A type of white blood cell called plasma cells produced in the bone marrow, are responsible for producing the antibodies that detect foreign invaders including viruses. However, researchers have discovered a gene mutation in the cells that when present can result in the cell going into abnormal cell proliferation, with associated antibody production. Antibodies are comprised of two long and two short protein chains. The short chains in the antibody are called the light chains. Over-production of light chains leads to deposition of the excess material in various cell types and organs, and this causes a potentially fatal disease called amyloidosis.
A research team from the Technical University of Munich (TUM) and Heidelberg University has now identified the mutation behind the disease in a patient.
A recent paper titled, 'Fatal amyloid formation in a patient’s antibody light chain is caused by a single point mutation', demonstrates that they have identified the mutation behind this fatal disease.
Antibodies are normally vital for the survival of human beings. They typically consist of two longer and thus heavier amino acid chains and two lighter ones. In rare cases, the plasma cells multiply excessively, flooding the body with light antibody chains.
In people suffering from light chain amyloidosis (AL amyloidosis), these light chains are deposited as extremely fine fibers, so-called amyloid fibrils, in tissue or in organs. The disease is often recognized only after the deposits already compromise the function of organs. In many cases AL amyloidosis is fatal.
"To date, little was known about the exact cause of this amyloidosis," says Johannes Buchner, professor of biotechnology at the Technical University of Munich. “Depending on the organ affected, the symptoms vary considerably. Furthermore, each patient produces different types of antibodies. The disease is thus difficult to diagnose at an early stage.”
A mutation triggers the deadly disease
Using various analytical and database-supported methods, the team of scientists succeeded in identifying eleven mutations caused by the disease in the antibodies of a patient with advanced AL amyloidosis.
Further investigations showed that exactly one mutation was responsible for the destabilization and formation of the disease-causing amyloid fibrils. This mutation causes the unstable light chain to lose its structure after breaking into fragments, which then form the deadly amyloid fibrils.
"Our study shows that mutations that lead to unstable light chains are an important factor in the occurrence of amyloidosis," says Pamina Kazman, who carried out the majority of the measurements. "In the long term, we hope that these and other studies will lead to new, earlier diagnostic methods and possibly even new treatment options."
The protein structures were determined at the synchrotron radiation sources of the Paul Scherrer Institute in Villigen (Switzerland) and the European synchrotron radiation source in Grenoble (France).