Specific heterozygous variants in HMGB1 cause an extremely rare congenital disorder, called BPTAS, which is characterized mainly by limb malformations including smaller-than-normal or extra fingers or toes and absent or underdeveloped shin bones. Researchers identified two de novo frameshift variants in HMGB1 in five patients and in their subsequent functional analyses they revealed a pathomechanism that might also be relevant for other rare diseases.

HMGB1 encodes high mobility group box protein 1, a nuclear protein involved for example in DNA organization and transcription. In its protein structure, HMGB1 has an intrinsically disordered region. Such flexible regions in proteins can play an important role in the partitioning of membrane-free structures by promoting the formation of protein droplets. The nucleolus is an essential cellular organelle within the nucleus that does not possess a membrane. It is the place where subunits of the ribosomes are synthesized. The researchers discovered that the identified HMGB1 variants lead to the formation of an arginine-rich basic tail replacing the protein’s intrinsically disordered region. This results in a change of the protein’s charge, affecting the process of phase separation in the nucleolus and impairing its function. The authors assume that this mechanism may also be relevant for a large number of similar variants in other genes, if they affect intrinsically disordered protein regions.

The study led by scientists from Berlin Charité and Max-Planck Institute for Molecular Genetics as well as Schleswig-Holstein University Hospital has been published in Nature.