title: Analysis of somatic hypermutation and antigenic selection in the clonal B cell in immunoglobulin light chain amyloidosis (AL).
abstract: Light chain amyloidosis (AL) is a protein folding disorder with an underlying B cell neoplasia where the monoclonal immunoglobulin light chains (LCs) produced from insoluble amyloid fibrils. The deposition of these fibrillar aggregates in vital organs causes severe organ dysfunction over time and is associated with high mortality. We have identified the postgerminal center status of the B cell clone by evaluating the presence of somatic hypermutation in the variable region of the LC gene in 27 (13 of the lambda and 14 of the kappa subtype) AL patients. Seven of the 27 clones showed statistically significant evidence of antigenic selection, using a multinomial algorithm. The framework region mutations were selected for conservation of protein structure in 13 of the 27 patients. Additionally, mutational clusterspots were identified at specific positions in the nucleotide and deduced protein sequence that could potentially contribute to destabilizing interactions resulting in a propensity to form amyloid.
authors.affiliation: Division of Hematology, Stabile 6-28, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. abraham.roshini@mayo.edu
authors.forename: Roshini S
authors.initials: RS
authors.lastname: Abraham
authors.forename: Susan M
authors.initials: SM
authors.lastname: Geyer
authors.forename: Marina
authors.initials: M
authors.lastname: Ramírez-Alvarado
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Price-Troska
authors.forename: Morie A
authors.initials: MA
authors.lastname: Gertz
authors.forename: Rafael
authors.initials: R
authors.lastname: Fonseca
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry; D000686:Amyloidosis / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology*; D002999:Clone Cells; D000939:Epitopes; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D027041:Somatic Hypermutation, Immunoglobulin
chemical_list: D000682:Amyloid; D000939:Epitopes; D007147:Immunoglobulin Light Chains