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dc.contributor.authorSnorradottir, Asbjorg Osk
dc.contributor.authorIsaksson, Helgi J
dc.contributor.authorIngthorsson, Saevar
dc.contributor.authorOlafsson, Elias
dc.contributor.authorPalsdottir, Astridur
dc.contributor.authorBragason, Birkir Thor
dc.date.accessioned2017-05-11T14:35:18Z
dc.date.available2017-05-11T14:35:18Z
dc.date.issued2017-04
dc.date.submitted2017
dc.identifier.citationPathological changes in basement membranes and dermal connective tissue of skin from patients with hereditary cystatin C amyloid angiopathy. 2017, 97 (4):383-394 Lab. Invest.en
dc.identifier.issn1530-0307
dc.identifier.pmid28067897
dc.identifier.doi10.1038/labinvest.2016.133
dc.identifier.urihttp://hdl.handle.net/2336/620181
dc.descriptionTo access publisher's full text version of this article click on the hyperlink belowen
dc.description.abstractHereditary cystatin C amyloid angiopathy (HCCAA) is a genetic disease caused by a mutation in the cystatin C gene. Cystatin C is abundant in cerebrospinal fluid and the most prominent pathology in HCCAA is cerebral amyloid angiopathy due to mutant cystatin C amyloid deposition with associated cerebral hemorrhages, typically in young adult carriers. Analyses of post-mortem brain samples shows that pathological changes are limited to arteries and regions adjacent to arteries. The severity of pathological changes at post-mortem has precluded the elucidation of the evolution of histological changes. Mutant cystatin C deposition in carriers is systemic and has, for example, been described in the skin, suggesting similar pathological mechanisms both in the brain and outside of the central nervous system. The aim of this study was to use skin biopsies from asymptomatic and symptomatic carriers to study intermediate events in HCCAA pathogenesis. We found that cystatin C deposition in minimally affected samples was limited to the basement membrane (BM) between the dermis and epidermis. When the deposits were more advanced, they extended to other BM regions in the skin. Our results showed that the immunoreactivity of the BM protein COLIV was increased to a similar extent in all carrier biopsies and cystatin C deposits were in close association with COLIV. The density of fibroblasts in the upper dermis of carrier skin was increased, whereas the distribution of other cell types examined did not differ compared with control biopsies. COLIV and cystatin C immunoreactivity in carrier biopsies was closely associated with the fibroblasts. The results of this study, in conjunction with our previous results regarding pathological BM changes in leptomeningeal arteries of patients, suggest that BM changes are early and important events in HCCAA pathogenesis that could facilitate cystatin C deposition and aggregation.
dc.description.sponsorshipIcelandic Centre for Research (RANNIS) University of Iceland Research Fund Memorial fund of Hafdis Kjartansdottir Memorial fund of Helga Jonsdottir and Sigurlidi Kristjansson Heilavernd funden
dc.language.isoenen
dc.publisherNature Publishing Groupen
dc.relation.urlhttp://www.nature.com/labinvest/journal/v97/n4/full/labinvest2016133a.htmlen
dc.rightsArchived with thanks to Laboratory investigation; a journal of technical methods and pathologyen
dc.subjectHeilablóðfallen
dc.subjectArfgengien
dc.subjectPTT12en
dc.subjectHEM12en
dc.subjectNEU12en
dc.subject.meshCerebral Amyloid Angiopathy, Familialen
dc.subject.meshBasement Membraneen
dc.titlePathological changes in basement membranes and dermal connective tissue of skin from patients with hereditary cystatin C amyloid angiopathy.en
dc.typeArticleen
dc.contributor.department[ 1 ] Univ Iceland, Inst Expt Pathol Keldur, Reykjavik, Iceland Show the Organization-Enhanced name(s) [ 2 ] Landspitali Univ Hosp, Dept Pathol, IS-101 Reykjavik, Iceland Show the Organization-Enhanced name(s) [ 3 ] Univ Iceland, Stem Res Unit, Biomed Ctr, Reykjavik, Iceland Show the Organization-Enhanced name(s) [ 4 ] Landspitali Univ Hosp, Dept Haematol Lab, Reykjavik, Iceland Show the Organization-Enhanced name(s) [ 5 ] Univ Iceland, Fac Med, Reykjavik, Iceland Show the Organization-Enhanced name(s) [ 6 ] Landspitali Univ Hosp, Dept Neurol, Reykjavik, Icelanden
dc.identifier.journalLaboratory investigation; a journal of technical methods and pathologyen
dc.rights.accessClosed - Lokaðen
html.description.abstractHereditary cystatin C amyloid angiopathy (HCCAA) is a genetic disease caused by a mutation in the cystatin C gene. Cystatin C is abundant in cerebrospinal fluid and the most prominent pathology in HCCAA is cerebral amyloid angiopathy due to mutant cystatin C amyloid deposition with associated cerebral hemorrhages, typically in young adult carriers. Analyses of post-mortem brain samples shows that pathological changes are limited to arteries and regions adjacent to arteries. The severity of pathological changes at post-mortem has precluded the elucidation of the evolution of histological changes. Mutant cystatin C deposition in carriers is systemic and has, for example, been described in the skin, suggesting similar pathological mechanisms both in the brain and outside of the central nervous system. The aim of this study was to use skin biopsies from asymptomatic and symptomatic carriers to study intermediate events in HCCAA pathogenesis. We found that cystatin C deposition in minimally affected samples was limited to the basement membrane (BM) between the dermis and epidermis. When the deposits were more advanced, they extended to other BM regions in the skin. Our results showed that the immunoreactivity of the BM protein COLIV was increased to a similar extent in all carrier biopsies and cystatin C deposits were in close association with COLIV. The density of fibroblasts in the upper dermis of carrier skin was increased, whereas the distribution of other cell types examined did not differ compared with control biopsies. COLIV and cystatin C immunoreactivity in carrier biopsies was closely associated with the fibroblasts. The results of this study, in conjunction with our previous results regarding pathological BM changes in leptomeningeal arteries of patients, suggest that BM changes are early and important events in HCCAA pathogenesis that could facilitate cystatin C deposition and aggregation.


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