Sequence diversity of the light chains in two clinical variants of AL amyloidosis

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Systemic AL amyloidosis arises from the misfolding of antibody light chains. The disease is highly heterogeneous with highly different clinical presentations and a bewildering complexity of different fibril proteins. To determine the molecular principles underlying the variable pathology of this disease we will focus on two specifically important clinical variants of lambda AL amyloidosis, namely patients with prominent heart or kidney involvement. The detail aims will be: (i) To collect genetic material and clinical data from well-defined patients. (ii) To provide the DNA-sequences of 50 light chain sequences from patients with dominant heart and kidney involvement each and from 100 light chains from patients with multiple myeloma without AL amyloidosis. (iii) To analyze the obtained light chains and compare them with available clinical data. This subproject will test the hypothesis that that amino acid sequence has a major influence on light chain fragmentation, misfolding and deposition. We will further collect important plasma cell-derived parameters of the patients (free light chains amount in serum, light chain isotype and clonal plasma cell size in the bone marrow) to include these factors together with light chains sequence in a comprehensive model for a better understanding of organ tropism and toxicity in AL amyloidosis. The obtained sequence data will be required by all other subproject of this research unit.