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• W1842594908 abstract "Apolipoprotein AI-derived (AApoAI) amyloidosis may present either as a non-hereditary form with wild-type protein deposits in atherosclerotic plaques or as a hereditary form due to germline mutations in the APOA1 gene. Currently, more than 50 apoAI variants are known, and 13 are associated with amyloidosis. We describe six patients with AApoAI amyloidosis due to APOA1 germline mutations that affect the larynx, small intestine, large intestine, heart, liver, kidney, uterus, ovary, or pelvic lymph nodes. In each patient, the amyloid showed a characteristic apple green birefringence when viewed under polarized light after Congo red staining and was immunoreactive with antibodies against apoAI. Sequence analyses revealed one known (p.Leu75Pro) and three novel APOA1 mutations that included gene variations leading to two different frameshifts (p.Asn74fs and p.Ala154fs) and one amino acid exchange (p.Leu170Pro). These three novel mutations extend our knowledge about both the location of the mutations and the organ distribution in hereditary AApoAI amyloidosis. Thirteen of the now sixteen amyloidogenic mutations are localized in two hot-spot regions that span residues 50 to 93 and 170 to 178. The organ distribution and clinical presentation of AApoAI amyloidosis seems to depend on the position of the mutation. Patients with alterations in codons 1 to 75 mostly develop hepatic and renal amyloidosis, while carriers of mutations in residues 173 to 178 mainly suffer from cardiac, laryngeal, and cutaneous amyloidosis. Apolipoprotein AI-derived (AApoAI) amyloidosis may present either as a non-hereditary form with wild-type protein deposits in atherosclerotic plaques or as a hereditary form due to germline mutations in the APOA1 gene. Currently, more than 50 apoAI variants are known, and 13 are associated with amyloidosis. We describe six patients with AApoAI amyloidosis due to APOA1 germline mutations that affect the larynx, small intestine, large intestine, heart, liver, kidney, uterus, ovary, or pelvic lymph nodes. In each patient, the amyloid showed a characteristic apple green birefringence when viewed under polarized light after Congo red staining and was immunoreactive with antibodies against apoAI. Sequence analyses revealed one known (p.Leu75Pro) and three novel APOA1 mutations that included gene variations leading to two different frameshifts (p.Asn74fs and p.Ala154fs) and one amino acid exchange (p.Leu170Pro). These three novel mutations extend our knowledge about both the location of the mutations and the organ distribution in hereditary AApoAI amyloidosis. Thirteen of the now sixteen amyloidogenic mutations are localized in two hot-spot regions that span residues 50 to 93 and 170 to 178. The organ distribution and clinical presentation of AApoAI amyloidosis seems to depend on the position of the mutation. Patients with alterations in codons 1 to 75 mostly develop hepatic and renal amyloidosis, while carriers of mutations in residues 173 to 178 mainly suffer from cardiac, laryngeal, and cutaneous amyloidosis. The amyloidoses are a large group of heterogeneous diseases characterized by insoluble protein and peptide aggregates oriented in a β-pleated sheet structure, forming amyloid fibrils of 10 to 12 nm diameter. More than 26 different proteins have been identified to form amyloid. Depending on the histoanatomical distribution and amount, amyloid may cause progressive and life-threatening organ dysfunction.1Westermark P Aspects on human amyloid forms and their fibril polypeptides.FEBS J. 2005; 272: 5942-5949Crossref PubMed Scopus (192) Google Scholar Amyloid may be acquired or hereditary in origin, and it can deposit locally or present as a systemic disease. Due to the diversity of the precursor proteins with no sequence homology between them, it has been impossible to find any common primary structural or functional motif that predicts the amyloidogenicity of a peptide or protein. In this respect, hereditary amyloidoses are particularly interesting. They are caused by germline mutations, which increase the propensity of the affected protein to form aggregates under particular circumstances. Variants of transthyretin, apolipoprotein AI (apoAI), apolipoprotein AII, fibrinogen Aα-chain, gelsolin, and lysozyme are some of the proteins known to cause hereditary amyloidosis. The most frequent form of hereditary amyloidosis is the transthyretin-derived ATTR amyloidosis, which clinically presents with polyneuropathy and/or cardiomyopathy.2Benson MD Kincaid JC The molecular biology and clinical features of amyloid neuropathy.Muscle Nerve. 2007; 36: 411-423Crossref PubMed Scopus (333) Google ScholarApolipoprotein AI-derived (AApoAI) amyloidosis can be present as a non-hereditary form with wild-type protein deposits in atherosclerotic plaques,3Mucchiano GI Jonasson L Häggqvist B Einarsson E Westermark P Apolipoprotein A-I-derived amyloid in atherosclerosis. Its association with plasma levels of apolipoprotein A-I and cholesterol.Am J Clin Pathol. 2001; 115: 298-303Crossref PubMed Scopus (51) Google Scholar or as a hereditary form with the variant protein depositing more systemically. The clinical manifestations of hereditary AApoAI amyloidosis frequently involve liver, kidney, larynx, skin, and myocardium. In rarer cases, amyloid is also found in the testes and adrenal glands.4Obici L Franceschini G Calabresi L Giorgetti S Stoppini M Merlini G Bellotti V Structure, function and amyloidogenic propensity of apolipoprotein A-I.Amyloid. 2006; 13: 191-205Crossref PubMed Scopus (110) Google Scholar ApoAI is a plasma protein of 28 kDa synthesized by the liver and the small intestine. It is the main protein of high-density lipoprotein particles and important for the formation and metabolism of high-density lipoprotein cholesterol esters.5Sorci-Thomas MG Thomas MJ The effects of altered apolipoprotein A-I structure on plasma HDL concentration.Trends Cardiovasc Med. 2002; 12: 121-128Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar Mature apoAI consist of 243 amino acids encoded by exons 3 and 4 of the APOA1 gene.6Karathanasis SK Zannis VI Breslow JL Isolation and characterization of the human apolipoprotein A-I gene.Proc Natl Acad Sci USA. 1983; 80: 6147-6151Crossref PubMed Scopus (158) Google Scholar More than 50 apoAI variants have been described,4Obici L Franceschini G Calabresi L Giorgetti S Stoppini M Merlini G Bellotti V Structure, function and amyloidogenic propensity of apolipoprotein A-I.Amyloid. 2006; 13: 191-205Crossref PubMed Scopus (110) Google Scholar and about half of them are associated with a decreased plasma level of high-density lipoprotein-apoAI. These apoAI variants either affect lecithin:cholesterol acyltransferase activity or promote the formation of amyloid.5Sorci-Thomas MG Thomas MJ The effects of altered apolipoprotein A-I structure on plasma HDL concentration.Trends Cardiovasc Med. 2002; 12: 121-128Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar To date, 13 mutations are known to be associated with hereditary AApoAI amyloidosis (Table 1).7van Allen MW Frohlich JA Davis JR Inherited predisposition to generalized amyloidosis. Clinical and pathological study of a family with neuropathy, nephropathy, and peptic ulcer.Neurology. 1969; 19: 10-25Crossref PubMed Google Scholar8Nichols WC Gregg RE Brewer Jr, HB Benson MD A mutation in apolipoprotein A-I in the Iowa type of familial amyloidotic polyneuropathy.Genomics. 1990; 8: 318-323Crossref PubMed Scopus (145) Google Scholar9Booth DR Tan SY Booth SE Hsuan JJ Totty NF Nguyen O Hutton T Vigushin DM Tennent GA Hutchinson WL A new apolipoprotein Al variant, Trp50Arg, causes hereditary amyloidosis.QJM. 1995; 88: 695-702PubMed Google Scholar10Soutar AK Hawkins PN Vigushin DM Tennent GA Booth SE Hutton T Nguyen O Totty NF Feest TG Hsuan JJ Apolipoprotein AI mutation Arg-60 causes autosomal dominant amyloidosis.Proc Natl Acad Sci USA. 1992; 89: 7389-7393Crossref PubMed Scopus (131) Google Scholar11Murphy CL Wang S Weaver K Gertz MA Weiss DT Solomon A Renal apolipoprotein A-I amyloidosis associated with a novel mutant Leu64Pro.Am J Kidney Dis. 2004; 44: 1103-1109Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar12Booth DR Tan SY Booth SE Tennent GA Hutchinson WL Hsuan JJ Totty NF Truong O Soutar AK Hawkins PN Bruguera M Caballeria J Sole M Campistol JM Pepys MB Hereditary hepatic and systemic amyloidosis caused by a new deletion/insertion mutation in the apolipoprotein AI gene.J Clin Invest. 1996; 97: 2714-2721Crossref PubMed Scopus (93) Google Scholar13Persey MR Booth DR Booth SE van Zyl-Smit R Adams BK Fattaar AB Tennent GA Hawkins PN Pepys MB Hereditary nephropathic systemic amyloidosis caused by a novel variant apolipoprotein A-I.Kidney Int. 1998; 53: 276-281Crossref PubMed Scopus (64) Google Scholar14Coriu D Dispenzieri A Stevens FJ Murphy CL Wang S Weiss DT Solomon A Hepatic amyloidosis resulting from deposition of the apolipoprotein A-I variant Leu75Pro.Amyloid. 2003; 10: 215-223Crossref PubMed Scopus (29) Google Scholar15Obici L Palladini G Giorgetti S Bellotti V Gregorini G Arbustini E Verga L Marciano S Donadei S Perfetti V Calabresi L Bergonzi C Scolari F Merlini G Liver biopsy discloses a new apolipoprotein A-I hereditary amyloidosis in several unrelated Italian families.Gastroenterology. 2004; 126: 1416-1422Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar16Hamidi AL Liepnieks JJ Hamidi AK Uemichi T Moulin G Desjoyaux E Loire R Delpech M Grateau G Benson MD Hereditary amyloid cardiomyopathy caused by a variant apolipoprotein A1.Am J Pathol. 1999; 154: 221-227Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar17Amarzguioui M Mucchiano G Häggqvist B Westermark P Kavlie A Sletten K Prydz H Extensive intimal apolipoprotein A1-derived amyloid deposits in a patient with an apolipoprotein A1 mutation.Biochem Biophys Res Commun. 1998; 242: 534-539Crossref PubMed Scopus (41) Google Scholar18Hamidi AK Liepnieks JJ Nakamura M Parker F Benson MD A novel apolipoprotein A-1 variant. Arg173Pro, associated with cardiac and cutaneous amyloidosis.Biochem Biophys Res Commun. 1999; 257: 584-588Crossref PubMed Scopus (74) Google Scholar19Obici L Bellotti V Mangione P Stoppini M Arbustini E Verga L Zorzoli I Anesi E Zanotti G Campana C Vigano M Merlini G The new apolipoprotein A-I variant Leu(174) → Ser causes hereditary cardiac amyloidosis, and the amyloid fibrils are constituted by the 93-residue N-terminal polypeptide.Am J Pathol. 1999; 155: 695-702Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar20Lachmann HJ Booth DR Booth SE Bybee A Gilbertson JA Gillmore JD Pepys MB Hawkins PN Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis.N Engl J Med. 2002; 346: 1786-1791Crossref PubMed Scopus (530) Google Scholar21de Sousa MM Vital C Ostler D Fernandes R Pouget-Abadie J Carles D Saraiva MJ Apolipoprotein AI and transthyretin as components of amyloid fibrils in a kindred with apoAI Leu178His amyloidosis.Am J Pathol. 2000; 156: 1911-1917Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar The majority of the germline mutations are nucleotide substitutions, but two variants are caused by deletions13Persey MR Booth DR Booth SE van Zyl-Smit R Adams BK Fattaar AB Tennent GA Hawkins PN Pepys MB Hereditary nephropathic systemic amyloidosis caused by a novel variant apolipoprotein A-I.Kidney Int. 1998; 53: 276-281Crossref PubMed Scopus (64) Google Scholar,17Amarzguioui M Mucchiano G Häggqvist B Westermark P Kavlie A Sletten K Prydz H Extensive intimal apolipoprotein A1-derived amyloid deposits in a patient with an apolipoprotein A1 mutation.Biochem Biophys Res Commun. 1998; 242: 534-539Crossref PubMed Scopus (41) Google Scholar and another one is due to a deletion/insertion mutation.12Booth DR Tan SY Booth SE Tennent GA Hutchinson WL Hsuan JJ Totty NF Truong O Soutar AK Hawkins PN Bruguera M Caballeria J Sole M Campistol JM Pepys MB Hereditary hepatic and systemic amyloidosis caused by a new deletion/insertion mutation in the apolipoprotein AI gene.J Clin Invest. 1996; 97: 2714-2721Crossref PubMed Scopus (93) Google ScholarTable 1ApoA1 Mutations Associated with AApoAI AmyloidosisVariant (mature protein)Clinical manifestations/found amyloid sitesReferencep.Gly26ArgRenal failure, gastrointestinal amyloid, peripheral neuropathy7van Allen MW Frohlich JA Davis JR Inherited predisposition to generalized amyloidosis. Clinical and pathological study of a family with neuropathy, nephropathy, and peptic ulcer.Neurology. 1969; 19: 10-25Crossref PubMed Google Scholar8Nichols WC Gregg RE Brewer Jr, HB Benson MD A mutation in apolipoprotein A-I in the Iowa type of familial amyloidotic polyneuropathy.Genomics. 1990; 8: 318-323Crossref PubMed Scopus (145) Google Scholarp.Trp50ArgRenal failure9Booth DR Tan SY Booth SE Hsuan JJ Totty NF Nguyen O Hutton T Vigushin DM Tennent GA Hutchinson WL A new apolipoprotein Al variant, Trp50Arg, causes hereditary amyloidosis.QJM. 1995; 88: 695-702PubMed Google Scholarp.Leu60ArgRenal failure10Soutar AK Hawkins PN Vigushin DM Tennent GA Booth SE Hutton T Nguyen O Totty NF Feest TG Hsuan JJ Apolipoprotein AI mutation Arg-60 causes autosomal dominant amyloidosis.Proc Natl Acad Sci USA. 1992; 89: 7389-7393Crossref PubMed Scopus (131) Google Scholarp.Leu64ProRenal failure11Murphy CL Wang S Weaver K Gertz MA Weiss DT Solomon A Renal apolipoprotein A-I amyloidosis associated with a novel mutant Leu64Pro.Am J Kidney Dis. 2004; 44: 1103-1109Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholarp.Leu60_Phe71delinsValThrLiver failure12Booth DR Tan SY Booth SE Tennent GA Hutchinson WL Hsuan JJ Totty NF Truong O Soutar AK Hawkins PN Bruguera M Caballeria J Sole M Campistol JM Pepys MB Hereditary hepatic and systemic amyloidosis caused by a new deletion/insertion mutation in the apolipoprotein AI gene.J Clin Invest. 1996; 97: 2714-2721Crossref PubMed Scopus (93) Google Scholarp.Glu70_Trp72delRenal failure13Persey MR Booth DR Booth SE van Zyl-Smit R Adams BK Fattaar AB Tennent GA Hawkins PN Pepys MB Hereditary nephropathic systemic amyloidosis caused by a novel variant apolipoprotein A-I.Kidney Int. 1998; 53: 276-281Crossref PubMed Scopus (64) Google Scholarp.Asn74fsGastrointestinal amyloid, renal failure, amyloid detected in uterus, ovaries, pelvic lymph nodesCurrent reportp.Leu75ProRenal failure, hepatic amyloid, gastrointestinal amyloid14Coriu D Dispenzieri A Stevens FJ Murphy CL Wang S Weiss DT Solomon A Hepatic amyloidosis resulting from deposition of the apolipoprotein A-I variant Leu75Pro.Amyloid. 2003; 10: 215-223Crossref PubMed Scopus (29) Google Scholar15Obici L Palladini G Giorgetti S Bellotti V Gregorini G Arbustini E Verga L Marciano S Donadei S Perfetti V Calabresi L Bergonzi C Scolari F Merlini G Liver biopsy discloses a new apolipoprotein A-I hereditary amyloidosis in several unrelated Italian families.Gastroenterology. 2004; 126: 1416-1422Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Current reportp.Leu90ProCardiomyopathy, cutaneous amyloid16Hamidi AL Liepnieks JJ Hamidi AK Uemichi T Moulin G Desjoyaux E Loire R Delpech M Grateau G Benson MD Hereditary amyloid cardiomyopathy caused by a variant apolipoprotein A1.Am J Pathol. 1999; 154: 221-227Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholarp.Lys107delAortic intimal amyloid17Amarzguioui M Mucchiano G Häggqvist B Westermark P Kavlie A Sletten K Prydz H Extensive intimal apolipoprotein A1-derived amyloid deposits in a patient with an apolipoprotein A1 mutation.Biochem Biophys Res Commun. 1998; 242: 534-539Crossref PubMed Scopus (41) Google Scholarp.Ala154fsRenal amyloidCurrent reportp.Leu170ProAmyloid in larynxCurrent reportp.Arg173ProCardiomyopathy, cutaneous and laryngeal amyloid18Hamidi AK Liepnieks JJ Nakamura M Parker F Benson MD A novel apolipoprotein A-1 variant. Arg173Pro, associated with cardiac and cutaneous amyloidosis.Biochem Biophys Res Commun. 1999; 257: 584-588Crossref PubMed Scopus (74) Google Scholarp.Leu174SerCardiomyopathy19Obici L Bellotti V Mangione P Stoppini M Arbustini E Verga L Zorzoli I Anesi E Zanotti G Campana C Vigano M Merlini G The new apolipoprotein A-I variant Leu(174) → Ser causes hereditary cardiac amyloidosis, and the amyloid fibrils are constituted by the 93-residue N-terminal polypeptide.Am J Pathol. 1999; 155: 695-702Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholarp.Ala175ProLaryngeal amyloid20Lachmann HJ Booth DR Booth SE Bybee A Gilbertson JA Gillmore JD Pepys MB Hawkins PN Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis.N Engl J Med. 2002; 346: 1786-1791Crossref PubMed Scopus (530) Google Scholarp.Leu178HisCardiomyopathy, cutaneous and laryngeal amyloid21de Sousa MM Vital C Ostler D Fernandes R Pouget-Abadie J Carles D Saraiva MJ Apolipoprotein AI and transthyretin as components of amyloid fibrils in a kindred with apoAI Leu178His amyloidosis.Am J Pathol. 2000; 156: 1911-1917Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar Open table in a new tab In this report, we describe six German patients with hereditary AApoAI amyloidosis, presenting with one known and three novel mutations in the APOA1 coding sequence.Case ReportsSix German patients (four women and two men) with hereditary AApoAI amyloidosis were studied. Patients were retrieved from the Amyloid Registries of the University Hospitals in Berlin and Heidelberg between June 2001 and August 2008. Following the identification of cases with AApoAI amyloidosis, all patients gave written informed consent for genomic analyses. The study was performed in accordance with the guidelines set out by the German government and the local Ethics Committee of the University of Berlin.Patient No. 1A normotensive woman was admitted with nephrotic syndrome at the age of 58 years, and a kidney biopsy was taken. No further clinical information was available from this patient.Patient No. 2A hysteroadnexectomy was performed in a 48-year-old woman because of a serous borderline tumor of the right ovary. She was on hemodialysis twice a week since June 2000 due to terminal renal failure. She also suffered from secondary hyperparathyroidism, anemia, and hypertension. Tissue samples were obtained from the hysteroadnexectomy specimens.Patient No. 3A rectal biopsy of this 67-year-old woman was submitted for the immunohistochemical classification of amyloid. Patients No. 2 and No. 3 are related. No further clinical information was available.Patient No. 4A 54-year-old woman had a short history of discomfort in the upper abdomen after an episode of diarrhea and nausea nine months earlier. Biopsies retained from a duodenoscopy and colonoscopy revealed amyloid. She also had a history of type I diabetes for 20 years and of renal failure without nephrotic syndrome. No symptoms of dyspnea, polyneuropathy, or other organ involvement were present. Analysis of a kidney biopsy excluded diabetic nephropathy and revealed minimal renal amyloidosis. Vasculopathy was determined as the main cause of renal failure. In the course of the clinical work-up for liver transplantation, a cardiac biopsy was obtained, and cardiac amyloidosis was found. The daughter, sister, mother, and grandmother of the patient all suffer from type I diabetes, while the father died of leukemia.Patient No. 5A 52-year-old man was suffering from swallowing complaints for 6 years. A biopsy from the vocal cord revealed amyloid deposits in the larynx. The patient showed no symptoms of systemic amyloidosis. All laboratory values were normal. Ultrasound of the abdomen as well as electrocardiogram and echocardiography were also normal. There was no family history of amyloidosis.Patient No. 6A 41-year-old man presented with elevated liver enzymes. The main symptom was itching. A liver biopsy revealed amyloidosis. The patient's grandmother had died of an undiagnosed liver disease at the age of 65 years.Materials and MethodsHistology and ImmunohistochemistryThe biopsies were fixed in formalin and embedded in paraffin. Serial sections were stained with H&E. Amyloid was analyzed by viewing Congo red-stained sections under polarized light. Immunohistochemistry was performed with commercially available monoclonal antibodies directed against AA amyloid (1:600) and polyclonal antibodies against amyloid P component (1:5000), fibrinogen (1:2000), lysozyme (1:3000), transthyretin (1:4000), λ-light chain (1:160,000), and κ-light chain (1:160,000) (all DAKO, Hamburg, Germany), as well as with non-commercially available polyclonal antibodies directed against apolipoprotein AI (1:1000),22Gregorini G Izzi C Obici L Tardanico R Röcken C Viola BF Capistrano M Donadei S Biasi L Scalvini T Merlini G Scolari F Renal apolipoprotein A-I amyloidosis: a rare and usually ignored cause of hereditary tubulointerstitial nephritis.J Am Soc Nephrol. 2005; 16: 3680-3686Crossref PubMed Scopus (70) Google Scholar λ-light chain-derived amyloid proteins (AL1, 1:3000),23Bohne S Sletten K Menard R Bühling F Vöckler S Wrenger E Roessner A Röcken C Cleavage of AL amyloid proteins and AL amyloid deposits by cathepsins B, K, and L.J Pathol. 2004; 203: 528-537Crossref PubMed Scopus (46) Google Scholar and anti-λ-light chain peptide antibodies (AL3,24Kuci H Ebert MP Röcken C Anti-lambda-light chain-peptide antibodies are suitable for the immunohistochemical classification of AL amyloid.Histol Histopathol. 2007; 22: 379-387PubMed Google Scholar 1:250 and AL7, 1:500, peptide used for antibody production as described by others25Hoshii Y Setoguchi M Iwata T Ueda J Cui D Kawano H Gondo T Takahashi M Ishihara T Useful polyclonal antibodies against synthetic peptides corresponding to immunoglobulin light chain constant region for immunohistochemical detection of immunoglobulin light chain amyloidosis.Pathol Int. 2001; 51: 264-270Crossref PubMed Scopus (63) Google Scholar). Immunostaining was done with the BenchMark XT immunostainer using the ultraView Universal Alkaline Phosphatase Red Detection Kit (both Ventana Medical Systems, Inc., Tucson, Arizona) or the NOVADetect DAB-Substrate Kit (Dianova, Hamburg, Germany). Before the incubation with primary antibodies, sections were pretreated with Cell Conditioning 1 according to the manufacturer's instructions (CC1; Ventana) or with sodium citrate (four times, 5 minutes, 600W, microwave oven). The specificity of the immunostaining was verified using specimens containing known classes of amyloid (AA amyloid, transthyretin, λ-light chain), or by using positive controls recommended by the manufacturers (remaining antibodies). Omission of the primary antibodies served as a negative control.DNA Sequence AnalysisGenomic DNA was isolated from peripheral blood leukocytes using the QIAamp DNA blood mini kit (Qiagen, Hilden, Germany). In one case, total genomic DNA was extracted from formalin-fixed paraffin-embedded tissue with the QIAamp DNA mini kit (Qiagen) as described by the manufacturer. Amplification of APOA1 exons 1–4 was performed by PCR with the following specific primer pairs (Biotez, Berlin, Germany): exon 1–2 (489 bp) forward 5′-AAGTTCCACATTGCCAGGAC-3′ and reverse 5′-AGAGGCAGCAGGTTTCTCAC-3′; exon 3 (376 bp) forward 5′-AGAGGCAGCAGGTTTCTCAC-3′ and reverse 5′-AATATCTGATGAGCTGGGCC-3′; exon 4a (493 bp) forward 5′-AAGAGAAGCTGAGCCCACT-3′ and reverse 5′-CCCTACAGCGACGAGCTG-3′; and exon 4b (400 bp) forward 5′-CTGGAAATGCTAGGCCAC-3′ and reverse 5′-CAGCTTCTTTCTTTTGGGAGAA-3′. A 30-μl reaction mixture contained 200 ng DNA, 1 μmol/L of the exon-specific primers, 1x PCR buffer, 1.5 U Taq polymerase, 0.2 μmol/L dNTPs, and Q-solution in concentrations recommended by the manufacturer (Qiagen). The following thermocycling conditions were used: initial denaturation at 94°C for 3 minutes, 40 cycles of 94°C for 1 minute, 60°C (61°C for the exon 4a primer pair) for 1.5 minutes, 72°C for 1 minute, and a final elongation step at 72°C for 7 minutes. A negative control with water instead of DNA was included in each PCR run, and blood isolated from an individual with wild-type APOA1 served as a positive control. The quality and size of the generated PCR products were analyzed by agarose gel electrophoresis. Fragments were purified with the ExoSAP-IT kit for PCR product clean-up (USB Corp., Cleveland, OH). The PCR products were sequenced in both directions with the ABI PRISM BigDye Terminator v3.1 Ready Reaction Cycle Sequencing kit (Applied Biosystems, Foster City, CA) using the same set of primers as described above. Sequences were analyzed on an ABI PRISM 3130 Genetic Analyzer.ResultsHistology and ImmunohistochemistryIn each patient, the amyloid deposits showed a characteristic apple green birefringence when viewed under polarized light after Congo red staining (Figure 1). Amyloid was present as glomerular (kidney), vascular, or interstitial deposits. In patient No. 1, focal glomerular amyloid deposits were found in a kidney biopsy. Patient No. 2 had massive vascular and interstitial deposits in the uterus, ovaries, soft tissue, and pelvic lymph nodes. Patients No. 3 and No. 4 were found to have massive vascular and interstitial amyloid deposits in the biopsies of the large and small intestine, respectively. Patient No. 4 also had interstitial amyloid deposits in an endomyocardial biopsy, while patient No. 5 had subepithelial deposits in a laryngeal biopsy. In patient No. 6, amyloid was found in a liver biopsy and was restricted to the portal tracts (Figure 1). Table 2 summarizes the biopsy sites where amyloid was found in our patients.Table 2AApoAI Patients, Mutations, and Tissue SitesPatient no.SexAge (y)Mutation (cDNA)Mutation (protein)Analyzed tissue sitesHistology1Female58c.460_461dupGCp.Ala154fsX47KidneyGlomerular amyloid deposits; no renal vascular deposits2Female48c.293_294insAp.Asn74LysfsUterus, ovaries, pelvic lymph nodesMassive vascular and interstitial amyloid deposits3Female67c.293_294insAp.Asn74LysfsLarge intestineInterstitial amyloid deposits4Female54c.296T>Cp.Leu75ProSmall intestine, HeartInterstitial amyloid deposits5Male52c.581T>Cp.Leu170ProLarynxSubepithelial and interstitial amyloidosis6Male41c.296T>Cp.Leu75ProLiverMassive amyloid deposits in portal tracts Open table in a new tab The amyloid deposits in every patient showed an intense and even staining with antibodies directed against amyloid P component and apoAI (Figure 1). No significant immunostaining was found with antibodies directed against AA amyloid, fibrinogen, lysozyme, β2-microglobulin, λ- and κ-light chain, or transthyretin.DNA Sequence AnalysisSequence analysis revealed a mutation in the coding sequence of the APOA1 gene in all six patients. Patient No. 1 had a GC duplication (c.460_461dupGC), leading to a frameshift (p.Ala154fsX48) resulting in a truncated protein of 200 amino acids instead of 243 amino acids. Two of the patients (2 and 3) carried an adenine insertion at nucleotide position 294 (c.293_294insA), which also leads to a frameshift (p.Asn74fsX106). Theoretically, this mutation would result in a mutant protein of 178 amino acids, where the first 73 residues are identical to the wild-type apoAI, and the remaining 105 amino acids are completely different. Patient No. 5 was heterozygous for a c.581T>C transition, resulting in a p.Leu170Pro substitution. These three mutations have heretofore not been described. One known mutation (c.296T>C or p.Leu75Pro) was found in patients 4 and 6.DiscussionHereditary amyloidosis was first described by Ostertag in 1932 and again in the early 1950's.26Ostertag Familiäre Amyloid-Erkrankung.Z Mensch Vererb Konstitutionsl. 1950; 30: 105-115Google Scholar,27Andrade C A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves.Brain. 1952; 75: 408-427Crossref PubMed Scopus (844) Google Scholar Even if it is considered to be a rare disease, it has to be separated from other forms of systemic amyloidosis, such as the more common immunoglobulin-derived AL amyloidosis, as these diseases require a different patient management. Lachmann et al reported that about 10% of the patients diagnosed with AL amyloidosis were misdiagnosed and had to be reclassified as hereditary amyloidosis, eg, transthyretin-derived ATTR amyloidosis or fibrinogen Aα-chain-derived AFib amyloidosis.20Lachmann HJ Booth DR Booth SE Bybee A Gilbertson JA Gillmore JD Pepys MB Hawkins PN Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis.N Engl J Med. 2002; 346: 1786-1791Crossref PubMed Scopus (530) Google Scholar In the patient series of the Amyloid Registry of the Charité University Hospital and of the University Hospital in Heidelberg, approximately 5% and 3% of the patients were found to suffer from hereditary amyloidosis, respectively (unpublished observation). Recent reports describe relatively large patient cohorts and families with hereditary amyloidosis22Gregorini G Izzi C Obici L Tardanico R Röcken C Viola BF Capistrano M Donadei S Biasi L Scalvini T Merlini G Scolari F Renal apolipoprotein A-I amyloidosis: a rare and usually ignored cause of hereditary tubulointerstitial nephritis.J Am Soc Nephrol. 2005; 16: 3680-3686Crossref PubMed Scopus (70) Google Scholar,28Caballeria J Bruguera M Sole M Campistol JM Rodes J Hepatic familial amyloidosis caused by a new mutation in the apolipoprotein AI gene: clinical and pathological features.Am J Gastroenterol. 2001; 96: 1872-1876Crossref PubMed Scopus (22) Google Scholar29Eriksson M Schönland S Bergner R Hegenbart U Lohse P Schmidt H Röcken C Three German fibrinogen Aalpha-chain amyloidosis patients with the p.Glu526Val mutation.Virchows Arch. 2008; 453: 25-31Crossref PubMed Scopus (18) Google Scholar30Eriksson M Büttner J Todorov T Yumlu S Schönland S Hegenbart U Kristen AV Dengler T Lohs" @default.
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• W1842594908 title "Hereditary Apolipoprotein AI-Associated Amyloidosis in Surgical Pathology Specimens" @default.
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