The new apolipoprotein A-I variant Leu174 → Ser causes hereditary cardiac amyloidosis, and the amyloid fibrils are constituted by the 93- residue N-terminal polypeptide

Laura Obici, Vittorio Bellotti, Palma Mangione, Monica Stoppini, Eloisa Arbustini, Laura Verga, Irene Zorzoli, Emesto Anesi, Giuseppe Zanotti, Carlo Campana, Mario Vigano, Giampaolo Merlini

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Abstract

We identified a novel missense mutation in the apolipoprotein A-I gene, T2069C Leu174 → Ser, in a patient affected by familial systemic nonneuropathic amyloidosis. The amyloid deposits mostly affected the heart of the proband, who underwent transplantation for end-stage congestive heart failure. Amyloid fibrils of myocardial and periumbilical fat samples immunoreacted exclusively with anti-ApoA-I antibodies. Amyloid fibrils extracted from the heart were constituted, according to amino acid sequencing and mass spectrometry analysis, by an amino-terminal polypeptide ending at Va193 of apolipoprotein A-I (apoA-I); no other significant fragments were detected. The mutation segregates with the disease; it was demonstrated in the proband and in an affected uncle and excluded in three healthy siblings. The plasma levels of high-density lipoprotein and apoA-I were significantly lower in the patient than in unaffected individuals. This represents the first case of familial apoA-I amyloidosis in which the mutation is outside the polypeptide fragment deposited as fibrils. Visualization of the mutation in the three-dimensional structure of lipid-free apoA-I, composed of four identical polypeptide chains, indicates that position 174 of one chain is located near position 93 of an adjacent chain and suggests that the amino acid replacement in position 174 is permissive for a proteolytic split at the C-terminal of Va193.

Original languageEnglish
Pages (from-to)695-702
Number of pages8
JournalAmerican Journal of Pathology
Volume155
Issue number3
Publication statusPublished - 1999

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Familial Amyloidosis
Apolipoprotein A-I
Amyloid
Peptides
Mutation
Protein Sequence Analysis
Amyloid Plaques
Amyloidosis
Missense Mutation
HDL Lipoproteins
Siblings
Mass Spectrometry
Heart Failure
Transplantation
Fats
Lipids
Amino Acids
Antibodies
Genes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

The new apolipoprotein A-I variant Leu174 → Ser causes hereditary cardiac amyloidosis, and the amyloid fibrils are constituted by the 93- residue N-terminal polypeptide. / Obici, Laura; Bellotti, Vittorio; Mangione, Palma; Stoppini, Monica; Arbustini, Eloisa; Verga, Laura; Zorzoli, Irene; Anesi, Emesto; Zanotti, Giuseppe; Campana, Carlo; Vigano, Mario; Merlini, Giampaolo.

In: American Journal of Pathology, Vol. 155, No. 3, 1999, p. 695-702.

Research output: Contribution to journalArticle

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abstract = "We identified a novel missense mutation in the apolipoprotein A-I gene, T2069C Leu174 → Ser, in a patient affected by familial systemic nonneuropathic amyloidosis. The amyloid deposits mostly affected the heart of the proband, who underwent transplantation for end-stage congestive heart failure. Amyloid fibrils of myocardial and periumbilical fat samples immunoreacted exclusively with anti-ApoA-I antibodies. Amyloid fibrils extracted from the heart were constituted, according to amino acid sequencing and mass spectrometry analysis, by an amino-terminal polypeptide ending at Va193 of apolipoprotein A-I (apoA-I); no other significant fragments were detected. The mutation segregates with the disease; it was demonstrated in the proband and in an affected uncle and excluded in three healthy siblings. The plasma levels of high-density lipoprotein and apoA-I were significantly lower in the patient than in unaffected individuals. This represents the first case of familial apoA-I amyloidosis in which the mutation is outside the polypeptide fragment deposited as fibrils. Visualization of the mutation in the three-dimensional structure of lipid-free apoA-I, composed of four identical polypeptide chains, indicates that position 174 of one chain is located near position 93 of an adjacent chain and suggests that the amino acid replacement in position 174 is permissive for a proteolytic split at the C-terminal of Va193.",
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T1 - The new apolipoprotein A-I variant Leu174 → Ser causes hereditary cardiac amyloidosis, and the amyloid fibrils are constituted by the 93- residue N-terminal polypeptide

AU - Obici, Laura

AU - Bellotti, Vittorio

AU - Mangione, Palma

AU - Stoppini, Monica

AU - Arbustini, Eloisa

AU - Verga, Laura

AU - Zorzoli, Irene

AU - Anesi, Emesto

AU - Zanotti, Giuseppe

AU - Campana, Carlo

AU - Vigano, Mario

AU - Merlini, Giampaolo

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AB - We identified a novel missense mutation in the apolipoprotein A-I gene, T2069C Leu174 → Ser, in a patient affected by familial systemic nonneuropathic amyloidosis. The amyloid deposits mostly affected the heart of the proband, who underwent transplantation for end-stage congestive heart failure. Amyloid fibrils of myocardial and periumbilical fat samples immunoreacted exclusively with anti-ApoA-I antibodies. Amyloid fibrils extracted from the heart were constituted, according to amino acid sequencing and mass spectrometry analysis, by an amino-terminal polypeptide ending at Va193 of apolipoprotein A-I (apoA-I); no other significant fragments were detected. The mutation segregates with the disease; it was demonstrated in the proband and in an affected uncle and excluded in three healthy siblings. The plasma levels of high-density lipoprotein and apoA-I were significantly lower in the patient than in unaffected individuals. This represents the first case of familial apoA-I amyloidosis in which the mutation is outside the polypeptide fragment deposited as fibrils. Visualization of the mutation in the three-dimensional structure of lipid-free apoA-I, composed of four identical polypeptide chains, indicates that position 174 of one chain is located near position 93 of an adjacent chain and suggests that the amino acid replacement in position 174 is permissive for a proteolytic split at the C-terminal of Va193.

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