Identification of a novel substitution in the constant region of a gene coding for an amyloidogenic κ1 light chain

J. Wally, G. Kica, Y. Zhang, T. Ericsson, L. H. Connors, Merrill Benson, J. J. Liepnieks, J. Murray, M. Skinner, R. L. Comenzo

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Current concepts regarding the association between immunoglobulin (Ig) light chain structure and AL amyloidosis (AL) emphasize Ig variable region amino acid substitutions because the majority of light chain amyloid fibrils that have been sequenced contain amino termini of the variable region with only small amounts of the constant region. In this report, we describe a patient with rapidly progressive AL whose amyloid deposits contained primarily monoclonal κ light chain constant region fragments. We sequenced and analyzed this AL protein, determining that it was an O18-O8 κ1 variant and that the constant region possessed an unusual Ser→Asn substitution at position 177. Using pre-mortem bone marrow cells, we cloned and sequenced the cDNA for this AL protein (HCAK1) and, using DNA from post-mortem somatic tissue, we cloned and sequenced the patient's κ germline O18-O8 donor and κ constant region (Cκ) gene segments. The cDNA that coded for HCAK1 contained a variable region that was derived from O18-O8, showing 96.1% homology to germline, and a Cκ that had a nucleotide substitution (AGC to AAC), resulting in the 177(Ser→Asn) replacement. Two Cκ genes were cloned from somatic tissue DNA, one identical to a known Cκ sequence and another containing this substitution which likely is a new Cκ allotype. Our findings indicate that further investigation is warranted into the contributions genetic polymorphisms and light chain constant regions may make to amyloidogenesis. Copyright (C) 1999 Elsevier Science B.V.

Original languageEnglish
Pages (from-to)49-56
Number of pages8
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1454
Issue number1
DOIs
StatePublished - May 31 1999

Fingerprint

Amyloidosis
Light
Genes
Complementary DNA
Immunoglobulin Variable Region
Immunoglobulin Light Chains
DNA
Amyloid Plaques
Genetic Polymorphisms
Amino Acid Substitution
Amyloid
Bone Marrow Cells
Proteins
Nucleotides
Tissue Donors

Keywords

  • Amyloid protein
  • Amyloidosis
  • Immunoglobulin gene
  • Kappa light chain constant region
  • Kappa light chain variable region

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Biophysics

Cite this

Identification of a novel substitution in the constant region of a gene coding for an amyloidogenic κ1 light chain. / Wally, J.; Kica, G.; Zhang, Y.; Ericsson, T.; Connors, L. H.; Benson, Merrill; Liepnieks, J. J.; Murray, J.; Skinner, M.; Comenzo, R. L.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1454, No. 1, 31.05.1999, p. 49-56.

Research output: Contribution to journalArticle

Wally, J. ; Kica, G. ; Zhang, Y. ; Ericsson, T. ; Connors, L. H. ; Benson, Merrill ; Liepnieks, J. J. ; Murray, J. ; Skinner, M. ; Comenzo, R. L. / Identification of a novel substitution in the constant region of a gene coding for an amyloidogenic κ1 light chain. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 1999 ; Vol. 1454, No. 1. pp. 49-56.
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