SHORT COMMUNICATION Familial Amyloidosis, Finnish Type: G654 + A Mutation of the Gelsolin Gene in Finnish Families and an Unrelated American Family A. DE LA CHAPELLE,* J. KERE,” G. H. SACK, JR.,t R. TOLVANEN,”
AND C. P. J. MAURY$
*Department of Medical Genetics, University of Helsinki, 00290 Helsinki, Finland; TDepartments of Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; and *Fourth Department of Medicine, University of Helsinki, 00 770 Helsinki, Finland ReceivedJanuary
The Finnish type of familial amyloid polyneuropathy (FAF) is an autosomal dominant form of systemic amyloidosis caused by a mutation in the gelsolin gene. The mutation leads to the expression of amyloidogenic mutant Asp187 + Asn gelsolin, an actin-modulating protein. We previously developed a DNA test based on amplification by the polymerase chain reaction followed by allele-specific oligonucleotide hybridization that identifies the base substitution adenine for guanine at nucleotide 654 in the gelsolin gene causing the disease. We show here that the same mutation is present in members of six apparently unrelated Finnish families and in a member of an unrelated American family. These results, taken together with previously published findings in nine additional Finnish families and another unrelated American family, indicate that most, perhaps all, FAF patients in Finland and possibly worldwide carry the same mutation. We suggest two alternative explanations: (i) the mutation arose in a very early common ancestor or (ii) the Asn187 mutation is particularly, perhaps uniquely, amyloido0 1992 Academic Press, Inc. genie.
Amyloidosis is the designation of disorders characterized by the accumulation in tissues of protein fibrils having a twisted P-pleated sheet conformation (5). Several plasma proteins or their fragments are known to be amyloidogenic and give rise to amyloid in various systemic forms of amyloidosis (1). Finnish-type familial amyloid polyneuropathy (FAF), first described by Meretoja (16), is also referred to as Meretoja disease or amyloid cranial neuropathy with lattice cornea1 dystrophy (McKusick No. 105120 (15)). Clinically, it is characterized by adult-onset typical “lattice” cornea1 dystrophy without major loss of vision, progressive cranial neuropathy, skin changes, and often renal and cardiac manifestations. By the 197Os, more than 300 cases had been recorded in Finland (17), and the number of affected persons was subsequently estimated at as many as 1000 (18). In striking contrast, the disorder is rare in other populations, five families having been published worldwide: one in the Netherlands (21), GENOMICS 13,898-901(1992). oc?ss-7543/92 $5.00 Copyright 0 1992 by Academic Press, All rights of reproduction in any form
898 Inc. reserved.
13, 1992
one in Denmark (2), and three in the United States (3, 19, 20). Maury et al. (11) first showed that the amyloid protein in Finnish amyloidosis derives from gelsolin. Subsequently, the amyloid subunit was shown to consist of a 71-amino-acid-long polypeptide fragment having an amino acid substitution Asp + Asn at a position corresponding to codon 187 in the gene for soluble plasma gelsolin (4,10,13). By means of a strategy of polymerase chain reaction (PCR)-mediated amplification followed by hybridization with allele-specific oligonucleotides (ASOs), the expected G to A nucleotide transition at position 654 has been demonstrated by us (12) and others (9). In this study we show that the same G654 + A mutation occurs in numerous Finnish families and in an American family with typical clinical features of FAF. The method we used was described previously (12). Briefly, DNA extracted from venous blood or fixed tissue was amplified using primers derived from published exon sequences of the gelsolin gene (8). The amplified 51-bp fragment extended between nucleotides 630 and 680 in exon 3 containing nucleotide 654 that harbors the mutation. Amplified DNA was dot-blotted onto nylon filters and hybridized with radioactively labeled ASOs corresponding either to the normal sequence or to the mutant sequence. After washing and autoradiography, the results were read as follows: Hybridization to the normal sequence (G654) only indicates a normal homo-
FIG. 1. Pedigree of a Finnish FAF family. Autoradiographs dot-blot hybridizations with the normal (G654) and mutated ASOs are shown below each pedigree symbol.
of the (A654)
SHORT
FIG. patient
2. (A) Pedigree (III-l) at age 51.
of the American
family
with
FAF.
899
COMMUNICATION
(B) Facial
zygote, whereas hybridization both to the normal sequence and to the mutated sequence (A654) indicates heterozygosity for the mutation. Hybridization to the mutant AS0 only indicates homozygosity for the mutation.
appearance
of individual
II-1
at age 62. (C) Facial
appearance
of study
Twenty-eight Finnish individuals belonging to 6 welldocumented families with Finnish amyloidosis were studied. Seventeen affected individuals had the G654 --* A mutation; of these, 2 were homozygously affected (14). Of the 15 positive individuals who were heterozygous for
900
SHORT
COMMUNICATION
the mutation, 13 had typical clinical manifestations. The remaining 2 individuals, 26 and 31 years of age, were themselves unaware of any symptoms of disease; however, in both cases microscopic investigation of the cornea revealed mild lattice dystrophy. Eleven clinically normal individuals were normal homozygotes. Affected individuals were from the family shown in Fig. 1 and from another two-generation family (four affected individuals studied in each), from a pedigree previously reported by us in which we now study one additional individual (six affected (12)) and from three additional pedigrees (one affected studied from each). None of these six Finnish families were aware of any relation between them. A member of an American family (20) also was shown to be heterozygous for the same mutation. The grandmother (I-l; Fig. 2A) of the patient studied was the first member of the family known to be affected with visual difficulties beginning in her fifth decade. She had several operations because of facial weakness and died at 82 while recovering from her last surgery. She knew of no affected relatives. She described the family as being “Scotch-Irish” but no other details are available. Her son (II-l; Fig. 2B) had the first evidence of facial weakness in his sixth decade and this progressed to lip paralysis, protrusion, and eversion. He was first seen in 1962 at Johns Hopkins at age 61, when he had pronounced facial weakness but normal sensation. At age 62 he was found to have cornea1 changes of lattice dystrophy. Electromyography could not stimulate the right facial nerve or facial muscles and disclosed no fibrillation potentials (consistent with a myopathy). Biopsy of facial muscles was compatible with neurogenic atrophy. Esophageal motility was normal but he had frequent sinus bradycardia. He had a series of facial reconstruction procedures to reduce drooling and to control his lower lip. At 75, a cardiac pacemaker was implanted. His facial weakness progressed and he died at 79 after a fall. His son, the study patient (III-l), was first seen in 1979 at age 45 when he had mild facial weakness with bilateral lower eyelid drooping (Fig. 2C). Mild cornea1 stromal lesions were present, but he was otherwise completely well. He was seen again at 51 when the cornea1 changes more closely resembled lattice dystrophy. His sister (111-3) had a four-lid blepharoplasty at age 44 and was troubled with persistent dryness of her eyes. At age 50 she had characteristic cornea1 changes of lattice dystrophy. His daughter (IV-l) had a normal eye examination at age 25. The present results bring to 15 the number of apparently unrelated Finnish families having the same Asn187 mutation. These are 6 families reported here, including the family in which we previously demonstrated cosegregation of the mutation with the disease (12); the original patient whose gelsolin amino acid sequence showed the mutation (ll), 5 unrelated patients studied by AS0 hybridization by Levy et al. (9); and members of 3 unrelated families studied by a slight modification of our method (7). We conclude that this mutation accounts for a large proportion of all Finnish FAF
cases. This is not surprising in view of Meretoja’s demographic and genealogic findings, suggesting the possibility that the Finnish families may have originated from a common ancestor who in the 1300s lived in a parish in Southern Finland (17). Our finding of the same mutation in an American family of Scotch-Irish extraction is interesting. Taken together with the recent demonstration of the same mutation in another American family (Gorevic et al. (6) studying the family described by Purcell et al. (19)) it raises the possibility that this mutation is present in most, if not all, FAF patients worldwide. To account for this hypothesis, we offer two alternative explanations. First, as all patients so far published are of apparently European ancestry, it is not totally inconceivable that a single ancestral mutation could have been transmitted to these individuals. However, it then remains to be explained why the disease is so rare in all populations but Finns, particularly as it has no effect on reproductive fitness. Indeed, in many individuals its only notable harmful effect is a cosmetic one in middle or old age. For the same reason one might also argue that the condition is grossly underdiagnosed or underreported, We note, furthermore, that the two American families with the mutation (Sack et al. (20), reported here; Purcell et al. (19), reported by Gorevic et al. (6)) are of Scotch-Irish and Irish ancestry, respectively. Thus they may share a not-sodistant ancestor. It will be of interest to determine the mutation in the Dutch, Danish, and third known American family (cf. Introduction). The second hypothesis to explain the worldwide occurrence of the same mutation is that it is particularly amyloidogenic. As reviewed by Benson (1) the molecular basis of an increasing number of amyloid diseases has now been elucidated. In only a small number of cases, such as the Met30 transthyretin mutation, the same mutation exists in different populations (discussed in Gorevic et al. (6)). The Asn187 mutation in FAF may be an example of a change leading to a very high, perhaps unique, propensity of gelsolin to form fibrillar amyloid. ACKNOWLEDGMENTS This work was supported by grants from the Sigrid JusBlius Foundation and the Academy of Finland. Part of the study was carried out at the Folkhlilsan Institute of Genetics. Lymphoblasts from the American patient were prepared by the Mental Retardation Research Center (MD 24061).
REFERENCES 1. 2.
3.
Benson, M. D. (1991). Inherited amyloidosis. J. Med. Genet. 28: 73-78. Boysen, G., Galassi, G., Kamieniecka, Z., Schlaeger, J., and Trojaborg, W. (1979). Familial amyloidosis with cranial neuropathy and cornea1 lattice dystrophy. J. Neural. Neurosurg. Psychiatry 42: 1020-1030. Darras, B. T., Adelman, L. S., Mora, 3. S., Rodzinger, R. A., and Munsat, T. L. (1986). Familial amyloidosis with cranial neuropathy and cornea1 lattice dystrophy. Neurology 36: 432-435.
SHORT
4. Ghiso,
J., Haltia, M., Prelli, F., Novello, J., and Frangione, (1990). Gelsolin variant (Am-187) in familial amyloidosis, nish type. Biochem. J. 272: 827-830.
cleotide
G. Fin-
7.
8.
E., Haltia, M., Fernandez-Madrid, I., Koivunen, O., Ghiso, J., Prelli, F., and Frangione, B. (1990). Mutation in gelsolin gene in Finnish hereditary amyloidosis. J. Ezp. Med. 172: 1865-1867.
10.
Maury, amyloid Relation Biophys.
11.
Maury, C. P. J., Alli, K., and Baumann, M. (1990a). Finnish hereditary amyloidosis: Amino acid sequence homology between the amyloid fibril protein and human plasma gelsolin. FEBS
C. P. J. (1990). Isolation and characterization of cardiac in familial amyloid polyneuropathy type IV (Finnish): of the amyloid protein to variant gelsolin. Biochim. Acta 1096: 84-86.
L&t.260:85-87. Maury, (1990b).
C. P. J., Kere, J., Tolvanen, R., and de la Chapelle, Finnish hereditary amyloidosis is caused by a single
in the gelsolin
gene. FEBS
Z&t.
276:
75-
13. Maury,
G. G. (1980). Amyloid deposits and amyloidosis: The B-fibrilloses. N. Engl. J. Med. 302: 1283-1292,1333-1343. Gorevic, P. D., Munoz, P. C., Gorgone, G., Purcell, J. J., Jr., Rodrigues, M., Ghiso, J., Levy, E.‘, Haltia, M., and Frangione, B. (1991). Amyloidosis due to a mutation of the gelsolin gene in an American family with lattice cornea1 dystrophy type II. N. Engl. J. Med. 325: 1780-1785. Hiltunen, T., Kiuru, S., Hongell, V., Heliii, T., Palo, J., and Peltonen, L. (1991). Finnish type of familial amyloidosis: Cosegregation of Aspl87-Asn mutation of gelsolin with the disease in three large families. Am. J. Hum. Genet. 49: 523-528. Kwiatkowski, D. J., Stossel, T. P., Orkin, S. H., Mole, J. E., Colten, H. R., and Yin, H. L. (1986). Plasma and cytoplasmic gelsolins are encoded by a single gene and contain a duplicated actin-binding domain. Nature 323: 455-458.
9. Levy,
12.
substitution
77. C. P. J. (1991). Gelsolin-related amyloidosis: Identification of the amyloid protein in Finnish hereditary amyloidosis as a fragment of variant gelsolin. J. Clin. Znuest. 8’7: 1195-1199.
5. Glenner, 6.
901
COMMUNICATION
A. nu-
14. Maury,
C. P. J., Kere, J., Tolvanen, R., and de la Chapelle, A. (1992). Homozygosity for the Asn187 gelsolin mutation in Finnish type familial amyloidosis is associated with severe renal disease. Genomics 13: 902-903.
15.
McKusick, V. A. (1990). “Mendelian Inheritance ed., pp. 58-59, Johns Hopkins University Press,
16.
Meretoja, J. (1969). Familial systemic paramyloidosis with lattice dystrophy of the cornea, progressive cranial neuropathy, skin changes and various internal symptoms: A previously unrecognized heritable syndrome. Ann. Clin. Res. 1: 314-324. Meretoja, J. (1973). Genetic aspects of familial amyloidosis with cornea1 lattice dystrophy and cranial neuropathy. Clin. Genet. 4: 173-185. Meretoja, J. (1976). Tautiperintomme: Suomalainen amyloiditauti (in Finnish). J. Finn. Med. Assoc. 31: 2234-2236.
17.
18. 19.
Purcell, Dooley, familial mology
in Man,” Baltimore,
ninth MD.
J. J., Jr., Rodrigues, M., Chishti, M. I., Riner, R. N., and J. M. (1983). Lattice cornea1 dystrophy associated with systemic amyloidosis (Meretoja’s syndrome). Ophthal90: 1512-1517.
20. Sack, G. H., Jr., Dumars, McKusick, ropathy.
21. Winkelman,
V. A. (1981). Johns Hopkins
K. W., Gummerson, K. S., Law, A., and Three forms of dominant amyloid neuMed. J. 149: 239-247.
J. E., Delleman, J. W., and Ansink, J. J. (1971). Ein hereditlires Syndrom, bestehend aus peripherer Polyneuropathie, Hautveranderungen und gittrigen Dystrophie der Hornhaut. Klin. Monatsbl. Auger&ilk. 159: 618-623.
AND C. P. J. MAURY$
*Department of Medical Genetics, University of Helsinki, 00290 Helsinki, Finland; TDepartments of Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; and *Fourth Department of Medicine, University of Helsinki, 00 770 Helsinki, Finland ReceivedJanuary
The Finnish type of familial amyloid polyneuropathy (FAF) is an autosomal dominant form of systemic amyloidosis caused by a mutation in the gelsolin gene. The mutation leads to the expression of amyloidogenic mutant Asp187 + Asn gelsolin, an actin-modulating protein. We previously developed a DNA test based on amplification by the polymerase chain reaction followed by allele-specific oligonucleotide hybridization that identifies the base substitution adenine for guanine at nucleotide 654 in the gelsolin gene causing the disease. We show here that the same mutation is present in members of six apparently unrelated Finnish families and in a member of an unrelated American family. These results, taken together with previously published findings in nine additional Finnish families and another unrelated American family, indicate that most, perhaps all, FAF patients in Finland and possibly worldwide carry the same mutation. We suggest two alternative explanations: (i) the mutation arose in a very early common ancestor or (ii) the Asn187 mutation is particularly, perhaps uniquely, amyloido0 1992 Academic Press, Inc. genie.
Amyloidosis is the designation of disorders characterized by the accumulation in tissues of protein fibrils having a twisted P-pleated sheet conformation (5). Several plasma proteins or their fragments are known to be amyloidogenic and give rise to amyloid in various systemic forms of amyloidosis (1). Finnish-type familial amyloid polyneuropathy (FAF), first described by Meretoja (16), is also referred to as Meretoja disease or amyloid cranial neuropathy with lattice cornea1 dystrophy (McKusick No. 105120 (15)). Clinically, it is characterized by adult-onset typical “lattice” cornea1 dystrophy without major loss of vision, progressive cranial neuropathy, skin changes, and often renal and cardiac manifestations. By the 197Os, more than 300 cases had been recorded in Finland (17), and the number of affected persons was subsequently estimated at as many as 1000 (18). In striking contrast, the disorder is rare in other populations, five families having been published worldwide: one in the Netherlands (21), GENOMICS 13,898-901(1992). oc?ss-7543/92 $5.00 Copyright 0 1992 by Academic Press, All rights of reproduction in any form
898 Inc. reserved.
13, 1992
one in Denmark (2), and three in the United States (3, 19, 20). Maury et al. (11) first showed that the amyloid protein in Finnish amyloidosis derives from gelsolin. Subsequently, the amyloid subunit was shown to consist of a 71-amino-acid-long polypeptide fragment having an amino acid substitution Asp + Asn at a position corresponding to codon 187 in the gene for soluble plasma gelsolin (4,10,13). By means of a strategy of polymerase chain reaction (PCR)-mediated amplification followed by hybridization with allele-specific oligonucleotides (ASOs), the expected G to A nucleotide transition at position 654 has been demonstrated by us (12) and others (9). In this study we show that the same G654 + A mutation occurs in numerous Finnish families and in an American family with typical clinical features of FAF. The method we used was described previously (12). Briefly, DNA extracted from venous blood or fixed tissue was amplified using primers derived from published exon sequences of the gelsolin gene (8). The amplified 51-bp fragment extended between nucleotides 630 and 680 in exon 3 containing nucleotide 654 that harbors the mutation. Amplified DNA was dot-blotted onto nylon filters and hybridized with radioactively labeled ASOs corresponding either to the normal sequence or to the mutant sequence. After washing and autoradiography, the results were read as follows: Hybridization to the normal sequence (G654) only indicates a normal homo-
FIG. 1. Pedigree of a Finnish FAF family. Autoradiographs dot-blot hybridizations with the normal (G654) and mutated ASOs are shown below each pedigree symbol.
of the (A654)
SHORT
FIG. patient
2. (A) Pedigree (III-l) at age 51.
of the American
family
with
FAF.
899
COMMUNICATION
(B) Facial
zygote, whereas hybridization both to the normal sequence and to the mutated sequence (A654) indicates heterozygosity for the mutation. Hybridization to the mutant AS0 only indicates homozygosity for the mutation.
appearance
of individual
II-1
at age 62. (C) Facial
appearance
of study
Twenty-eight Finnish individuals belonging to 6 welldocumented families with Finnish amyloidosis were studied. Seventeen affected individuals had the G654 --* A mutation; of these, 2 were homozygously affected (14). Of the 15 positive individuals who were heterozygous for
900
SHORT
COMMUNICATION
the mutation, 13 had typical clinical manifestations. The remaining 2 individuals, 26 and 31 years of age, were themselves unaware of any symptoms of disease; however, in both cases microscopic investigation of the cornea revealed mild lattice dystrophy. Eleven clinically normal individuals were normal homozygotes. Affected individuals were from the family shown in Fig. 1 and from another two-generation family (four affected individuals studied in each), from a pedigree previously reported by us in which we now study one additional individual (six affected (12)) and from three additional pedigrees (one affected studied from each). None of these six Finnish families were aware of any relation between them. A member of an American family (20) also was shown to be heterozygous for the same mutation. The grandmother (I-l; Fig. 2A) of the patient studied was the first member of the family known to be affected with visual difficulties beginning in her fifth decade. She had several operations because of facial weakness and died at 82 while recovering from her last surgery. She knew of no affected relatives. She described the family as being “Scotch-Irish” but no other details are available. Her son (II-l; Fig. 2B) had the first evidence of facial weakness in his sixth decade and this progressed to lip paralysis, protrusion, and eversion. He was first seen in 1962 at Johns Hopkins at age 61, when he had pronounced facial weakness but normal sensation. At age 62 he was found to have cornea1 changes of lattice dystrophy. Electromyography could not stimulate the right facial nerve or facial muscles and disclosed no fibrillation potentials (consistent with a myopathy). Biopsy of facial muscles was compatible with neurogenic atrophy. Esophageal motility was normal but he had frequent sinus bradycardia. He had a series of facial reconstruction procedures to reduce drooling and to control his lower lip. At 75, a cardiac pacemaker was implanted. His facial weakness progressed and he died at 79 after a fall. His son, the study patient (III-l), was first seen in 1979 at age 45 when he had mild facial weakness with bilateral lower eyelid drooping (Fig. 2C). Mild cornea1 stromal lesions were present, but he was otherwise completely well. He was seen again at 51 when the cornea1 changes more closely resembled lattice dystrophy. His sister (111-3) had a four-lid blepharoplasty at age 44 and was troubled with persistent dryness of her eyes. At age 50 she had characteristic cornea1 changes of lattice dystrophy. His daughter (IV-l) had a normal eye examination at age 25. The present results bring to 15 the number of apparently unrelated Finnish families having the same Asn187 mutation. These are 6 families reported here, including the family in which we previously demonstrated cosegregation of the mutation with the disease (12); the original patient whose gelsolin amino acid sequence showed the mutation (ll), 5 unrelated patients studied by AS0 hybridization by Levy et al. (9); and members of 3 unrelated families studied by a slight modification of our method (7). We conclude that this mutation accounts for a large proportion of all Finnish FAF
cases. This is not surprising in view of Meretoja’s demographic and genealogic findings, suggesting the possibility that the Finnish families may have originated from a common ancestor who in the 1300s lived in a parish in Southern Finland (17). Our finding of the same mutation in an American family of Scotch-Irish extraction is interesting. Taken together with the recent demonstration of the same mutation in another American family (Gorevic et al. (6) studying the family described by Purcell et al. (19)) it raises the possibility that this mutation is present in most, if not all, FAF patients worldwide. To account for this hypothesis, we offer two alternative explanations. First, as all patients so far published are of apparently European ancestry, it is not totally inconceivable that a single ancestral mutation could have been transmitted to these individuals. However, it then remains to be explained why the disease is so rare in all populations but Finns, particularly as it has no effect on reproductive fitness. Indeed, in many individuals its only notable harmful effect is a cosmetic one in middle or old age. For the same reason one might also argue that the condition is grossly underdiagnosed or underreported, We note, furthermore, that the two American families with the mutation (Sack et al. (20), reported here; Purcell et al. (19), reported by Gorevic et al. (6)) are of Scotch-Irish and Irish ancestry, respectively. Thus they may share a not-sodistant ancestor. It will be of interest to determine the mutation in the Dutch, Danish, and third known American family (cf. Introduction). The second hypothesis to explain the worldwide occurrence of the same mutation is that it is particularly amyloidogenic. As reviewed by Benson (1) the molecular basis of an increasing number of amyloid diseases has now been elucidated. In only a small number of cases, such as the Met30 transthyretin mutation, the same mutation exists in different populations (discussed in Gorevic et al. (6)). The Asn187 mutation in FAF may be an example of a change leading to a very high, perhaps unique, propensity of gelsolin to form fibrillar amyloid. ACKNOWLEDGMENTS This work was supported by grants from the Sigrid JusBlius Foundation and the Academy of Finland. Part of the study was carried out at the Folkhlilsan Institute of Genetics. Lymphoblasts from the American patient were prepared by the Mental Retardation Research Center (MD 24061).
REFERENCES 1. 2.
3.
Benson, M. D. (1991). Inherited amyloidosis. J. Med. Genet. 28: 73-78. Boysen, G., Galassi, G., Kamieniecka, Z., Schlaeger, J., and Trojaborg, W. (1979). Familial amyloidosis with cranial neuropathy and cornea1 lattice dystrophy. J. Neural. Neurosurg. Psychiatry 42: 1020-1030. Darras, B. T., Adelman, L. S., Mora, 3. S., Rodzinger, R. A., and Munsat, T. L. (1986). Familial amyloidosis with cranial neuropathy and cornea1 lattice dystrophy. Neurology 36: 432-435.
SHORT
4. Ghiso,
J., Haltia, M., Prelli, F., Novello, J., and Frangione, (1990). Gelsolin variant (Am-187) in familial amyloidosis, nish type. Biochem. J. 272: 827-830.
cleotide
G. Fin-
7.
8.
E., Haltia, M., Fernandez-Madrid, I., Koivunen, O., Ghiso, J., Prelli, F., and Frangione, B. (1990). Mutation in gelsolin gene in Finnish hereditary amyloidosis. J. Ezp. Med. 172: 1865-1867.
10.
Maury, amyloid Relation Biophys.
11.
Maury, C. P. J., Alli, K., and Baumann, M. (1990a). Finnish hereditary amyloidosis: Amino acid sequence homology between the amyloid fibril protein and human plasma gelsolin. FEBS
C. P. J. (1990). Isolation and characterization of cardiac in familial amyloid polyneuropathy type IV (Finnish): of the amyloid protein to variant gelsolin. Biochim. Acta 1096: 84-86.
L&t.260:85-87. Maury, (1990b).
C. P. J., Kere, J., Tolvanen, R., and de la Chapelle, Finnish hereditary amyloidosis is caused by a single
in the gelsolin
gene. FEBS
Z&t.
276:
75-
13. Maury,
G. G. (1980). Amyloid deposits and amyloidosis: The B-fibrilloses. N. Engl. J. Med. 302: 1283-1292,1333-1343. Gorevic, P. D., Munoz, P. C., Gorgone, G., Purcell, J. J., Jr., Rodrigues, M., Ghiso, J., Levy, E.‘, Haltia, M., and Frangione, B. (1991). Amyloidosis due to a mutation of the gelsolin gene in an American family with lattice cornea1 dystrophy type II. N. Engl. J. Med. 325: 1780-1785. Hiltunen, T., Kiuru, S., Hongell, V., Heliii, T., Palo, J., and Peltonen, L. (1991). Finnish type of familial amyloidosis: Cosegregation of Aspl87-Asn mutation of gelsolin with the disease in three large families. Am. J. Hum. Genet. 49: 523-528. Kwiatkowski, D. J., Stossel, T. P., Orkin, S. H., Mole, J. E., Colten, H. R., and Yin, H. L. (1986). Plasma and cytoplasmic gelsolins are encoded by a single gene and contain a duplicated actin-binding domain. Nature 323: 455-458.
9. Levy,
12.
substitution
77. C. P. J. (1991). Gelsolin-related amyloidosis: Identification of the amyloid protein in Finnish hereditary amyloidosis as a fragment of variant gelsolin. J. Clin. Znuest. 8’7: 1195-1199.
5. Glenner, 6.
901
COMMUNICATION
A. nu-
14. Maury,
C. P. J., Kere, J., Tolvanen, R., and de la Chapelle, A. (1992). Homozygosity for the Asn187 gelsolin mutation in Finnish type familial amyloidosis is associated with severe renal disease. Genomics 13: 902-903.
15.
McKusick, V. A. (1990). “Mendelian Inheritance ed., pp. 58-59, Johns Hopkins University Press,
16.
Meretoja, J. (1969). Familial systemic paramyloidosis with lattice dystrophy of the cornea, progressive cranial neuropathy, skin changes and various internal symptoms: A previously unrecognized heritable syndrome. Ann. Clin. Res. 1: 314-324. Meretoja, J. (1973). Genetic aspects of familial amyloidosis with cornea1 lattice dystrophy and cranial neuropathy. Clin. Genet. 4: 173-185. Meretoja, J. (1976). Tautiperintomme: Suomalainen amyloiditauti (in Finnish). J. Finn. Med. Assoc. 31: 2234-2236.
17.
18. 19.
Purcell, Dooley, familial mology
in Man,” Baltimore,
ninth MD.
J. J., Jr., Rodrigues, M., Chishti, M. I., Riner, R. N., and J. M. (1983). Lattice cornea1 dystrophy associated with systemic amyloidosis (Meretoja’s syndrome). Ophthal90: 1512-1517.
20. Sack, G. H., Jr., Dumars, McKusick, ropathy.
21. Winkelman,
V. A. (1981). Johns Hopkins
K. W., Gummerson, K. S., Law, A., and Three forms of dominant amyloid neuMed. J. 149: 239-247.
J. E., Delleman, J. W., and Ansink, J. J. (1971). Ein hereditlires Syndrom, bestehend aus peripherer Polyneuropathie, Hautveranderungen und gittrigen Dystrophie der Hornhaut. Klin. Monatsbl. Auger&ilk. 159: 618-623.
