Gelsolin-derived familial amyloidosis caused by asparagine or tyrosine substitution for aspartic acid at residue 187.
Dominantly inherited familial amyloidosis, Finnish type (FAF) is caused by the accumulation of a 71-amino acid amyloidogenic fragment of mutant gelsolin (GSN). FAF is common in Finland but is very rare elsewhere. In Finland and in two American families, the mutation is a G654A transition leading to an Asp to Asn substitution at residue 187. We found the same mutation in a Dutch family but a Danish FAF family had a G654T mutation, predicting Asp to Tyr at residue 187. We also found the G654T transversion in a Czech family. Using GSN polymorphisms, different haplotypes were found in the Danish and Czech families. We conclude that substitution of the uncharged Asn or Tyr for the acidic Asp at residue 187 creates a conformation that may be preferentially amyloidogenic for GSN.
de la Chapelle
A
A
Department of Medical Genetics, University of Helsinki, Finland.
Tolvanen
R
R
Boysen
G
G
Santavy
J
J
Bleeker-Wagemakers
L
L
Maury
C P
CP
Kere
J
J
D000483:Alleles; D000595:Amino Acid Sequence; D000686:Amyloidosis / Q000235:genetics*; D001483:Base Sequence; D002135:Calcium-Binding Proteins / Q000235:genetics*; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D018260:Gelsolin; D005799:Genes, Dominant; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation
D002135:Calcium-Binding Proteins; D018260:Gelsolin; D008840:Microfilament Proteins; D004247:DNA