Blood, Vol. 94 No. 10 (November 15), 1999:
pp. 3559-3566
Mutational Analysis in Murine Models for Myeloma-Associated Fanconi's
Syndrome or Cast Myeloma Nephropathy
C. Decourt,
A. Rocca,
F. Bridoux,
F. Vrtovsnik,
J.L. Preud'homme,
M. Cogné, and
G. Touchard
From the Laboratoire d'Immunologie, CNRS EP118, Centre Hospitalier
Universitaire de Limoges, Limoges; the Laboratoire d'Immunologie CNRS
ESA 6031, Université de Poitiers; Service de Néphrologie,
Centre Hospitalier Universitaire de Poitiers, INSERM U426,
Hôpital Bichat, Paris; and Institut Universitaire de France,
Limoges, France.
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 V
I
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.
