Monthly Archives: March 2015

Loss of ADAM17 is associated with severe multiorgan dysfunction.

Posted on March 31, 2015 by Bandsma RH, van Goor H, Yourshaw M, Horlings RK, Jonkman MF, Schölvinck EH, Karrenbeld A, Scheenstra R, Kömhoff M, Rump P, Koopman-Keemink Y, Nelson SF, Escher JC, Cutz E, Martín MG


Loss of ADAM17 is associated with severe multiorgan dysfunction.

Hum Pathol. 2015 Mar 5;

Authors: Bandsma RH, van Goor H, Yourshaw M, Horlings RK, Jonkman MF, Schölvinck EH, Karrenbeld A, Scheenstra R, Kömhoff M, Rump P, Koopman-Keemink Y, Nelson SF, Escher JC, Cutz E, Martín MG

Abstract
ADAM metallopeptidase domain 17 (ADAM17) is responsible for processing large numbers of proteins. Recently, 1 family involving 2 patients with a homozygous mutation in ADAM17 were described, presenting with skin lesions and diarrhea. In this report, we describe a second family confirming the existence of this syndrome. The proband presented with severe diarrhea, skin rash, and recurrent sepsis, eventually leading to her death at the age of 10 months. We performed exome sequencing and detailed pathological and immunological investigations. We identified a novel homozygous frameshift mutation in ADAM17 (NM_003183.4:c.308dupA) leading to a premature stop codon. CD4(+) and CD8(+) T-cell stimulation assays showed severely diminished tumor necrosis factor-α and interleukin-2 production. Skin biopsies indicated a focal neutrophilic infiltrate and spongiotic dermatitis. Interestingly, the patient developed unexplained systolic hypertension and nonspecific hepatitis with apoptosis. This report provides evidence for an important role of ADAM17 in human immunological response and underscores its multiorgan involvement.

PMID: 25804906 [PubMed – as supplied by publisher]

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Large-Scale Electron Microscopy Maps of Patient Skin and Mucosa Provide Insight into Pathogenesis of Blistering Diseases.

Posted on March 21, 2015 by Sokol E, Kramer D, Diercks GF, Kuipers J, Jonkman MF, Pas HH, Giepmans BN


Large-Scale Electron Microscopy Maps of Patient Skin and Mucosa Provide Insight into Pathogenesis of Blistering Diseases.
J Invest Dermatol. 2015 Mar 19;
Authors: Sokol E, Kramer D, Diercks GF, Kuipers J, Jonkman MF,… Continue reading →






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Health-related quality of life in epidermolysis bullosa: Validation of the Dutch QOLEB questionnaire and assessment in the Dutch population.

Posted on March 11, 2015 by Yuen WY, Frew JW, Veerman K, van den Heuvel ER, Murrell DF, Jonkman MF


Related Articles

Health-related quality of life in epidermolysis bullosa: Validation of the Dutch QOLEB questionnaire and assessment in the Dutch population.

Acta Derm Venereol. 2014 Jul;94(4):442-7

Authors: Yuen WY, Frew JW, Veerman K, van den Heuvel ER, Murrell DF, Jonkman MF

Abstract
Defining the health-related quality of life (HRQoL) in patients suffering from the heritable blistering disease epidermolysis bullosa (EB) is important in assessing the efficacy of new treatments. The quality of life in EB questionnaire (QOLEB) is an English 17-item EB-specific HRQoL measurement tool. The aim of this study was to develop a validated and reliable QOLEB in Dutch and assess the HRQoL in Dutch EB patients. The QOLEB was translated to Dutch according to protocol. Fifty-five adult patients across 4 EB subtypes participated. The QOLEB had excellant correlation with the Skindex-29 (ρs = 0.86), good correlation with the SF-36 physical score (ρs = -0.75), and moderate correlation with the SF-36 mental score (ρs = -0.43). The discriminative validity between the 4 different EB subtypes was significant (p = 0.002). The internal consistency was excellent (α = 0.905), and the test-retest reliability strong (ρs = 0.88). In conclusion, the Dutch QOLEB is a reliable and valid instrument for the assessment of the HRQoL in adult EB patients.

PMID: 24337132 [PubMed – indexed for MEDLINE]

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Mutation in exon 1a of PLEC, leading to disruption of plectin isoform 1a, causes autosomal-recessive skin-only epidermolysis bullosa simplex.

Posted on March 1, 2015 by Gosty?ska KB, Nijenhuis M, Lemmink H, Pas HH, Pasmooij AM, Lang KK, Castañón MJ, Wiche G, Jonkman MF


Mutation in exon 1a of PLEC, leading to disruption of plectin isoform 1a, causes autosomal-recessive skin-only epidermolysis bullosa simplex.

Hum Mol Genet. 2015 Feb 24;

Authors: Gostyńska KB, Nijenhuis M, Lemmink H, Pas HH, Pasmooij AM, Lang KK, Castañón MJ, Wiche G, Jonkman MF

Abstract
PLEC, the gene encoding the cytolinker protein plectin, has eight tissue specific isoforms in humans, arising by alternate splicing of the first exon. To date, all PLEC mutations that cause epidermolysis bullosa simplex (EBS) were found in exons common to all isoforms. Due to the ubiquitous presence of plectin in mammalian tissues, EBS from recessive plectin mutations is always associated with extracutaneous involvement including muscular dystrophy, pyloric atresia and cardiomyopathy. We studied a consanguineous family with sisters having isolated blistering suggesting EBS. Skin disease started with foot blisters at walking age and became generalized at puberty while sparing mucous membranes. DNA sequencing revealed a homozygous nonsense mutation (c.46C>T; p.Arg16X) in the first exon of the plectin variant encoding plectin isoform 1a (P1a). Immunofluorescence antigen mapping, transmission electron microscopy, western blot analysis and qRT-PCR were performed on patient skin and cultured keratinocytes, control myocardium and striated muscle samples. We found hypoplastic hemidesmosomes and intra-epidermal ‘pseudojunctional’ cleavage fitting EBS. Screening for cardiomyopathy and muscle dystrophy showed no abnormalities. We report the first cases of autosomal-recessive EBS from P1a deficiency affecting skin, while mucous membranes, heart and muscle are spared. The dominant expression of the P1a isoform in epidermal basal cell layer and cultured keratinocytes suggests that mutations in the first exon of isoform 1a cause skin-only EBS without extracutaneous involvement. Our study characterizes yet another of the eight isoforms of plectin and adds a tissue specific phenotype to the spectrum of ‘plectinopathies’ produced by mutations of unique first exons of this gene.

PMID: 25712130 [PubMed – as supplied by publisher]

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