Primary amyloidosis is a lethal disorder characterized by extracellular deposition of fibrils (amyloid) constituted of monoclonal light chain (LC) variable region (VL) fragments most frequently of X isotype. Deposition is systemic and progressive, but a single organ, or a combination of a few organs, usually dominates the clinical picture and affects prognosis and treatment. The mechanisms underlying VL gene amyloidogenicity and organ targeting are unknown, and characterization of VL gene usage may provide insights into these biologically and clinically relevant aspects. To these aims, we sequenced the monoclonal VL regions from 49 consecutive X amyloid patients. Patients were enrolled at the coordinating center of a National Amyloid Program. The predominant organ involved was kidney (#18, 37%), heart (#16, 33%), liver (#4, 8%), PNS, muscle (#3 each, 6%), OI (#2, 4%), or lung, skin, soft tissues (#1 each, 2%). Amyloid LC variable regions were isolated by an inverse PCR-based strategy (Perfetti et al, Blood 91:2948, 1998) and compared to germline databases. A monoclonal light chain V region was isolated in all cases. LC variable regions manifested somatic mutations, but the degree of mutation varied among the different VX families. We found the following gene family usage: XIII (#24, 49%), XVI (#11, 22%), XII (#8, 16%), XI (#5, 10%), and XIV (#1, 2%). Thirteen (43%) of the 30 X germline genes were used: 3r and 6a (#11 each, 22%), 3h (#5, 10%) 2a2, 31 (#4 each, 8%), Ib, 3m (#3 each, 6%), 2b2, 2e (#2 each, 5%), le, le, 3j, 4b (#1 each, 2%). The 3r gene was associated to various amyloid organ targets. By contrast, the known amyloid-associated XVI family gene, 6a, was frequently rearranged (8 of 11 cases, 73%) in patients with predominant or exclusive kidney involvement (Comenzo et al, Br J Haematol 106:744, 1999). Our results demonstrate that the most frequently used family is the XIII (49%), that two genes, 3r and 6a (22% each), encode for almost half of pathogenic X light chains, and that 6a appears to preferentially generate amyloid in the kidneys. Since 3r is rearranged at a frequency of 7-8% in the normal repertoire (Farner et al, J Immunol 162:2137, 1999), this same gene must have significant amyloidogenic properties.
|Issue number||11 PART I|
|Publication status||Published - 2000|
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