Variation of the AL protein primary structure in two clinical variants of AL amyloidosis

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A key limitation of the research into AL amyloidosis arises from the fact that hardly any AL protein is known by its exact primary structure. Crucial features such as on posttranslational modifications and proteolytic cleavage remained therefore obscure. The detail aims will be: (i) to collect tissue, urine and serum from AL patients, (ii) to determine the primary structure of approximately 100 AL proteins, (iii) to analyze the light chains in serum and urine, (iv) to correlate AL protein properties with patient characteristics. Through this work we will test the hypothesis that proteolytic truncation or posttranslational modifications contribute to determining the pathogenicity of a given light chain, the organ tropism of the amyloid and the clinical outcome of the disease. This work will elucidate the natural diversity of AL proteins as an essential first step to reveal common principles in the mechanism of AL protein formation and thus in the etiology of AL amyloidosis in vivo. We will in particular test whether inclusion of these protein structural features improves the prediction of the clinical presentation of the affected patients or whether posttranslational modifications might underlie the development of different patient cohorts.