Human Molecular Genetics, Vol 5, 1237-1243, Copyright © 1996 by Oxford University Press
H Kangas, T Paunio, N Kalkkinen, A Jalanko and L Peltonen
Amyloidoses are a group of diseases where abnormal fibrillar protein
deposits accumulate in patients' tissues. In familial amyloidosis of the
Finnish type (FAF), or gelsolin-related amyloidosis, the amyloid subunit
protein consists of gelsolin peptides of amino acids 173-243 with the
disease causing substitution at Asp187. Gelsolin is an actin- modulating
protein and exists in both secretory and intracellular forms both encoded
by a single gene in chromosome 9. We have previously shown that the
FAF-associated forms of secretory gelsolin carrying the Asp187Asn or
Asp187Tyr mutations are abnormally processed in cells, resulting in the
secretion of an aberrant 68 kDa carboxyterminal fragment. Here we
demonstrate by N-terminal sequencing that the amino terminus of this
abnormal fragment is the amino acid 173 and thus represents the N-terminus
of the FAF amyloid. We also provide evidence that the same truncated
gelsolin can be found among the aberrant gelsolin fragments detected in
patients' CSF. Finally, we also expressed the FAF-associated forms of
intracellular gelsolin in COS-1 cells, and found no abnormality in their
processing opposite to secretory form. Our results provide strong evidence
that the secretory gelsolin is solely responsible for the amyloid formation
in FAF.
ARTICLES
In vitro expression analysis shows that the secretory form of gelsolin is the sole source of amyloid in gelsolin-related amyloidosis
Department of Human Molecular Genetics, National Public Health Institute, Helsinki, Finland.
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