Universität zu Köln

Grether, Nicolai B., Napravnik, Felix, Imhof, Thomas, Linke, Reinhold P., Brasen, Jan H., Schmitz, Jessica, Dohrn, Maike, Schneider, Christian, Svacina, Martin K. R., Stetefeld, Jorg, Koch, Manuel ORCID: 0000-0002-2962-7814 and Lehmann, Helmar C. (2022). Amyloidogenicity assessment of transthyretin gene variants. Ann. Clin. Transl. Neurol., 9 (8). S. 1252 - 1264. HOBOKEN: WILEY. ISSN 2328-9503

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Abstract

Objective: Hereditary transthyretin-mediated amyloidosis is a treatable condition caused by amyloidogenic variants in the transthyretin-gene resulting in severe peripheral neuropathy or cardiomyopathy. Only about a third of over 130 known variants are clearly pathogenic, most are classified as variants of uncertain significance. A clear delineation of these into pathogenic or non-pathogenic is highly desirable but hampered by low frequency and penetrance. We thus sought to characterize their amylogenic potential by an unbiased in vitro approach. Methods: Thioflavin T and turbidity assays were used to compare the potential of mammalian cell expressed wt-transthyretin and 12 variant proteins (either variants of uncertain significance, benign, pathogenic) to aggregate and produce amyloid fibrils in vitro. As proof of principle, the assays were applied to transthyretin-Ala65Val, a variant that was newly detected in a family with peripheral neuropathy and amyloid deposits in biopsies. In silico analysis was performed to compare the position of the benign and pathogenic variants. Results: Transthyretin-Ala65Val showed a significantly higher amyloidogenic potential than wt-transthyretin, in both turbidity- and Thioflavin T-assays, comparable to known pathogenic variants. The other eight tested variants did not show an increased amyloidogenic potential. In silico structural analysis further confirmed differences between pathogenic and benign variants in position and interactions. Interpretation: We propose a biochemical approach to assess amyloidogenic potential of transthyretin variants. As exemplified by transthyretin-Ala65Val, data of three assays together with histopathology clearly demonstrates its amyloidogenicity.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Grether, Nicolai B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Napravnik, Felix UNSPECIFIED UNSPECIFIED UNSPECIFIED Imhof, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Linke, Reinhold P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Brasen, Jan H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmitz, Jessica UNSPECIFIED UNSPECIFIED UNSPECIFIED Dohrn, Maike UNSPECIFIED UNSPECIFIED UNSPECIFIED Schneider, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Svacina, Martin K. R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stetefeld, Jorg UNSPECIFIED UNSPECIFIED UNSPECIFIED Koch, Manuel UNSPECIFIED orcid.org/0000-0002-2962-7814 UNSPECIFIED Lehmann, Helmar C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-685810
DOI:	10.1002/acn3.51626
Journal or Publication Title:	Ann. Clin. Transl. Neurol.
Volume:	9
Number:	8
Page Range:	S. 1252 - 1264
Date:	2022
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	2328-9503
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language FAMILIAL AMYLOID POLYNEUROPATHY; WILD-TYPE TRANSTHYRETIN; HEART-FAILURE; ATTR VAL30MET; TTR; DENATURATION; PENETRANCE Multiple languages Clinical Neurology; Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68581