Two Types of Fibrils in ATTR Amyloidosis: Implications for Clinical Phenotype and Treatment Outcome

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MARC

Ihse, Elisabet,1977-Uppsala universitet,Molekylär och morfologisk patologi (author)

Two Types of Fibrils in ATTR Amyloidosis : Implications for Clinical Phenotype and Treatment Outcome

BookEnglish2011

Publisher, publication year, extent ...

Uppsala :Acta Universitatis Upsaliensis,2011
65 s.
electronicrdacarrier

Numbers

LIBRIS-ID:oai:DiVA.org:uu-160980
ISBN:9789155482343
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-160980URI

Supplementary language notes

Language:English
Summary in:English

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SwePubSwePub

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Subject category:vet swepub-contenttype
Subject category:dok swepub-publicationtype

Series

Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine,1651-6206 ;727

Notes

Systemic amyloidoses are a group of lethal diseases where proteins aggregate into fibrillar structures, called amyloid fibrils, that deposits throughout the body. Transthyretin (TTR) causes one type of amyloidosis, in which the aggregates mainly infiltrate nervous and cardiac tissue. Almost a hundred different mutations in the TTR gene are known to trigger the disease, but wild-type (wt) TTR is also incorporated into the fibrils, and may alone form amyloid. Patients with the TTRV30M mutation show, for unknown reasons, two clinical phenotypes. Some have an early onset of disease without cardiomyopathy while others have a late onset and cardiomyopathy. It has previously been described that amyloid fibrils formed from TTRV30M can have two different compositions; either with truncated molecules beside full-length TTR (type A) or only-full-length molecules (type B). In this thesis, the clinical importance of the two types of amyloid fibrils was investigated. We found that the fibril composition types are correlated to the two clinical phenotypes seen among TTRV30M patients, with type A fibrils present in late onset patients and type B fibrils in early onset patients. The only treatment for hereditary TTR amyloidosis has been liver transplantation, whereby the liver producing the mutant TTR is replaced by an organ only producing wt protein. However, in some patients, cardiac symptoms progress post-transplantationally. We demonstrated that the propensity to incorporate wtTTR differs between fibril types and tissue types in TTRV30M patients, with cardiac amyloid of type A having the highest tendency. This offers an explanation to why particularly cardiac amyloidosis develops after transplantation, and suggests which patients that are at risk for such development. By examining patients with other mutations than TTRV30M, we showed that, in contrast to the general belief, a fibril composition with truncated TTR is very common and might even be the general rule. This may explain why TTRV30M patients often have a better outcome after liver transplantation than patients with other mutations. In conclusion, this thesis has contributed with one piece to the puzzle of understanding the differences in clinical phenotype and treatment response between TTR amyloidosis patients, by demonstrating corresponding differences at a molecular level.

Subject headings and genre

NATURVETENSKAP Biologi Biokemi och molekylärbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Biochemistry and Molecular Biology hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Cell- och molekylärbiologi hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Cell and Molecular Biology hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Andra medicinska och farmaceutiska grundvetenskaper hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Other Basic Medicine hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Klinisk laboratoriemedicin hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Clinical Laboratory Medicine hsv//eng
amyloid
transthyretin
familial amyloidotic polyneuropathy
TTRV30M
non-TTRV30M
wild-type
liver transplantation
cardiomyopathy
fibril composition
Biokemi
Biochemistry
Biology with specialization in Molecular Biology
Biologi med inriktning mot molekylärbiologi
Experimentell patologi
Experimental Pathology
Medical Biochemistry
Medicinsk biokemi
Molecular Biology
Molekylärbiologi
Pathology
Patologi

Added entries (persons, corporate bodies, meetings, titles ...)

Westermark, Per,ProfessorUppsala universitet,Molekylär och morfologisk patologi (thesis advisor)
Hammarström, Per,ProfessorLinköpings Universitet, Inst för fysik, kemi och biologi (opponent)
Uppsala universitetMolekylär och morfologisk patologi (creator_code:org_t)

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NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Other Basic Medi ...

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