title: A novel fibrotic disorder associated with increased dermal fibroblast proliferation and downregulation of genes of the microfibrillar network.
abstract: Clinical evaluation of a young woman with subcutaneous fibrotic nodules, progressive distal joint contractures and marfanoid stature revealed a previously unrecognized fibrotic disorder characterized by several unique phenotypic features and some features overlapping with known disorders. Mutational analysis of the FBN1 and FBN2 genes excluded Marfan syndrome and congenital contractural arachnodactyly. MMP2 gene sequence analysis excluded multicentric osteolysis, nodulosis and arthropathy. The lack of mutations within the MAGP2 gene also excluded an MAGP2-associated disorder. In order to establish the mechanistic basis for the severe skin pathology noted in this patient, we performed transcriptional profiling of dermal fibroblasts, and candidate gene expression studies in conjunction with immunocytochemistry and cell-based and functional assays. Data from these experiments have further excluded any previously recognized fibrotic disorder and identified a unique pattern of gene expression in this patient consistent with progressive fibrosis. The pathogenic mechanisms included persistent proliferation of dermal fibroblasts in coexistence with a disarray of the microfibrillar network. Collagen accumulation, moreover, could be linked to extensive crosslinking resulting from increased activities of lysyl oxidases (LOX and LOXL), and lack of remodelling due to deficiencies in collagenolytic matrix metalloproteinases. The disorder may represent a novel syndrome in which transforming growth factor-β1-independent dermal fibrosis, unlike known microfibrillar disorders caused by single gene deficiencies, associates with a disarray of the microfibrillar network.
authors.affiliation: John A. Burns School of Medicine, University of Hawaii at Manoa, 1960 East West Road, Honolulu, HI 96822, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Szauter
authors.forename: A
authors.initials: A
authors.lastname: Ordas
authors.forename: R M
authors.initials: RM
authors.lastname: Laxer
authors.forename: E
authors.initials: E
authors.lastname: Pope
authors.forename: D
authors.initials: D
authors.lastname: Wherrett
authors.forename: B
authors.initials: B
authors.lastname: Alman
authors.forename: M
authors.initials: M
authors.lastname: Mink
authors.forename: C D
authors.initials: CD
authors.lastname: Boyd
authors.forename: K
authors.initials: K
authors.lastname: Csiszar
authors.forename: A
authors.initials: A
authors.lastname: Hinek
mesh_terms: D000328:Adult; D001706:Biopsy; D049109:Cell Proliferation; D003285:Contractile Proteins / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004252:DNA Mutational Analysis; D020405:Dermis / Q000473:pathology* / Q000648:ultrastructure; D015536:Down-Regulation; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D005355:Fibrosis / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D008840:Microfilament Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods; D000072260:RNA Splicing Factors; D017422:Sequence Analysis, DNA; D055815:Young Adult; D054392:Adipokines
chemical_list: D003285:Contractile Proteins; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D020778:Matrix Metalloproteinase 2; D008840:Microfilament Proteins; D000072260:RNA Splicing Factors; C000605722:FBN1 protein, human; D054392:Adipokines; C000605723:FBN2 protein, human; C115627:MFAP5 protein, human; C016598:microfibrillar protein; C522361:MMP2 protein, human