Mutational analysis in murine models for myeloma-associated Fanconi's syndrome or cast myeloma nephropathy

We have designed an in vivo model in which murine hybridoma cell clones pro ducing human Ig light chains (LC) are administered to mice, Depending on wh ich monoclonal LC is expressed, this model mimicks either cast myeloma neph ropathy or the pathological condition defined as myeloma-associated Fanconi 's syndrome (FS) with LC crystallization. Morphological alterations of the kidney cells are thus obtained in mice. Atl studied LC are closely related human monoclonal V kappa I proteins, which differ by a limited number of su bstitutions within the variable region. In the case of an FS monoclonal LC, we show that limited changes introduced through site-directed mutagenesis in the variable domain may suppress formation of intracellular crystals wit hin tubular cells. We also show that multiple peculiarities of the variable region are simultaneously needed to allow LC crystallization; this propert y thus likely results from a unique LC tridimensional conformation imposed by concomitant somatic mutations of a specific germinally encoded framework . (C) 1999 by The American Society of Hematology.