Publications by authors named "Maria C Bolling"

17 Publications

  • Page 1 of 1

Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues.

J Clin Invest 2021 Jul 22. Epub 2021 Jul 22.

Department of Cardiology, University Medical Center Groningen, Groningen, Netherlands.

The start codon c.1A>G mutation in KLHL24, encoding ubiquitin-ligase KLHL24, results in the loss of 28 N-terminal amino acids (KLHL24-ΔN28) by skipping the initial start codon. In skin, KLHL24-ΔN28 leads to gain of function, excessively targeting intermediate filament keratin-14 for proteasomal degradation, ultimately causing epidermolysis bullosa simplex (EBS). The majority of these EBS-patients are also diagnosed with dilated cardiomyopathy (DCM), but the pathological mechanism in the heart is unknown. As desmin is the cardiac homologue of keratin-14, we hypothesized that KLHL24-ΔN28 leads to excessive degradation of desmin, resulting in DCM. Dynamically loaded engineered heart tissues (dyn-EHTs) were generated from human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes from two patients and three (non)familial controls. Ten-fold lower desmin protein levels were observed in patient-derived dyn-EHTs, in line with diminished desmin levels detected in patients' explanted heart. This was accompanied by tissue dilatation, impaired mitochondrial function, decreased force values and increased cardiomyocyte stress. HEK293 transfection studies confirmed KLHL24-mediated desmin degradation. KLHL24 RNA interference or direct desmin overexpression recovered desmin protein levels, restoring morphology and function in patient-derived dyn-EHTs. To conclude, presence of KLHL24-ΔN28 in cardiomyocytes leads to excessive degradation of desmin, affecting tissue morphology and function, that can be prevented by restoring desmin protein levels.
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http://dx.doi.org/10.1172/JCI140615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409593PMC
July 2021

Dynamic loading of human engineered heart tissue enhances contractile function and drives a desmosome-linked disease phenotype.

Sci Transl Med 2021 07;13(603)

Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA.

The role that mechanical forces play in shaping the structure and function of the heart is critical to understanding heart formation and the etiology of disease but is challenging to study in patients. Engineered heart tissues (EHTs) incorporating human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes have the potential to provide insight into these adaptive and maladaptive changes. However, most EHT systems cannot model both preload (stretch during chamber filling) and afterload (pressure the heart must work against to eject blood). Here, we have developed a new dynamic EHT (dyn-EHT) model that enables us to tune preload and have unconstrained contractile shortening of >10%. To do this, three-dimensional (3D) EHTs were integrated with an elastic polydimethylsiloxane strip providing mechanical preload and afterload in addition to enabling contractile force measurements based on strip bending. Our results demonstrated that dynamic loading improves the function of wild-type EHTs on the basis of the magnitude of the applied force, leading to improved alignment, conduction velocity, and contractility. For disease modeling, we used hiPSC-derived cardiomyocytes from a patient with arrhythmogenic cardiomyopathy due to mutations in the desmoplakin gene. We demonstrated that manifestation of this desmosome-linked disease state required dyn-EHT conditioning and that it could not be induced using 2D or standard 3D EHT approaches. Thus, a dynamic loading strategy is necessary to provoke the disease phenotype of diastolic lengthening, reduction of desmosome counts, and reduced contractility, which are related to primary end points of clinical disease, such as chamber thinning and reduced cardiac output.
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http://dx.doi.org/10.1126/scitranslmed.abd1817DOI Listing
July 2021

Juvenile and adult vulvar pemphigoid, an under recognized entity: Case series of fourteen patients.

JAAD Case Rep 2021 Jul 24;13:75-80. Epub 2021 May 24.

Department of Dermatology, Center of Blistering Diseases, European Reference Network-Skin Member, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

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http://dx.doi.org/10.1016/j.jdcr.2021.05.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213975PMC
July 2021

Assessment of Diagnostic Strategy for Mucous Membrane Pemphigoid.

JAMA Dermatol 2021 Jul;157(7):780-787

University of Groningen, University Medical Center Groningen, Department of Dermatology, Center of Blistering Diseases, European Reference Network-Skin Member, the Netherlands.

Importance: An accurate diagnosis of mucous membrane pemphigoid (MMP) is essential to reduce diagnostic and therapeutic delay.

Objective: To assess the diagnostic accuracy of direct immunofluorescence microscopy on mucosal biopsy specimens and immunoserology in a large cohort of patients with suspected MMP.

Design, Setting, And Participants: This retrospective cohort study was carried out in a single tertiary care center for blistering diseases between January 2002 and March 2019. Eligible participants were patients with suspected MMP and paired data on at least a mucosal biopsy specimen for direct immunofluorescence microscopy (DIF) and indirect immunofluorescence microscopy (IIF) on a human salt-split skin substrate (SSS). In addition, an optional DIF test on a skin biopsy specimen and one or more performed routine immunoserologic tests were analyzed. Data analysis was conducted from April 2019, to June 2020.

Main Outcomes And Measures: Diagnostic accuracy of DIF, IIF SSS, and immunoblot for BP180 and BP230.

Results: Of the 787 participants, 121 (15.4%) received the diagnosis of MMP (50 men [41.3%], 71 women [58.7%]; mean [SD] age at diagnosis, 60.1 [17.7] years). Sixty-seven of the patients with MMP (55.4%) had monosite involvement, of which oral site was the most frequently affected (51 [42.1%]). No significant difference was found between the sensitivity of DIF on a perilesional buccal biopsy and a normal buccal biopsy (89.3% vs 76.7%). Three patients with solitary ocular involvement showed a positive DIF of only the oral mucosa. In 6 patients with a negative mucosal DIF, a skin biopsy confirmed diagnosis of MMP. Overall, IIF SSS was less sensitive (44.6%), but highly specific (98.9%). The sensitivity of immunoblot (66.1%) was higher compared to SSS, but with lower specificity (91.3%).

Conclusions And Relevance: This comparative diagnostic accuracy study of a cohort of 787 patients found a high sensitivity of a mucosal DIF biopsy for diagnosis of MMP, and lower sensitivity of serologic analysis. A biopsy can be taken from either perilesional or normal buccal mucosa. An additional DIF biopsy of another mucosal site or of affected or unaffected skin may increase the diagnostic yield and is recommended in patients with negative DIF results and high clinical suspicion.
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http://dx.doi.org/10.1001/jamadermatol.2021.1036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082433PMC
July 2021

Meta-Analysis of Mutations in or Identified in a Large Cohort of 224 Patients.

Genes (Basel) 2021 01 9;12(1). Epub 2021 Jan 9.

Department of Medical Sciences/Dermatology, Uppsala University, SE-751 85 Uppsala, Sweden.

The autosomal recessive congenital ichthyoses (ARCI) are a nonsyndromic group of cornification disorders that includes lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. To date mutations in ten genes have been identified to cause ARCI: , , , , , , , , , and . The main focus of this report is the mutational spectrum of the genes and , which encode the epidermal lipoxygenases arachidonate 12-lipoxygenase, i.e., 12R type (12R-LOX), and the epidermis-type lipoxygenase-3 (eLOX3), respectively. Deficiency of 12R-LOX and eLOX3 disrupts the epidermal barrier function and leads to an abnormal epidermal differentiation. The type and the position of the mutations may influence the ARCI phenotype; most patients present with a mild erythrodermic ichthyosis, and only few individuals show severe erythroderma. To date, 88 pathogenic mutations in and 27 pathogenic mutations in have been reported in the literature. Here, we presented a large cohort of 224 genetically characterized ARCI patients who carried mutations in these genes. We added 74 novel mutations in and 25 novel mutations in . We investigated the spectrum of mutations in and in our cohort and additionally in the published mutations, the distribution of these mutations within the gene and gene domains, and potential hotspots and recurrent mutations.
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http://dx.doi.org/10.3390/genes12010080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826849PMC
January 2021

The effectiveness of rituximab in pemphigus and the benefit of additional maintenance infusions: Daily practice data from a retrospective study.

J Am Acad Dermatol 2020 Nov 12;83(5):1503-1505. Epub 2020 Jun 12.

Department of Dermatology, Center for Blistering Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1016/j.jaad.2020.06.024DOI Listing
November 2020

Immunoglobulin M bullous pemphigoid: An enigma.

JAAD Case Rep 2020 Jun 21;6(6):518-520. Epub 2020 Apr 21.

Department of Dermatology, University of Groningen, University Medical Center Groningen, Center for Blistering Diseases, Groningen, Netherlands.

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http://dx.doi.org/10.1016/j.jdcr.2020.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256243PMC
June 2020

Hyperkeratotic hand eczema: Eczema or not?

Contact Dermatitis 2020 Sep 1;83(3):196-205. Epub 2020 Jun 1.

Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: Hyperkeratotic hand eczema (HHE) is a typical clinical hand eczema subtype with a largely unknown pathophysiology.

Objective: To investigate histopathology, expression of keratins (K), epidermal barrier proteins, and adhesion molecules in HHE.

Methods: Palmar skin biopsies (lesional and perilesional) were obtained from seven HHE patients and two healthy controls. Moreover, 135 candidate genes associated with palmoplantar keratoderma were screened for mutations.

Results: Immunofluorescence staining showed a significant reduction of K9 and K14 in lesional skin. Upregulation was found for K5, K6, K16, and K17 in lesional skin compared with perilesional and healthy palmar skin. Further, upregulation of involucrin and alternating loricrin staining, both in an extracellular staining pattern, was found. Filaggrin expression was similar in lesional, perilesional, and control skin. No monogenetic mutations were found.

Conclusion: Currently, the phenotype of HHE is included in the hand eczema classification system; however, it can be argued whether this is justified. The evident expression of filaggrin and involucrin in lesional skin does not support a pathogenesis of atopic eczema. The upregulation of K6, K16, and K17 and reduction of K9 and K14 might contribute to the underlying pathogenesis. Unfortunately, comparison with hand eczema studies is not possible yet, because similar protein expression studies are lacking.
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http://dx.doi.org/10.1111/cod.13572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496397PMC
September 2020

Oral Lesions in Autoimmune Bullous Diseases: An Overview of Clinical Characteristics and Diagnostic Algorithm.

Am J Clin Dermatol 2019 Dec;20(6):847-861

Department of Dermatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.

Autoimmune bullous diseases are a group of chronic inflammatory disorders caused by autoantibodies targeted against structural proteins of the desmosomal and hemidesmosomal plaques in the skin and mucosa, leading to intra-epithelial or subepithelial blistering. The oral mucosa is frequently affected in these diseases, in particular, in mucous membrane pemphigoid, pemphigus vulgaris, and paraneoplastic pemphigus. The clinical symptoms are heterogeneous and may present with erythema, blisters, erosions, and ulcers localized anywhere on the oral mucosa, and lead to severe complaints for the patients including pain, dysphagia, and foetor. Therefore, a quick and proper diagnosis with adequate treatment is needed. Clinical presentations of autoimmune bullous diseases often overlap and diagnosis cannot be made based on clinical features alone. Immunodiagnostic tests are of great importance in differentiating between the different diseases. Direct immunofluorescence microscopy shows depositions of autoantibodies along the epithelial basement membrane zone in mucous membrane pemphigoid subtypes, or depositions on the epithelial cell surface in pemphigus variants. Additional immunoserological tests are useful to discriminate between the different subtypes of pemphigoid, and are essential to differentiate between pemphigus and paraneoplastic pemphigus. This review gives an overview of the clinical characteristics of oral lesions and the diagnostic procedures in autoimmune blistering diseases, and provides a diagnostic algorithm for daily practice.
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http://dx.doi.org/10.1007/s40257-019-00461-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872602PMC
December 2019

KLHL24: Beyond Skin Fragility.

J Invest Dermatol 2019 01;139(1):22-24

University of Groningen, University Medical Center Groningen, Department of Dermatology, Center for Blistering Diseases, Groningen, The Netherlands. Electronic address:

KLHL24 mutations have recently been associated with epidermolysis bullosa simplex. Initial studies focused on skin fragility. However, the picture of KLHL24 mutations causing extracutaneous human disease is emerging, with dilated cardiomyopathy as a strong association. In addition, neurological disease is suspected as well. Careful clinical follow-up and functional studies of (mutated) KLHL24 in these tissues are needed.
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http://dx.doi.org/10.1016/j.jid.2018.08.010DOI Listing
January 2019

Generalized Ichthyotic Peeling Skin Syndrome due to FLG2 Mutations.

J Invest Dermatol 2018 08 2;138(8):1881-1884. Epub 2018 Mar 2.

University of Groningen, University Medical Center Groningen, Department of Dermatology, Center for Blistering Diseases, Groningen, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2018.01.038DOI Listing
August 2018

Extensive acantholysis as the major histological feature of a severe case of Dowling Meara-epidermolysis bullosa simplex: a reappraisal of acantholysis in the newborn.

Eur J Dermatol 2011 Nov-Dec;21(6):966-71

Department of Dermatology, Hospital Clínic and University School of Medicine, C/ Villaroel 170, CP: 08036 Barcelona, Spain.

Epidermolysis bullosa (EB) is a heterogeneous group of inherited skin disorders characterized by blistering and skin fragility secondary to mechanical trauma. Epidermolysis bullosa simplex (EBS) is the most frequent form of EB, with Dowling-Meara (DM-EBS) subtype being the most severe form in this group. Conventional histopathological evaluation is usually of low value in the diagnosis of EB, and significant histological features have rarely been reported in this group of diseases. We describe a case of severe DM-EBS in which acantholysis was observed in the histological examination. This finding led us to consider other diagnoses, such as neonatal pemphigus vulgaris or lethal acantholytic EB. Histological, immunological, ultrastructural and genetic tests were performed, leading to a final diagnosis of DM-EBS. Therefore, we believe that DM-EBS should be considered in the differential diagnosis of a newborn with blisters, where acantholysis is the main histological feature.
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http://dx.doi.org/10.1684/ejd.2011.1497DOI Listing
April 2012

Lethal acantholytic epidermolysis bullosa.

Dermatol Clin 2010 Jan;28(1):131-5

St John's Institute of Dermatology, King's College London, Guy's Campus, London, UK.

Lethal acantholytic epidermolysis bullosa (LAEB) is an autosomal recessive disorder caused by mutations in the gene encoding the desmosomal protein, desmoplakin (DSP). It is recognized as a distinct form of suprabasal epidermolysis bullosa simplex, although only a single case has been reported. The phenotype comprises severe fragility of skin and mucous membranes with marked transcutaneous fluid loss. Other features include total alopecia, neonatal teeth, and anonychia. Skin biopsy reveals abnormal desmosomes with suprabasal clefting and acantholysis and disconnection of keratin intermediate filaments from desmosomes. The DSP abnormalities present in the affected individual involved expression of truncated DSP polypeptides that lacked the tail domain of the protein. This part of DSP has a vital role in binding to keratin filaments. The affected neonate died after 10 days because of heart failure with evidence of loss of epithelial integrity in the skin, lung, gastrointestinal tract, and bladder. This article provides a clinicopathologic overview of this unique desmosomal genodermatosis, set in the context of other DSP gene mutations, both dominant and recessive, that can cause a spectrum of skin, hair, and heart abnormalities.
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http://dx.doi.org/10.1016/j.det.2009.10.015DOI Listing
January 2010

A new pathogenic keratin 5 mutation in a Hindoestan family with localized epidermolysis bullosa simplex.

Eur J Dermatol 2010 Jan-Feb;20(1):27-9. Epub 2009 Oct 2.

Department of Dermatology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands.

Epidermolysis bullosa simplex is an autosomal dominant inherited skin blistering disorder caused by mutations in the genes KRT5 or KRT14 coding for the basal epidermal keratins 5 and 14, respectively. We describe a novel heterozygous pathogenic missense mutation (KRT5:c.596A>T, p.Lys199Met) in a Hindoestan male with early onset localized epidermolysis bullosa simplex that segregated with the phenotype in the family. We also found a new heterozygous amino acid substitution polymorphism in the variable keratin 14 N-terminal head domain (KRT14:c.88C>T, p.Arg30Cys), that did not segregate with the phenotype.
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http://dx.doi.org/10.1684/ejd.2010.0804DOI Listing
April 2010

Skin and heart: une liaison dangereuse.

Exp Dermatol 2009 Aug 23;18(8):658-68. Epub 2009 Jun 23.

Department of Dermatology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

Both skin and heart are subject to shear mechanical stress and need to be stress-resistant in a flexible way. The intercellular connecting structures in skin and heart, the desmosomes, that have to resist these forces show remarkable resemblance in epidermis and myocardium. Mutations in desmosomal proteins lead to inherited desmosomal cardiocutaneous syndromes (DCCS): une liaison dangereuse. This article will critically review the cutaneous and cardiac features as well as the molecular background of DCCS, such as Naxos disease and Carvajal syndrome caused by deficiencies of plakoglobin and desmoplakin respectively. In addition, potential other desmosomal gene candidates for an involvement in cardiocutaneous syndromes are considered. The skin features in these syndromes may be the hallmark for the presence of progressive and ultimately lethal cardiac disease. Knowledge of these skin features and early recognition of such a syndrome may provide opportunities to halt or slow down cardiac disease progression, treat arrhythmias and even prevent sudden death.
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http://dx.doi.org/10.1111/j.1600-0625.2009.00908.xDOI Listing
August 2009

Revertant mosaicism in junctional epidermolysis bullosa due to multiple correcting second-site mutations in LAMB3.

J Clin Invest 2007 May;117(5):1240-8

Center for Blistering Diseases, Department of Dermatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, NL-9700 RB Groningen, The Netherlands.

Revertant mosaicism due to in vivo reversion of an inherited mutation has been described in the genetic skin disease epidermolysis bullosa (EB) for the genes KRT14 and COL17A1. Here we demonstrate the presence of multiple second-site mutations, all correcting the germline mutation LAMB3:c.628G-->A;p.E210K, in 2 unrelated non-Herlitz junctional EB patients with revertant mosaicism. Both probands had a severe reduction in laminin-332 expression in their affected skin. Remarkably, the skin on the lower leg of patient 078-01 (c.628G-->A/c.1903C-->T) became progressively clinically healthy, with normal expression of laminin-332 on previously affected skin. In the other proband, 029-01 (c.628G-->A/c.628G-->A), the revertant patches were located at his arms, shoulder, and chest. DNA analysis showed different second-site mutations in revertant keratinocytes of distinct biopsy specimens (c.565-3T-->C, c.596G-->C;p.G199A, c.619A-->C;p.K207Q, c.628+42G-->A, and c.629-1G-->A), implying that there is not a single preferred mechanism for the correction of a specific mutation. Our data offer prospects for EB treatment in particular cases, since revertant mosaicism seems to occur at a higher frequency than expected. This opens the possibility of applying revertant cell therapy in mosaic EB of the LAMB3 gene by using autologous naturally corrected keratinocytes, thereby bypassing the recombinant gene correction phase.
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http://dx.doi.org/10.1172/JCI30465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1857245PMC
May 2007
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