A transgenic mouse model reproduces human hereditary systemic amyloidosis.

Amyloidoses are rare life-threatening diseases caused by protein misfolding of normally soluble proteins. The fatal outcome is predominantly due to renal failure and/or cardiac dysfunction. Because amyloid fibrils formed by all amyloidogenic proteins share structural similarity, amyloidoses may be studied in transgenic models expressing any amyloidogenic protein.

Carbamylation of the amino-terminal residue (Gly1) of mouse serum amyloid A promotes amyloid formation in a cell culture model.

Amyloid A (AA) amyloidosis is a fatal protein deposition disease afflicting a small percentage of patients with chronic inflammation. Factors other than inflammation that determine development of AA amyloidosis remain largely unknown. The subunit protein comprising AA amyloid fibrils is derived from serum amyloid A (SAA), specifically its amino-terminal portion.

Hereditary systemic immunoglobulin light-chain amyloidosis.

Several members of a family died from renal failure as a result of systemic amyloidosis. Extensive studies to detect previously documented gene mutations associated with amyloidosis failed to identify a causative factor. In search of the genetic basis for this syndrome, amyloid fibrils were isolated from renal tissue of a member of the kin who died while on renal dialysis.

Amyloid fibrils containing fragmented ATTR may be the standard fibril composition in ATTR amyloidosis.

Abstract The clinical phenotype of familial ATTR amyloidosis depends to some extent on the particular mutation, but differences exist also within mutations. We have previously described that two types of amyloid fibril compositions exist among Swedish ATTRV30M amyloidosis patients, one consisting of a mixture of intact and fragmented ATTR (type A) and one consisting of mainly intact ATTR (type B). The fibril types are correlated to phenotypic differences.

Human SAA1-derived amyloid deposition in cell culture: a consistent model utilizing human peripheral blood mononuclear cells and serum-free medium.

Amyloid A (AA) amyloidosis is a fatal disease caused by extracellular deposition of fibrils derived from serum AA (SAA). AA amyloid fibril formation has previously been modeled in macrophage cultures using highly amyloidogenic mouse SAA1.1, but attempts to do the same with human SAA invariably failed.

κ I light chain AL amyloidosis presenting with rapidly progressive renal and hepatic failure with unusual renal amyloid distribution.

A 65-year-old man suffering from generalized edema and jaundice was admitted to our hospital. Laboratory findings revealed marked renal dysfunction with heavy proteinuria as well as liver dysfunction with severe obstructive jaundice. On renal biopsy, the diagnosis of AL amyloidosis associated with κ I light chain was made.

Progression of transthyretin amyloid neuropathy after liver transplantation.

Objective: To biochemically characterize peripheral nerve amyloid in subjects with transthyretin (TTR) amyloidosis and assess effect of orthotopic liver transplantation (OLT) on progression of neuropathy.

Methods: Amyloid fibrils were isolated from peripheral nerve tissues of 6 patients with TTR amyloidosis who were heterozygous for an amyloid-associated TTR mutation. Ratio of variant to wild-type TTR in the fibrils was determined by amino acid sequencing of tryptic peptides containing either the variant amino acid residue or the corresponding normal amino acid.

Hereditary fibrinogen A alpha-chain amyloidosis: phenotypic characterization of a systemic disease and the role of liver transplantation.

Variants of fibrinogen A alpha-chain (AFib) cause the most common type of hereditary renal amyloidosis in Europe and, possibly, the United States as well. Variant fibrinogen is produced in the liver, and solitary renal allografts fail within 1 to 7 years with recurrent amyloidosis. We assessed 22 AFib patients for combined liver and kidney transplantation (LKT) and report the clinical features and outcome.

Biochemical characterisation of amyloid by endomyocardial biopsy.

Cardiomyopathy is a major cause of death in patients with systemic amyloidosis. There are several forms of systemic amyloidosis which cause cardiomyopathy and determination of the exact type of amyloid in each affected patient is essential for treatment and determination of prognosis. In this study, we tested the feasibility of determining the type of amyloidosis by biochemical analysis of endomyocardial biopsies.

Lambda II immunoglobulin light chain protein in primary localized rectal amyloidosis.

Rectal involvement is usually part of a systemic amyloidosis, whereas, localized rectal amyloidosis is a rare entity. We present a case of asymptomatic localized rectal amyloidoma. Amyloid fibrils were isolated from rectal biopsy tissue and characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) which showed bands at 17 kDa, 21 kDa and 28 kDa, a broad doublet band at 7-8 kDa and weaker bands at 15 kDa and 24 kDa.

Progression of cardiac amyloid deposition in hereditary transthyretin amyloidosis patients after liver transplantation.

It has been hypothesized that transthyretin (TTR) amyloidosis may progress after orthotopic liver transplantation (OLT) as a result of continued amyloid fibril synthesis and deposition from normal TTR. To test this hypothesis amyloid fibrils were isolated from cardiac tissues of three patients who died 1(1/2) to 5(1/2) years after OLT: two with Val30Met and one with Thr60Ala TTR. The ratio of variant to normal TTR in each case was determined and compared with the ratio of variant to normal in cardiac tissues from seven patients who died with TTR amyloidosis but who had not had liver transplantation.

Structural analyses of fibrinogen amyloid fibrils.

Hereditary fibrinogen amyloidosis is characterized by deposition of amyloid fibrils in renal glomeruli. The subunit protein of the amyloid fibrils is a proteolytic fragment of the fibrinogen Aalpha-chain. To investigate the structure of fibrinogen amyloid, fibrils were extracted from the tissues of a patient and studied by X-ray fiber diffraction and electron microscopy.

Cellular events associated with the initial phase of AA amyloidogenesis: insights from a human monocyte model.

Reactive amyloidosis is a systemic protein deposition disease that develops in association with chronic inflammation. The deposits are composed of extracellular, fibrillar masses of amyloid A (AA) protein, an N-terminal fragment of the acute-phase serum protein serum amyloid A (SAA). The pathogenic conversion of SAA into amyloid has been studied in two human cell culture models, peritoneal cells and peripheral blood monocytes.

Biochemical characterization of vitreous and cardiac amyloid in Ile84Ser transthyretin amyloidosis.

Plasma transthyretin (TTR) is synthesized in the liver and is the source for visceral amyloid deposits in TTR amyloidosis. However, TTR is also synthesized in the retinal pigment epithelium of the eye and choroid plexus of the brain. It has been postulated that vitreous amyloid, which is associated with approximately 20% of the known amyloidogenic TTR mutations, results from local synthesis of TTR in the eye.

Aging in heterozygous Dnmt1-deficient mice: effects on survival, the DNA methylation genes, and the development of amyloidosis.

We previously reported that heterozygous DNA methyltransferase 1-deficient (Dnmt1(+/-)) mice maintain T-cell immune function and DNA methylation levels with aging, whereas controls develop autoimmunity, immune senescence, and DNA hypomethylation. We therefore compared survival, cause of death, and T-cell DNA methylation gene expression during aging in Dnmt1(+/-) mice and controls. No difference in longevity was observed, but greater numbers of Dnmt1(+/-) mice developed jejunal apolipoprotein AII amyloidosis.

Thermodynamic stability of a kappaI immunoglobulin light chain: relevance to multiple myeloma.

Immunoglobulin light chains have two similar domains, each with a hydrophobic core surrounded by beta-sheet layers, and a highly conserved disulfide bond. Differential scanning calorimetry and circular dichroism were used to study the folding and stability of MM-kappaI, an Ig LC of kappaI subtype purified from the urine of a multiple myeloma patient. The complete primary structure of MM-kappaI was determined by Edman sequence analysis and mass spectrometry.

Kappa III immunoglobulin light chain origin of localized orbital amyloidosis.

Isolated orbital amyloidosis is a rare condition in which intra-muscular deposits result in proptosis and restriction of eye movement. Previous reports have suggested an immunoglobulin origin of the amyloid fibrils, but this has not been proven biochemically. A case is presented in which initial unilateral orbital amyloidosis progressed to bilateral disease.

Chemical characterization of a lambda I amyloid protein isolated from formalin-fixed and paraffin-embedded tissue sections.

Amyloid protein was isolated from formalin-fixed paraffin-embedded heart tissue sections from a patient with primary (AL) amyloidosis by extraction with 6 M guanidine HCl. SDS-PAGE analysis of extracted material showed a major band at 16 kDa and a minor band at 18 kDa. Edman degradation analysis before and after pyroglutamate aminopeptidase treatment showed that the amyloid protein contained N-terminal pyroglutamic acid and was derived from an immunoglobulin lambda light chain.

Renal transplantation for apolipoprotein AII amyloidosis.

Apolipoprotein AII (ApoAII) amyloidosis, first reported in 2001 in a family with renal amyloidosis, is associated with mutations in the stop codon of the apolipoprotein AII gene resulting in a carboxyl terminal peptide extension of 21 amino acid residues in the protein. Since death from this form of amyloidosis is due to renal failure, kidney dialysis and renal transplantation are presently the only two therapeutic options. We report the case of a Caucasian man who developed proteinuria in his late 20's, had renal biopsy at the age of 33 which gave the diagnosis of renal amyloidosis, and required continuous ambulatory peritoneal dialysis by age 45.

Contribution of wild-type transthyretin to hereditary peripheral nerve amyloid.

To elucidate the contribution of wild-type transthyretin (TTR) to amyloid polyneuropathy in TTR amyloidosis, we biochemically investigated amyloid fibrils isolated from sciatic nerve of an autopsied patient with TTR Ala25Ser variant and compared the amount of wild-type and variant TTR in the nerve to that in the heart. Amyloid subunit protein from isolated fibrils was solubilized in 6M guanidine HCl and purified by gel filtration chromatography. The relative amounts of variant and wild-type TTR in the purified protein were estimated from the recovered amounts of tryptic peptides with Ser25 or Ala25.

Hereditary systemic amyloidosis associated with a new apolipoprotein AII stop codon mutation Stop78Arg.

Unlabelled: Hereditary systemic amyloidosis associated with a new apolipoprotein AII stop codon mutation Stop78Arg.

Background: Mutations in the gene for apolipoprotein AII (apoAII) have recently been found to cause hereditary renal amyloidosis. In each case amyloid deposition has been associated with a peptide extension at the carboxyl-terminus of apoAII, the result of mutations in the normal stop codon.