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University of Groningen Epidermolysis Bullosa Simplex Bolling, Maria University of Groningen Epidermolysis bullosa simplex Bolling, Maria Caroline IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2010 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Bolling, M. C. (2010). Epidermolysis bullosa simplex: new insights in desmosomal cardiocutaneous syndromes. s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 10-10-2021 5 Chromosomal microdeletion explains extracutaneous features observed in a patient with the monogenic genodermatosis Kindler syndrome SJ White1*, MC Bolling2*, GT Spijker2, MP van den Berg3, PC van den Akker4, RG Hislop5, WHI McLean1, MF Jonkman2 1Epithelial Genetics Group, Division of Molecular Medicine, Colleges of Life Sciences and Medicine, Dentistry & Nursing, University of Dundee, Dundee, DD1 5EH, UK; Departments of 2Dermatology, 3Cardiology, and 4Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; and 5Human Genetics Unit, NHS Tayside, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK. Accepted for publication in the Journal of Investigative Dermatology * Both authors contributed equally to this work. Chapter 5 Abstract Kindler syndrome [MIM#173650] is an autosomal recessive genodermatosis that shares some features with epidermolysis bullosa. The molecular basis of the condition is loss-of-function mutations in the FERMT1 (or KIND1) gene encoding the actin/membrane-associated focal adhesion protein fermitin-family-homologue-1 (FFH-1, or kindlin-1). Here, we report on the oldest patient yet described with clinical mucocutaneous and intestinal features of Kindler syndrome, such as poikiloderma, recurrent actinic keratoses, cutaneous squamous cell carcinoma, gingival erosions, esophageal and urethral strictures, and intestinal problems. A seemingly homozygous FERMT1 loss-of-function mutation was found ([c.423_435del; c.448_450del], p.Ser142LeufsX14). However, additional clinical features not readily explainable by FFH-1 loss- of-function were present, like cardiac hypertrophy with intraventricular conduction delay, mild dysmorphic features, mental retardation, and joint deformities. Therefore, array comparative genomic hybridization (aCGH) was performed that revealed a heterozygous ~3 megabase microdeletion of chromosome 20p12.3 leading to monoallelic loss of several genes including FERMT1. Additionally, the gene BMP2 was lost which has been associated with a cardiogenetic arrhythmia disorder, facial dysmorphisms, mental retardation and skeletal malformations. Thus our patient has a contiguous gene syndrome. This study underscores the importance of performing aCGH in cases of seemingly homozygous mutations in monogenic disorders with additional unexplainable clinical features, to exclude a contiguous gene syndrome. 112 Contiguous gene defect in Kindler syndrome Introduction Kindler syndrome (KS; [MIM#173650]) is a rare autosomal recessive genodermatosis, with principal features of acral blistering and photosensitivity from early childhood.1, 2 Blistering tends to resolve with age, followed by a diffuse, progressive poikiloderma in later life. Many additional symptoms have been reported.3, 4 Loss of fermitin family homologue-1 (FFH-1, or kindlin-1) expression encoded by the gene FERMT1 (or KIND1), causes KS.5, 6 FFH-1 belongs to a family of proteins that additionally includes FFH-2 and FFH-3, which localize to actin-cell matrix adhesion sites (focal adhesions) and are involved in regulating integrin function.7, 8 KS is the first genodermatosis resulting from defects in the transmembrane linking of the actin cytoskeleton to the extracellular matrix. Loss of FFH-1 in keratinocytes results in reduced cell proliferation, loss of cell polarity, decreased adhesion and increased apoptosis.9 To date, 40 different recessive FERMT1 mutations have been identified, the majority of which are predicted to lead to loss-of- function of FFH-1.4-6, 10-22 Here we report on the oldest patient with mucocutaneous features of KS and an unusual, seemingly homozygous FERMT1 mutation who displayed additional clinical features such as mental retardation, cardiac abnormalities, and skeletal malformation not readily explainable by FFH-1 loss of function. Subsequently, array comparative genomic hybridisation (aCGH) showed that this patient has a contiguous gene syndrome. Materials and Methods Immunofluorescence and electron microscopic analysis of patient’s skin samples One 4 mm-diameter punch biopsy (for immunofluorescence) and one 2 mm-diameter punch biopsy (for electron microscopy (EM)) were taken from atrophic skin of the dorsal aspect of the hand. The sample for immunofluorescence was snap frozen and the sample for EM was fixed in 2% glutaraldehyde. EM and immunofluorescence analysis were then performed as previously described.23 The following antibodies were used for immunofluorescence analysis: anti- Kindlin-1 C-terminus (rabbit polyclonal, gift from Prof. J.A. McGrath, London, UK), anti-keratin 5 (rabbit polyclonal BL18, gift from Prof. E.B. Lane, Dundee, Scotland), anti-keratin 14 (mouse clone RCK107, Abcam, Cambridge, UK), anti-laminin-332 (mouse clone GB3, Abcam, Cambridge, UK), anti-type VII collagen (mouse clone LH7.2) and anti-α-actinin (mouse clone BM-75.2) (both Sigma Aldrich, St. Louis, MO), anti-α3 integrin (mouse clone J143), anti-α6 integrin (rat clone GOH3), anti-β4 integrin (mouse clone 58XB4) (all gifts from Dr. A. Sonnenberg, Amsterdam, NL), anti-plectin (mouse clone HD121, gift from Dr. K. Owaribe, Nagoya, Japan), anti-actin (rabbit polyclonal, gift from Prof. G. Gabbiani, Geneva, Switzerland). FERMT1 gene mutation analysis After informed consent, genomic DNA was obtained from the proband. PCR amplification of the FERMT1 gene was performed as described previously with slight modifications.5 Specific 113 Chapter 5 details on primers and amplification conditions can be obtained by contacting the authors. The study was conducted according to the Declaration of Helsinki Principles. The medical ethical committee of the University Medical Center Groningen, the Netherlands, approved all described studies. Array comparative genomic hybridisation analysis An aCGH was performed on patient genomic DNA and sex-matched reference DNA (Promega, Southampton, UK) by using a CytoChip (version 2) bacterial artificial chromosome (BAC) array (BlueGnome, Cambridge, UK). Other than labelling 600ng (rather than 400ng) of each DNA sample, this test was done according to the manufacturer’s protocol. Briefly, the DNA samples were labelled overnight with Cy3-dCTP or Cy5-dCTP (GE Healthcare, Uppsala, Sweden) using the BioPrime labelling kit (Invitrogen, Paisley, UK). Unincorporated label was removed using Autoseq G50 columns (GE Healthcare). Overnight dye-swap hybridisations and washes were carried-out using a Tecan HS 400 Pro hybridisation station. Array slides were scanned on an Axon 4100A (Molecular Devises, Sunnyvale, CA, USA) and data analysed with BlueFuse (version 3.5) software (BlueGnome, Cambridge, UK). Results Mucocutaneous features of Kindler syndrome with additionally mental retardation, cardiac and skeletal abnormalities The patient is a 63-year-old Caucasian male with a history of blistering and photosensitivity (figure 1a; more detailed clinical images available as supplementary figure S1, at the end of the chapter). As far as is known, no family history of skin disorders was present. Blistering mostly affecting trunk and extremities was present from birth and was more pronounced in the summer, on sun exposure and on minor trauma. The tendency to blister decreased later in life. However, skin fragility and easily erosive skin persisted throughout life. The skin was generally very dry with a wrinkled, so-called ‘cigarette paper’ appearance, particularly on sun-exposed sites. There had been widespread progressive atrophy of the skin and ichthyosiform desquamation mainly on the chest, back and extremities. Telangiectases and areas of hyperpigmentation were evident. Although the patient avoided sun exposure when possible, he nonetheless developed recurrent actinic keratoses on the face and a squamous cell carcinoma of the dorsum of the left hand at age 59. Hair appeared normal. The nails, however, were fragile with a tendency to onychoschizia. Bilateral ectropion was present from early age and the patient suffered recurrent conjunctivitis. Recurrent operations were necessary to correct the reappearing
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