering-Plough; Stichting Studiefonds Dermatologie; University of Groningen

(Rijksuniversiteit Groningen); Universitair Medisch Centrum Groningen (UMCG); Wyeth.

The financial support by the J.P. Nater Foundation and Stichting Vlinderkind (www.vlinderkind.nl)

for part of the research described in this thesis is gratefully acknowledged.

Epidermolysis bullosa simplex

New insights in

desmosomal cardiocutaneous syndromes

Proefschrift

ter verkrijging van het doctoraat in de

Medische Wetenschappen

aan de Rijksuniversiteit Groningen

op gezag van de

Rector Magnificus, dr. F. Zwarts,

in het openbaar te verdedigen op

woensdag 21 april 2010

om 14.45 uur

door

Maria Caroline Bolling

geboren op 7 juni 1980

te Gouda

Promotor: Prof. dr. M.F. Jonkman

Beoordelingscommissie: Prof. dr. M.P. van den Berg

Prof. dr. W.H.I. McLean

Prof. dr. R.J. Sinke

ISBN: 978-90-8891-155-2

To the people in my heart

´I´ve got you under my skin,

Je t´ai dans ma peau´

Paranimfen: P.C. van den Akker

A.M.G. Pasmooij

7

Contents

List of abbreviations 9

Chapter 1 Introduction 13

Aim and outline of the thesis 37

Chapter 2 Mutations in KRT5 and KRT14 cause basal 57

epidermolysis bullosa simplex in 75% of the patients

Chapter 3 Plectin mutations in basal epidermolysis bullosa 81

simplex with wild-type KRT5 and KRT14 genes

Chapter 4 A novel mutation in the L12 domain of keratin 1 is 99

associated with mild epidermolytic ichthyosis

Chapter 5 Chromosomal microdeletion explains extracutaneous 111

features in a in a patient with the monogenic

genodermatosis Kindler syndrome

Chapter 6 Skin and heart: une liaison dangereuse 127

Chapter 7 PLEC1 mutations underlie adult-onset dilated 159

cardiomyopathy in epidermolysis bullosa simplex

with muscular dystrophy

Chapter 8 Lethal acantholytic epidermolysis bullosa simplex due 171

to a novel homozygous mutation in DSP:

expanding the phenotype and implications for

desmoplakin function in skin and heart

Chapter 9 Discussion and future perspectives 189

Summary 231

Nederlandse samenvatting (Dutch summary) 247

Dankwoord/Acknowledgements 267

List of publications 273

9

List of abbreviations

List of abbreviations

ABD actin-binding domain

aCGH array comparative genomic hybridisation

AD autosomal dominant

ARVC arrhythmogenic right ventricular cardiomyopathy

ALVC arrhythmogenic right ventricular cardiomyopathy

bp basepair

β4 β4 integrin subunit of integrin α6β4

BMZ basement membrane zone

cDNA coding DNA

Cx43 connexin-43

DCCS desmosomal cardio-cutaneous syndrome

DCM dilated cardiomyopathy

DDD Dowling-Degos Disease

DEB dystrophic epidermolysis bullosa

DNA deoxyribonucleic acid

DP desmoplakin

Dsc desmocollin

Dsg desmoglein

EB epidermolysis bullosa

EBS epidermolysis bullosa simplex

EBS-AR epidermolysis bullosa simplex autosomal recessive

EBS-DM epidermolysis bullosa simplex Dowling Meara

EBS-loc epidermolysis bullosa simplex localized

EBS-migr epidermolysis bullosa simplex with migratory circinate erythema

EBS-MP epidermolysis bullosa simplex with mottled pigmentation

ECG electrocardiogram

EI epidermolytic ichthyosis

EM electron microscopy

FA focal adhesion

FFH-1 fermitin family homologue-1

fs frameshift

gDNA genomic DNA

ICS intercellular substance

ID intercalated disc

IDP inner dense plaque

IF intermediate filament

10

List of abbreviations

JEB junctional epidermolysis bullosa

K1 keratin 1

K5 keratin 5

K10 keratin 10

K14 keratin 14

KS Kindler syndrome

LAEB lethal acantholytic epidermolysis bullosa

MD muscular dystrophy

NFJS Naegeli Franceschetti Jadassohn Syndrome

ODP outer dense plaque

OMIM Online Mendelian Inheritance in Man

PA pyloric atresia

PCR polymerase chain reaction

PG plakoglobin

PKP plakophilin

PPK palmoplantar keratoderma

PTC premature termination codon

PV pemphigus vulgaris

RNA ribonucleic acid

SF-EDS skin fragility - ectodermal dysplasia syndrome

SF-WH skin fragility - woolly hair syndrome

SNP single nucleotide polymorphism

SR spectrin-repeat

BP180 type XVII collagen

WPW Wolff Parkinson White syndrome