Apolipoprotein CII Amyloidosis Associated With p.Lys41Thr Mutation

Sanjeev M Sethi, Surendra Dasari, Emmanuelle Plaisier, Pierre Ronco, Samih H. Nasr, Isabelle Brocheriou, Jason D. Theis, Julie A. Vrana, Michael T. Zimmermann, Patrick S. Quint, Ellen McPhail, Paul J. Kurtin

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Introduction: Apolipoprotein CII amyloidosis (AApoCII) is a rare form of amyloidosis. Here, we report a novel mutation associated with AApoCII amyloidosis in 5 patients and describe their clinical, renal biopsy, and mass spectrometry findings. Methods: Five patients with renal AApoCII p.Lys41Thr amyloidosis were identified from our amyloid mass spectrometry cohort. Clinical features, kidney biopsy, and mass spectrometry findings were analyzed in this rare type of amyloidosis. Results: The patients were older adults (mean age of 71.6 years at diagnosis), presented with nephrotic-range proteinuria, and often had declining renal function. All renal biopsy specimens showed massive mesangial nodules composed of weakly eosinophilic, periodic acid−Schiff negative, Congo red–positive amyloid deposits. There were no interstitial, vascular, or medullary deposits. In all cases, immunofluorescence studies were negative for Igs and electron microscopy showed amyloid fibrils. Proteomic analysis of Congo red−positive amyloid deposits detected large amounts of apolipoprotein CII (APOC2) protein. We also detected APOC2 p.Lys41Thr mutant protein in amyloid deposits of all patients. DNA sequencing in 1 patient confirmed the presence of the mutation. Both mutant and wild-type forms of APOC2 were detected in amyloid deposits of all patients. Molecular dynamic simulations showed the variant mediating a collapse of the native structure of APOC2, thereby destabilizing the protein. Conclusion: We propose that AApoCII p.Lys41Thr amyloidosis is a new form of amyloidosis seen in elderly individuals, histologically exhibiting massive glomerular involvement, leading to nephrotic-range proteinuria and progressive chronic kidney disease.

Original languageEnglish (US)
JournalKidney International Reports
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Apolipoprotein C-II
Amyloidosis
Amyloid Plaques
Mutation
Kidney
Congo
Mass Spectrometry
Biopsy
Proteinuria
Amyloid
Structure Collapse
Mutant Proteins
Molecular Dynamics Simulation
Chronic Renal Insufficiency
DNA Sequence Analysis
Proteomics
Fluorescent Antibody Technique
Blood Vessels
Electron Microscopy
Proteins

Keywords

  • amyloidosis
  • apolipoprotein CII
  • kidney
  • mutation
  • p.Lys41Thr
  • proteomics

ASJC Scopus subject areas

  • Nephrology

Cite this

Apolipoprotein CII Amyloidosis Associated With p.Lys41Thr Mutation. / Sethi, Sanjeev M; Dasari, Surendra; Plaisier, Emmanuelle; Ronco, Pierre; Nasr, Samih H.; Brocheriou, Isabelle; Theis, Jason D.; Vrana, Julie A.; Zimmermann, Michael T.; Quint, Patrick S.; McPhail, Ellen; Kurtin, Paul J.

In: Kidney International Reports, 01.01.2018.

Research output: Contribution to journalArticle

Sethi, SM, Dasari, S, Plaisier, E, Ronco, P, Nasr, SH, Brocheriou, I, Theis, JD, Vrana, JA, Zimmermann, MT, Quint, PS, McPhail, E & Kurtin, PJ 2018, 'Apolipoprotein CII Amyloidosis Associated With p.Lys41Thr Mutation', Kidney International Reports. https://doi.org/10.1016/j.ekir.2018.04.009
Sethi, Sanjeev M ; Dasari, Surendra ; Plaisier, Emmanuelle ; Ronco, Pierre ; Nasr, Samih H. ; Brocheriou, Isabelle ; Theis, Jason D. ; Vrana, Julie A. ; Zimmermann, Michael T. ; Quint, Patrick S. ; McPhail, Ellen ; Kurtin, Paul J. / Apolipoprotein CII Amyloidosis Associated With p.Lys41Thr Mutation. In: Kidney International Reports. 2018.
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AU - Dasari, Surendra

AU - Plaisier, Emmanuelle

AU - Ronco, Pierre

AU - Nasr, Samih H.

AU - Brocheriou, Isabelle

AU - Theis, Jason D.

AU - Vrana, Julie A.

AU - Zimmermann, Michael T.

AU - Quint, Patrick S.

AU - McPhail, Ellen

AU - Kurtin, Paul J.

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N2 - Introduction: Apolipoprotein CII amyloidosis (AApoCII) is a rare form of amyloidosis. Here, we report a novel mutation associated with AApoCII amyloidosis in 5 patients and describe their clinical, renal biopsy, and mass spectrometry findings. Methods: Five patients with renal AApoCII p.Lys41Thr amyloidosis were identified from our amyloid mass spectrometry cohort. Clinical features, kidney biopsy, and mass spectrometry findings were analyzed in this rare type of amyloidosis. Results: The patients were older adults (mean age of 71.6 years at diagnosis), presented with nephrotic-range proteinuria, and often had declining renal function. All renal biopsy specimens showed massive mesangial nodules composed of weakly eosinophilic, periodic acid−Schiff negative, Congo red–positive amyloid deposits. There were no interstitial, vascular, or medullary deposits. In all cases, immunofluorescence studies were negative for Igs and electron microscopy showed amyloid fibrils. Proteomic analysis of Congo red−positive amyloid deposits detected large amounts of apolipoprotein CII (APOC2) protein. We also detected APOC2 p.Lys41Thr mutant protein in amyloid deposits of all patients. DNA sequencing in 1 patient confirmed the presence of the mutation. Both mutant and wild-type forms of APOC2 were detected in amyloid deposits of all patients. Molecular dynamic simulations showed the variant mediating a collapse of the native structure of APOC2, thereby destabilizing the protein. Conclusion: We propose that AApoCII p.Lys41Thr amyloidosis is a new form of amyloidosis seen in elderly individuals, histologically exhibiting massive glomerular involvement, leading to nephrotic-range proteinuria and progressive chronic kidney disease.

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