Mutational Analysis in Murine Models for Myeloma-Associated Fanconi’s Syndrome or Cast Myeloma Nephropathy

Abstract

We have designed an in vivo model in which murine hybridoma cell clones producing human Ig light chains (LC) are administred to mice. Depending on which monoclonal LC is expressed, this model mimicks either cast myeloma nephropathy 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. All studied LC are closely related human monoclonal VκI proteins, which differ by a limited number of substitutions 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 within tubular cells. We also show that multiple peculiarities of the variable region are simultaneously needed to allow LC crystallization; this property thus likely results from a unique LC tridimensional conformation imposed by concomitant somatic mutations of a specific germinally encoded framework.