title: Unraveling of the polymorphic C lambda 2-C lambda 3 amplification and the Ke+Oz- polymorphism in the human Ig lambda locus.
abstract: Two polymorphisms of the human Ig(lambda) (IGL) locus have been described. The first polymorphism concerns a single, 2- or 3-fold amplification of 5.4 kb of DNA in the C(lambda)2-C(lambda)3 region. The second polymorphism is the Mcg(-)Ke(+)Oz(-) isotype, which has only been defined via serological analyses in Bence-Jones proteins of multiple myeloma patients and was assumed to be encoded by a polymorphic C(lambda)2 segment because of its high homology with the Mcg(-)Ke(-)Oz(-) C(lambda)2 isotype. It has been speculated that the Mcg(-)Ke(+)Oz(-) isotype might be encoded by a C(lambda) gene segment of the amplified C(lambda)2-C(lambda)3 region. We now unraveled both IGL gene polymorphisms. The amplification polymorphism appeared to result from a duplication, triplication, or quadruplication of a functional J-C(lambda)2 region and is likely to have originated from unequal crossing over of the J-C(lambda)2 and J-C(lambda)3 region via a 2.2-kb homologous repeat. The amplification polymorphism was found to result in the presence of one to five extra functional J-C(lambda)2 per genome regions, leading to decreased Ig(kappa):Ig(lambda) ratios on normal peripheral blood B cells. Via sequence analysis, we demonstrated that the Mcg(-)Ke(+)Oz(-) isotype is encoded by a polymorphic C(lambda)2 segment that differs from the normal C(lambda)2 gene segment at a single nucleotide position. This polymorphism was identified in only 1.5% (2 of 134) of individuals without J-C(lambda)2 amplification polymorphism and was not found in the J-C(lambda)2 amplification polymorphism of 44 individuals, indicating that the two IGL gene polymorphisms are not linked.
authors.affiliation: Department of Immunology, Erasmus University Rotterdam/University Hospital Rotterdam, Rotterdam, The Netherlands.
authors.forename: Mirjam
authors.initials: M
authors.lastname: van der Burg
authors.forename: Barbara H
authors.initials: BH
authors.lastname: Barendregt
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: van Gastel-Mol
authors.forename: Talip
authors.initials: T
authors.lastname: Tümkaya
authors.forename: Anton W
authors.initials: AW
authors.lastname: Langerak
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: van Dongen
mesh_terms: D044466:Asian People / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001536:Bence Jones Protein / Q000235:genetics; D015139:Blotting, Southern; D005784:Gene Amplification / Q000276:immunology*; D005787:Gene Frequency / Q000276:immunology; D005819:Genetic Markers / Q000276:immunology; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000097:blood / Q000737:chemistry / Q000235:genetics*; D007132:Immunoglobulin Isotypes / Q000097:blood / Q000737:chemistry / Q000235:genetics*; D007145:Immunoglobulin kappa-Chains / Q000032:analysis / Q000097:blood / Q000235:genetics; D007146:Immunoglobulin lambda-Chains / Q000097:blood / Q000737:chemistry / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000276:immunology*; D044465:White People / Q000235:genetics
chemical_list: D005819:Genetic Markers; D007127:Immunoglobulin Constant Regions; D007132:Immunoglobulin Isotypes; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D001536:Bence Jones Protein