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C P Maury

Publications and source records attributed to C P Maury.

At least 19 recordsLinked to original sources
PubMed2003

Fibrillogenesis in gelsolin-related familial amyloidosis.

To clarify the mechanisms involved in amyloid formation in Finnish-type familial amyloidosis (FAF), we have tested the in vitro fibrillogenicity of synthetic wild-type and mutated gelsolin peptide analogs and studied the fragmentation patterns of gelsolin in the circulation of FAF patients with the Asn-187 or Tyr-187 gelsolin mutation. Fibril formation of synthetic peptides having sequence homology with wild-type or mutant gelsolins was monitored by Congo-red staining and polarization microscopy, negative staining electron microscopy and quantitative thioflavine-T fluorometry. Immunoblotting with anti-gelsolin and amyloid-specific antibodies and sequence analyses were used to study the fragmentation pattern of gelsolin. Ultrastructurally amyloid-like fibrils were formed from mutant Asn-187 and Tyr-187 gelsolin peptides. Fluorometric analysis revealed highly accelerated fibril formation from the mutant peptides as compared with the corresponding wild-type peptides. Addition of mercaptoethanol alone or in combination with dithiotreitol tended to enhance fibril formation of the 9-mer and 11-mer Asn peptides. Blocking of the C-terminal carboxyl of the mutant Asn-187 gelsolin182-192 peptide by amidation increased amyloidogenicity. The Tyr-187 gelsolin mutation, corresponding to the naturally occurring mutation in the Danish subtype of FAF, required acidic conditions to form fibrils meeting the criteria of amyloid. In FAF patients, in addition to the full-sized gelsolin, a series of lower-molecular mass C-terminal fragments of gelsolin (70,000-45,000 Da) was found in the circulation. In homozygous FAF(Asn-187) the 65-kDa fragment containing the amyloid forming region and the 55-kDa fragment, devoid of that region, was the major gelsolin species in the plasma. The results indicate that the 65-kDa gelsolin fragment derived by alpha-gelsolinase cleavage at the mutation-induced novel proteolysis site Arg172-Ala173 represents the putative circulating precursor protein of tissue amyloid in FAF and that the Asp187Asn/Tyr substitution in gelsolin creates a conformation that is highly fibrillogenic.

Amino Acid Sequence↗
PubMed2001

Apolipoprotein E phenotypes in rheumatoid arthritis with or without amyloidosis.

The role of apolipoprotein (apo) E in the pathogenesis of reactive amyloidosis is unclear. Here we evaluated the apoE phenotype distribution and apolipoprotein e allele frequencies in 55 adult patients with seropositive, erosive RA with amyloid and compared them with 55 matched RA patients without amyloid The apoE isotypes were determined by isoelectric focusing and immunoblotting. RA patients without amyloid had more often the apoE 3/3 phenotype (71%) than the RA+A patients (49%, P<0.05) or Finnish control subjects (47%, P<0.01) and the frequency of the apo epsilon3 allele was significantly higher among the RA patients without amyloid than among RA+A patients (P<0.05) or control subjects (P<0.01). The prevalence of the apoE3/4 phenotype among the RA+A patients, although higher, did not significantly differ from the RA patients without amyloid (40% and 26%, respectively, NS) or Finnish control subjects (40% and 35%, respectively, NS). The frequency of the apo epsilon4 allele among the RA+A patients did not signficantly differ from that of RA patients without amyloid (0.23 and 0.13, respectively, NS) or Finnish control subjects (both 0.23). However, the apo epsilon4 frequency of 0.13 among the RA patients without amyloid was significantly lower than that of Finnish control subjects (0.23, P<0.05). We conclude that the prevalence of the apoE4 isotype is not increased in patients with RA complicated by amyloidosis when compared with Finnish control subjects. Since the frequency of the apo epsilon4 allele is significantly decreased in RA patients without amyloid when compared with Finnish control subjects, the presence of the apoE4 in a patient with RA could, though, represent a relative risk factor for developing reactive amyloidosis.

Adult↗
PubMed2000

Danish type gelsolin related amyloidosis: 654G-T mutation is associated with a disease pathogenetically and clinically similar to that caused by the 654G-A mutation (familial amyloidosis of the Finnish type).

BACKGROUND: Familial amyloidosis of the Finnish type (FAF, Finnish hereditary amyloidosis) is caused by a 654G-A mutation in the gelsolin gene on chromosome 9 resulting in the expression of mutant Asn-187 gelsolin which is abnormally proteolytically processed generating amyloidogenic fragments that polymerize into amyloid fibrils. We have recently shown that in a Danish and a Czech family with a clinical syndrome similar to FAF, including corneal lattice dystrophy, cranial neuropathy and skin changes, the disease is caused by another mutation at the same position, namely 654G-T predicting a Try-for-Asp substitution at 187 in secreted gelsolin. AIM: To undertake a closer examination of the Danish subtype of FAF and report immunohistochemical and biochemical findings. RESULTS: Immunostaining of plasma gelsolin isolated from heterozygous FAF of the Danish subtype revealed a pattern similar to that found in FAF-Asn 187. The > 60 kDa gelsolin species contain an epitope characteristic of the amyloid forming region as revealed by an amyloid specific antibody, whereas the approximately 50 kDa fragments are devoid of it. Compared with the wild-type gelsolin peptide (Asp-187), the corresponding mutant peptide (Tyr-187) showed dramatically increased fibrillogenicity as revealed by quantitative thioflavine-T based fluorimetry; ultrastructurally, amyloid-like fibrils were formed by the mutant peptide. Immunohistochemistry showed that antibodies directed against residues 231-242 of secreted gelsolin, representing the carboxy terminus of the sequence forming the amyloid protein (residues 173-243) laid down in the tissues in a fibrillar form in FAF, specifically labelled the amyloid deposited in rectum and skin in the Danish (654G-T) subtype. CONCLUSIONS: The 654G-T mutation in the gelsolin gene gives rise to an amyloid disease clinically and pathogenetically similar to that caused by the 654G-A mutation.

Amyloid↗
PubMed1997

Alzheimer's disease-associated presenilins 1 and 2: accelerated amyloid fibril formation of mutant 410 Cys-->Tyr and 141 Asn-->Ile peptides.

Mutations in the presenilin 1 gene on chromosome 14 and in the related gene on chromosome 1 have been identified in individuals with early-onset familial Alzheimer's disease. The functions of the presenilin gene products as well as the relation of the presenilin mutations to amyloidogenesis are unclear. Here we show that peptides homologous to two disease-associated mutant forms of presenilin 1 and 2, respectively, show highly increased amyloid fibril formation as compared with the wild-type peptide homologues. The 410 Cys -->Tyr (S-182) 14-residue peptide and the 141 Asn-->Ile (E5-1) 15-residue peptide spontaneously assemble to fibrils of 7 to 9 nm width with strong Congophilic characteristics. Thioflavine-T fluorometry reveals a 7- to 18-fold higher rate of amyloid fibril formation of the mutant peptides as compared with the corresponding wild-type homologues. The results provide new insights into the mechanisms by which presenilin mutations lead to Alzheimer-type neuropathology: missense mutations in the presenilin genes may create products that are intrinsically highly amyloidogenic and directly involved in pathogenesis.

Alzheimer Disease↗
PubMed1997

Identification of the circulating amyloid precursor and other gelsolin metabolites in patients with G654A mutation in the gelsolin gene (Finnish familial amyloidosis): pathogenetic and diagnostic implications.

Familial amyloidosis of the Finnish type (FAF) is an autosomal dominant type of systemic amyloidosis caused by a G654A (Asn-187) or G654T (Tyr-187) mutation in the gelsolin gene. Herein we show that patients with the Asn-187 gelsolin mutation have, in addition to full-sized gelsolin, a series of lower-Mr C-terminal fragments of gelsolin (Mr of 70,000-45,000) in the circulation, and that a 50 to 55-kd fragment of gelsolin is excreted in the urine. In homozygous FAF (Asn-187), the 65-kd fragment, which contains the amyloid-forming region (Ala173-Met243), and the 55-kd fragment, which is devoid of that region, are the major gelsolin species in plasma; whereas normal gelsolin, as well as a 70-kd fragment identified as the C-terminal portion of gelsolin starting at Glu122, and a 45-kd fragment starting at Ser384, are minor components. In patients heterozygous for the Asn-187 mutation--the usual form of the expression of the dominant disease--normal-sized gelsolin is the major circulating form; the 65- and 55-kd fragments represent minor components. Immunodetection of the plasma 65-kd gelsolin fragment, which is disease-specific, and measurement of the urinary gelsolin fragment provide useful means for diagnosing FAF.

Amino Acid Sequence↗
PubMed1994

Amyloid fibril formation in gelsolin-derived amyloidosis. Definition of the amyloidogenic region and evidence of accelerated amyloid formation of mutant Asn-187 and Tyr-187 gelsolin peptides.

BACKGROUND: We have recently shown that the actin-modulating cytoskeletal and plasma protein gelsolin is involved in the pathogenesis of familial amyloidosis of Finnish type. To define the amyloidogenic region(s) in gelsolin and clarify the mechanisms involved in amyloid formation, we tested the amyloidogenicity of synthetic gelsolin peptide analogues. EXPERIMENTAL DESIGN: The in vitro amyloid fibril formation was studied using 22 synthetic peptides 7 to 30 residues long having sequence homology with wild-type or mutant gelsolins. Amyloid formation was monitored by Congo-red staining and polarization microscopy of the peptide aggregates, by negative staining electron microscopy, and by quantitative fluorometry with thioflavine T. RESULTS: Ultrastructurally, amyloid-like fibrils were formed from the mutant Asn-187 and Tyr-187 gelsolin peptides corresponding to the naturally occurring missense mutations found in familial gelsolin amyloidosis syndromes, as well as from a gelsolin peptide having a Val-187 substitution. The shortest peptide tested that was capable of forming amyloid-like fibrils was 9-residue mutant Asn-187 peptide. The corresponding wild-type peptide did not form amyloid. Quantitative fluorometry at the emission maximum 482 nm revealed highly accelerated amyloid fibril formation of the mutant Asn-187, Tyr-187 and Val-187 peptides as compared with the corresponding wild-type peptides. CONCLUSIONS: We have defined the amyloidogenic region of gelsolin to a 9-residue sequence in the highly conserved repetitive motif B and showed that residue 187 represents a critical site where a substitution of an amino acid with a charged side chain (Asp) with an amino acid with an uncharged (Asn) or hydrophobic side chain (Tyr, Val) creates a conformation that is highly amyloidogenic thus providing an explanation for the amyloidogenicity of the Asn-187 and Tyr-187 gelsolin variants.

Amino Acid Sequence↗
PubMed1993

Variant plasma gelsolin responsible for familial amyloidosis (Finnish type) has defective actin severing activity.

Familial amyloidosis, Finnish type is caused by a single base mutation in gelsolin, an actin filament severing and capping protein that is present in most tissues and in blood plasma. The mutation replaces aspartic acid with asparagine at residue 187 of the plasma sequence. This renders the gelsolin susceptible to proteolysis as a consequence of which amyloid protein is formed. Here it is shown that the mutant protein in plasma from a patient homozygous for this mutation lacks both actin severing and nucleating activities. Evidence is presented that the cleaved mutant gelsolin has dissociated under non-denaturing conditions and that the resultant 65,000 and 55,000 M(r) C-terminal fragments aggregate.

Actins↗
PubMed1993

Demonstration of a circulating 65K gelsolin variant specific for familial amyloidosis, Finnish type.

Familial amyloidosis, Finnish type (FAF), is a dominantly inherited form of systemic amyloidosis caused by a point mutation G654 to A654 in the gelsolin gene. The mutation leads to the expression of mutant Asn-187 gelsolin and the accumulation of amyloid in tissues. Here we demonstrate that patients with FAF have an abnormal 65K gelsolin species in the circulation that cosegregates with the disease. The 65K variant is detected by immunoblotting using a monoclonal antigelsolin antibody or polyclonal antipeptide (P-gel 231-242) antibodies. The 65K gelsolin variant is lacking in normal subjects and unaffected family members. It is the putative circulating precursor of tissue amyloid in FAF.

Alleles↗
PubMed1993

Homozygous familial amyloidosis, Finnish type: demonstration of glomerular gelsolin-derived amyloid and non-amyloid tubular gelsolin.

The immunohistochemical findings in the kidneys of two sisters with homozygous familial amyloidosis of Finnish type, an autosomal dominant disorder of gelsolin catabolism, is described. The disease, manifesting with nephrotic syndrome and end-stage renal failure was characterized by heavy glomerular deposits of gelsolin-derived amyloid. Immunostaining also revealed the presence of gelsolin in the tubular epithelium that was Congo-red negative. It is concluded that homozygous Finnish amyloidosis leads to a severe nephropathy due to the deposition of fragments of mutant gelsolin.

Adult↗
PubMed1992

Creation of amyloid fibrils from mutant Asn187 gelsolin peptides.

The amyloid protein in familial amyloidosis, Finnish type, is a 71 amino acid long fragment of the inner region of mutant Asp187----Asn gelsolin. The mechanism of gelsolin amyloid formation was tested with synthetic 11 and 30 residue peptides corresponding to the normal and mutant sequence of gelsolin. Fibrils meeting the morphologic criteria of amyloid were formed from the mutant Asn187 peptides. Substitution of the normal Asp187 residue with the mutant Asn residue resulted in a 9-fold increase in fibrillogenicity as determined by quantitative fluorometry. The present study demonstrates the first successful in vitro creation of amyloid-like fibrils from Asn187 gelsolin peptides and provides evidence that amyloid formation in Finnish amyloidosis is a direct consequence of the Asp187----Asn substitution in gelsolin.

Amino Acid Sequence↗
PubMed1992

Familial amyloidosis, Finnish type: G654----a mutation of the gelsolin gene in Finnish families and an unrelated American family.

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, amyloidogenic.

Amino Acid Sequence↗
PubMed1992

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.

Alleles↗
PubMed1992

Exclusion of the gelsolin gene on 9q32-34 as the cause of familial lattice corneal dystrophy type I.

Familial lattice corneal dystrophy type I (LCD1) is a localized form of inherited amyloidosis limited to the corneal stroma. Recently the Finnish form of hereditary amyloidosis with lattice corneal dystrophy has been shown to be due to a mutation in the gelsolin gene (G654----A; Asp187----Asn). In this paper we exclude the gelsolin gene as the cause of the autosomal dominant form of isolated LCD1.

Amyloidosis↗
PubMed1991

Serum amyloid A levels in acute graft-versus-host disease in bone marrow transplant recipients.

We studied serum amyloid A levels of 31 bone marrow transplant recipients with and without acute graft-versus-host disease. Before transplantation the mean SAA concentration was 5.1 +/- 0.8 mg/l (mean +/- SEM). It remained low in patients with no signs of aGVHD but increased significantly during aGVHD to 54.0 +/- 8.2 mg/l (p less than 0.001 compared to pre-BMT value). Severe infections also induced high SAA levels.

Adrenal Cortex Hormones↗