Finnish amyloidosis: from protein to gene

The Finnish type of hereditary amyloidosis (McKusick No. 105120) represents a clinically and biochemically distinct entity among the amyloid polyneuropathy syndromes. It was first described in 1969 by Meretoja as a heritable syndrome of systemic paramyloidosis with lattice dystrophy of the cornea, cranial neuropathy, skin changes and various internal symptoms [l]. By the end of the 1970s more than 300 cases of this autosomal dominant form of hereditary amyloidosis had been recorded in Finland, with a clustering of the cases in two neighbouring southern Finnish districts, South Hame and Kymenlaakso [2, 31. However, the disease is not limited to Finland, and cases have been described from other countries including The Netherlands [4], Denmark [5] and the United States [6, 71. In contrast to the Portuguese, Swedish, Japanese, Polish, Danish, Illinois and Appalachian amyloid polyneuropathy syndromes, which were all shown to be related to amyloid fibril deposits of the transthyretin (prealbumin) type [8], the biochemical nature of the amyloid fibrils in the Finnish type remained unidentified for a long time. A breakthrough in this field of research occurred in January 1990 when it was reported that the amyloid fibril protein in Finnish amyloidosis represents a new type of amyloid protein, the amino acid sequence of which is homologous with gelsolin [9]. Gelsolin is a calciumand polyphosphoinisitideregulated actin-modulating protein, which occurs in both a cytoplasmic and a secreted form. Both types of gelsolin are derived by alternative transcriptional initiation sites and message processing from a single gene located on chromosome 9 [lo-121. Gelsolin binds actin monomers, nucleates actin filament growth and severs actin filaments. The function of circulating gelsolin has not been defined but it may be required for the clearance of actin filaments that are released into the bloodstream and the extracellular space in response to tissue injury. The amyloid fibrils in Finnish amyloidosis are formed by polymerization of gelsolin fragments derived from the inner region of the molecule [9, 13, 14,151. The major fragment is a 71-amino-acid polypeptide that represents residues 173 to 243 of mature gelsolin [14]. It is significant that the amyloid protein forms part of a functional domain of the gelsolin molecule that is involved in the binding of actin filaments. Thus, impaired degradation of the amyloidogenic region of gelsolin and the accumulation of the fragments into amyloid during fibrillogenesis may lcad to disturbances in functionally important gelsolin-actin interactions. Why do gelsolin Gagments accumulate and polymerize to form amyloid fibrils in Finnish amyloidosis? In contrast to one report, which claimed a normal sequence of the first 1 5 N-terminal amino acid residues of the amyloid protein [15], detailed structural analysis of the amyloid protein has revealed a single amino acid substitution (Asp + Asn) at position 15 of the amyloid fibril protein [ 13, 14, 16. 171, corresponding to position 187 in the precursor gelsolin molecule. This substitution renders the variant gelsolin molecule highly amyloidogenic. The disease was finally elucidated by application of the polymerase chain reaction and allele-specific oligonucleotide hybridization analyses of genomic DNA in Finnish amyloidosis. A point mutation was found in the gelsolin gene segment that encodes the amyloid protein [18, 191. The G + A base substitution that was demonstrated is responsible for expression of the mutant Asn-18 7 gelsolin molecule, and is the direct cause of the disease. Finnish hereditary amyloidosis, also referred to in the literature as Meretoja amyloidosis or familial amyloid polyneuropathy type IV (Finnish), can now be classified as an inborn error of gelsolin metabolism. It is noteworthy that Finnish amyloidosis also represents the first human disease that has been shown to be linked to a mutation in the gelsolin gene. The availability of a DNAtest for mutationspecific diagnosis of Finnish amyloidosis [ 181 provides a potential opportunity for detection of presymptomatic gene carriers and prenatal diagnosis of the disease. C. P. J. MAURY, MD Fourth Department of Medicine University of Helsinki Unioninkatu 38 SF-001 70 Helsinki