Anders Vahlquist

Uppsala University, Uppsala, Uppsala, Sweden

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Publications (181)693.19 Total impact

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    ABSTRACT: Heterozygous mutations in the DSG1 gene are known to cause autosomal dominant striate palmoplantar keratoderma (PPK) (MIM 148700).(1,2) A new phenotype due to biallelic mutations in DSG1 which is characterized by severe dermatitis, multiple allergies and metabolic wasting has been recently described as SAM syndrome (MIM 615508).(3,4) In one Norwegian family with two affected half-brothers (III-2, III-4) we observed a very phenotype which includes variable combinations of skin symptoms such as severe PPK, circumscribed skin erosions and psoriasiform erythroderma. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Aug 2015 · British Journal of Dermatology

  • No preview · Article · Jan 2015 · Acta Dermato Venereologica
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    ABSTRACT: Abstract is missing (Short Communication).
    Preview · Article · Jul 2014 · Acta Dermato Venereologica
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    ABSTRACT: Palmoplantar keratoderma of the Gamborg-Nielsen type (PPK-GN) is a rare autosomal recessive skin disorder described in patients from Sweden. Mal de Meleda (MDM) is also a rare autosomal recessive inherited PPK first reported in 5 families from the island of Meleda. The 2 conditions phenotypically overlap and are characterised by palmoplantar erythematous hyperkeratotic plaques. The genetic background giving rise to PPK-GN has hitherto been unknown, whereas MDM is known to be caused by mutations in the gene encoding secreted Ly-6/uPAR-related protein 1, SLURP-1. In the present study we scrutinised individuals affected by PPK-GN for mutations in the SLURP1 gene and identified 2 different mutations. Fourteen Swedish patients were homozygous for a previously described mutation, c.43T>C, while one individual was a compound heterozygote with one copy of a novel mutation, c.280T>A, in addition to one copy of the c.43T>C mutation. Hereby we confirm that PPK-GN is an allelic variant of MDM.
    Preview · Article · Mar 2014 · Acta Dermato-Venereologica
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    ABSTRACT: Congenital skin fragility is a heterogeneous disorder with epidermolysis bullosa and various skin infections as the leading causes. However, even rare diseases must be considered in the differential diagnosis of neonatal skin blistering, including some genetic syndromes with extracutaneous involvement. One such syndrome is ectodermal dysplasia due to deficiency of desmoplakin, a desmosomal protein essential for cellular cohesion in both epithelia and cardiac tissues. Desmoplakin is encoded by the DSP gene, which is localized on chromosome 6p24. Both dominant and recessive mutations in this gene have been reported to cause skin fragility and keratinization defects. We report a child born with a fragile epidermis, alopecia, thick nails, and focal hyperkeratoses on the digits and knees. She was found to have a deficiency of desmoplakin caused by compound heterozygous DSP mutations. She has gradually developed signs of a left ventricular cardiomyopathy.
    Preview · Article · Jan 2014 · Clinical and Experimental Dermatology
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    ABSTRACT: Loss-of-function mutations in FLG (encoding filaggrin) are a predisposing factor for atopic dermatitis (AD) and cause ichthyosis vulgaris (IV). Patients with AD and IV display impaired skin barrier and dry skin, and altered epidermal expression of genes in pro-inflammatory and lipid metabolic pathways are often evident. To evaluate the effect of three different moisturizers on skin barrier function and epidermal gene expression in patients with AD/IV in relation to FLG mutation status. Patients (n = 43) were classified according to their FLG status: AD with FLG+/+ (n = 14), AD with FLG+/- (n = 14), and AD/IV with FLG-/- (n = 15). Dryness score and transepidermal water loss (TEWL) were monitored on volar forearms, and punch biopsies were taken for analysis of gene expression. Measurements were repeated after 4 weeks of treatment with either of two moisturizers on each forearm. Treatment with any of the three moisturizers significantly reduced dryness score and TEWL in the group as a whole. FLG-/- patients displayed the largest reduction in dryness score. Only minute changes occurred in the mRNA expression of 15 selected epidermal genes. Moisturizing treatment improves dry skin and certain aspects of abnormal skin barrier function, especially in patients with AD/IV and dual FLG mutations, but does not normalize the epidermal gene expression profile.
    No preview · Article · Dec 2013 · Journal of the European Academy of Dermatology and Venereology
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    ABSTRACT: Oral liarozole, a retinoic acid metabolism-blocking agent, may be an alternative to systemic retinoid therapy in patients with lamellar ichthyosis. To demonstrate the efficacy and safety of once-daily oral liarozole in the treatment of moderate/severe lamellar ichthyosis. A double-blind, multinational, parallel phase II/III trial (NCT00282724). Patients aged ≥14 years with moderate/severe lamellar ichthyosis (Investigator's Global Assessment [IGA] score ≥3) were randomized 3:3:1 to receive oral liarozole (75 or 150 mg) or placebo once-daily for 12 weeks. Assessments included: IGA; a five-point scale for erythema, scaling and pruritus severity; Short Form-36 health survey; Dermatology Life Quality Index (DLQI); and safety parameters. The primary efficacy variable was response rate at week 12 (responder: ≥2 point decrease in IGA from baseline). Sixty-four patients were enrolled. At week 12, 11/27 (41%; 75 mg liarozole), 14/28 (50%; 150 mg liarozole) and 1/9 (11%; placebo) patients were responders; difference between groups (150 mg liarozole vs. placebo) was not significant (P = 0.056). Mean IGA and scaling scores decreased from baseline in both liarozole groups at weeks 8 and 12 vs. placebo; erythema and pruritus scores were similar between treatment groups. Improvement in DLQI score was observed in both liarozole groups. Treatment with liarozole for 12 weeks was well tolerated. The primary efficacy variable did not reach statistical significance, possibly owing to small sample size following premature termination. However, once-daily oral liarozole, 75 and 150 mg, improved scaling and DLQI and was well tolerated in patients with moderate/severe lamellar ichthyosis. This article is protected by copyright. All rights reserved.
    Full-text · Article · Sep 2013 · British Journal of Dermatology
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    ABSTRACT: Missense mutations affecting membrane-bound transcription factor protease, site 2 (MBTPS2) have been associated with IFAP syndrome with or without BRESHECK syndrome, with keratosis follicularis spinulosa decalvans, and Olmsted syndrome. This metalloprotease activates, by intramembranous trimming in conjunction with the protease MBTPS1, regulatory factors involved in sterol control of transcription and in cellular stress response. In this study, eleven different MBTPS2 missense mutations detected in patients from 13 unrelated families were correlated with the clinical phenotype, with their effect on cellular growth in media without lipids, and their potential role for sterol control of transcription. Seven variants were novel [c.774C>G (p.I258M); c.758G>C (p.G253A); c.686T>C (p.F229S); c.1427T>C (p.L476S); c.1430A>T (p.D477V); c.1499G>A (p.G500D); c.1538T>C (p.L513P)], four had previously been reported in unrelated sibships [c.261G>A (p.M87I); c.1286G>A (p.R429H); c.1424T>C (p.F475S); c.1523A>G (p.N508S)]. In the enzyme, the mutations cluster in transmembrane domains. Amino-acid exchanges near the active site are more detrimental to functionality of the enzyme and, clinically, associated with more severe phenotypes. In male patients, a genotype-phenotype correlation begins to emerge, linking the site of the mutation in MBTPS2 with the clinical outcome described as IFAP syndrome with or without BRESHECK syndrome, KFSDX, Olmsted syndrome, or possibly further X-linked traits with an oculocutaneous component.
    Full-text · Article · Mar 2013 · Human Mutation
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    Hao Li · Anders Vahlquist · Hans Törmä
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    ABSTRACT: BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) is caused by mutations in ≥10 different genes, of which transglutaminase-1 (TGM1) predominates. A rare form is ichthyosis prematurity syndrome (IPS) caused by mutations in SLC27A4 encoding fatty acid transporter protein 4 (FATP4), believed to be an acyl-CoA synthetase activating long- and very-long-chain FA. Another ARCI is caused by mutations in NIPAL4, coding for ichthyin, which is proposed to be a magnesium transporter or a trans-membrane receptor. A possible interaction between FATP4 and ichthyin has not been studied before. OBJECTIVE: To find common denominators in the pathogenesis of ARCI. METHODS: FATP4 and ichthyin were analyzed by immunofluorescence and proximity ligation assay (PLA) in healthy and ARCI patient skin and in in vitro models of ARCI epidermis. RESULTS: Both proteins were expressed in the upper stratum granulosum of normal epidermis and PLA confirmed a close interaction between FATP4 and ichthyin. In IPS skin lacking FATP4 we found reduced ichthyin expression and this finding could be reproduced in organotypic epidermis with siRNA silenced SLC27A4. In contrast, increased FATP4 staining was found in patients with ichthyin (NIPAL4) mutations and in organotypic epidermis with silenced NIPAL4. In patients with TGM1 mutations, the expression of both FATP4 and ichthyin was increased, but the PLA signal was low probably indicating a malfunctioning protein interaction. CONCLUSION: Our study suggests that FATP4, ichthyin and TGM1 interact in lipid processing essential for maintaining the epidermal barrier function. It is also hypothesized that ichthyin serves as Mg(2+)-transporter for FATP4 in this process.
    Full-text · Article · Dec 2012 · Journal of dermatological science
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    ABSTRACT: A Danish-Swedish collaboration was established to identify and classify a Danish cohort of patients with epidermolytic ichthyosis, also known as epidermolytic hyperkeratosis. Patients were recruited from 5 dermatology departments in Denmark, and data were obtained using a structured questionnaire and a systematic examination together with photographs, histopathological descriptions and blood samples for mutational analysis. Sixteen patients from 12 families with generalized or naevoid epidermolytic ichthyosis and ichthyosis bullosa of Siemens were identified. Five families had mutations in K1 and 6 families had mutations in K10. Nine patients had been treated with systemic retinoids (etretinate, acitretin, isotretinoin or alitretinoin), but only 3 patients had acceptable treatment responses and chose to continue therapy. In conclusion epidermolytic ichthyosis is a rare disease with a prevalence of approximately 1 in 350,000 in Denmark and a high percentage of de novo mutations (75%). We identified 4 novel disease-causing mutations.
    Full-text · Article · Aug 2012 · Acta Dermato-Venereologica
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    Hao Li · Elizabeth P Loriè · Judith Fischer · Anders Vahlquist · Hans Törmä
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    ABSTRACT: Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of skin barrier diseases due inter alia to mutations in transglutaminase-1 (TGM1), in lipoxygenases (LOXs) of the hepoxilin pathway, and in ichthyin, a putative Mg(2+) transporter encoded by the NIPAL4 gene. In search of a common pathogenic pathway for ARCI, we investigated the epidermal expression of TGM1, 12R-LOX, eLOX-3, and ichthyin in skin biopsies from four healthy controls and nine patients with ARCI. In healthy skin, TGM1, ichthyin, and the LOX enzymes were predominantly expressed in the upper epidermis where colocalization signals could also be demonstrated by in situ proximity ligation assay. In patients with ALOX12B mutations and abnormal 12R-LOX expression, the colocalization signal for eLOX-3 and TGM1 was increased 4-fold. In contrast, patients with NIPAL4 mutations and abnormal ichthyin expression showed increased 12R-LOX and eLOX-3 staining and a colocalization signal of these LOXs that was three times the normal intensity. Treatment of these patients with a retinoid-mimetic drug, liarozole, normalized the expression of 12R-LOX and attenuated the colocalization signal. Altogether, our data indicate that ichthyin and TGM1 are functionally closely related in the lipid processing and that this metabolic pathway can be modified by retinoids.
    Full-text · Article · May 2012 · Journal of Investigative Dermatology
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    ABSTRACT: X-linked recessive ichthyosis (XLRI) is due to deletions or inactivating mutations in the steroid sulfatase (STS) gene. This results in an accumulation of cholesterol sulphate affecting the packing of intercorneocyte lipids. XLRI is characterized by dry, scaly skin and increased skin barrier permeability; patients are often dependent on daily use of moisturizers. To examine the biophysical and molecular changes in the skin of patients with XLRI compared with healthy volunteers, and to analyse the effects of moisturizers on the patients' barrier function. Patients with XLRI (n=14) and healthy controls (n=14) were included in the study. Skin dryness score, transepidermal water loss (TEWL) and skin surface pH were monitored at baseline, and punch biopsies were obtained for mRNA expression profiles determined by oligonucleotide arrays. Measurements were repeated in the patients with XLRI after a 4-week treatment with three different moisturizers on the volar forearms. Patients with XLRI showed, compared with healthy controls, increased dryness and TEWL, equal skin pH and altered expression of 27 genes. There were no signs of activation of inflammation or repair pathways. Five selected genes were significantly altered also on quantitative polymerase chain reaction analysis. Treatment with the moisturizers showed similar effects: they improved skin dryness but had no effect on TEWL, pH or expression of selected genes. Despite a dysfunctional skin barrier, the limited number of genes altered in XLRI skin suggests that no inflammatory or repair mechanisms are triggered. Treatment with moisturizers does not have any major impact on the skin barrier properties of patients with XLRI.
    No preview · Article · Apr 2012 · British Journal of Dermatology
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    Agneta Gånemo · Mette Sommerlund · Anders Vahlquist

    Full-text · Article · Jan 2012 · Acta Dermato-Venereologica
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    ABSTRACT: Autosomal recessive congenital ichthyosis (ARCI) is a group of disorders characterized by abnormal desquamation of the skin and a disrupted epidermal water barrier. Ichthyin/NIPAL4 gene mutations have been identified in a subgroup of ARCI patients, but the role of ichthyin in epidermis remains elusive. In order to obtain new insights concerning the characteristics of ichthyin and the ARCI pathogenesis, we studied the expression and localization of ichthyin and related epidermal components in cultured keratinocytes and skin sections from patients with Ichthyin mutations and healthy controls. We observed an up-regulation of Ichthyin mRNA levels after in vitro differentiation of keratinocytes from both a patient with Ichthyin mutations and controls. Confocal and electron microscopy analyses of immunolabeled skin sections revealed that ichthyin localizes to desmosomes and keratins in both patients with mutant Ichthyin and controls, with an increased immunolabeling in patients. Nile red lipid analysis of skin sections exposed intra-cellular lipid accumulations in cells of the granular and cornified layers in patients but not in controls, consistent with the pathognomonic lipid membrane structures previously identified in epidermis from patients. Our combined findings indicate that ichthyin is associated with keratins and desmosomes in epidermis and is involved in lipid metabolism, possibly through processing of lamellar bodies. These results provide new clues to the understanding of the epidermal water barrier and the pathogenesis in ARCI.
    No preview · Article · Jan 2012 · Archives for Dermatological Research
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    Dataset: Table S2
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    ABSTRACT: Enrichment of chromosomal regions in all AD patients. Chromosomal regions (cytobands) enriched in 2292 induced genes and 2076 repressed genes using DAVID bioinformatics resource. Cytobands are sorted by p-value and previously described genetic association to AD is marked yellow. (DOCX)
    Preview · Dataset · Dec 2011
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    Dataset: Table S3
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    ABSTRACT: Candidate genes mapped to altered pathways depending on FLG genotype. Each annotated gene with corresponding p-value and fold change depending on FLG genotype and corresponding cytoband. Cytobands with previously reported AD association marked with yellow. (DOCX)
    Preview · Dataset · Dec 2011
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    Dataset: Table S4
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    ABSTRACT: Quantitative Real-Time PCR mRNA expression depending on FLG genotype. Selected genes with corresponding p-values and ratio of up- or down regulation in patient groups depending on FLG genotype compared to a healthy control group. (XLS)
    Preview · Dataset · Dec 2011
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    Dataset: Table S1
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    ABSTRACT: Human Gene 1.0 ST array mRNA expression. P-values and fold change of each annotated gene are mean values of five subjects from each patient group (FLG+/+, FLG+/− and FLG−/−) compared to a five subjects from the healthy control group (using the March 2006: UCSC hg18, NCBI Build 36). (XLSX)
    Preview · Dataset · Dec 2011
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    ABSTRACT: Several common genetic and environmental disease mechanisms are important for the pathophysiology behind atopic dermatitis (AD). Filaggrin (FLG) loss-of-function is of great significance for barrier impairment in AD and ichthyosis vulgaris (IV), which is commonly associated with AD. The molecular background is, however, complex and various clusters of genes are altered, including inflammatory and epidermal-differentiation genes. The objective was to study whether the functional and molecular alterations in AD and IV skin depend directly on FLG loss-of-function, and whether FLG genotype determines the type of downstream molecular pathway affected. Patients with AD/IV (n = 43) and controls (n = 15) were recruited from two Swedish outpatient clinics and a Swedish AD family material with known FLG genotype. They were clinically examined and their medical history recorded using a standardized questionnaire. Blood samples and punch biopsies were taken and trans-epidermal water loss (TEWL) and skin pH was assessed with standard techniques. In addition to FLG genotyping, the STS gene was analyzed to exclude X-linked recessive ichthyosis (XLI). Microarrays and quantitative real-time PCR were used to compare differences in gene expression depending on FLG genotype. Several different signalling pathways were altered depending on FLG genotype in patients suffering from AD or AD/IV. Disease severity, TEWL and pH follow FLG deficiency in the skin; and the number of altered genes and pathways are correlated to FLG mRNA expression. We emphasize further the role of FLG in skin-barrier integrity and the complex compensatory activation of signalling pathways. This involves inflammation, epidermal differentiation, lipid metabolism, cell signalling and adhesion in response to FLG-dependent skin-barrier dysfunction.
    Full-text · Article · Dec 2011 · PLoS ONE

  • No preview · Article · Jul 2011 · Journal of dermatological science

Publication Stats

5k Citations
693.19 Total Impact Points

Institutions

  • 1972-2014
    • Uppsala University
      • • Department of Immunology, Genetics and Pathology
      • • Department of Medical Sciences
      • • The Rudbeck Laboratory
      • • Department of Medicinal Chemistry
      Uppsala, Uppsala, Sweden
  • 1977-2012
    • Uppsala University Hospital
      • Department of Dermatology
      Uppsala, Uppsala, Sweden
  • 2005
    • Philipps University of Marburg
      Marburg, Hesse, Germany
  • 2002
    • Akademiska Sjukhuset
      Uppsala, Uppsala, Sweden
  • 1990-1997
    • University Hospital Linköping
      • Department of Dermatology
      Linköping, Östergötland, Sweden
  • 1988-1996
    • Linköping University
      • Faculty of Health Sciences
      Linköping, Östergötland, Sweden
  • 1992
    • Aarhus University Hospital
      • Department of Dermatology
      Aarhus, Central Jutland, Denmark