Only three individuals have been diagnosed with an extremely rare genetic disease that causes them to age very rapidly. Researchers have now described exactly what the genetic mutations do and how this manifests itself. One researcher involved says that this knowledge will not directly enable a cure but will contribute to improving understanding of the disease and the people who have it.
Only three people have a very special accelerated ageing disease called Néstor-Guillermo progeria syndrome (NGPS) caused by mutations in the BAF1 gene thatlead to accelerated ageing, so individuals with NGPS or another type of progeria age very rapidly.
Because NGPS is so extremely rare, researchers know very little about it and why mutations in BAF-1 so extensively change the ageing process.
However, this is changing through a new study in which researchers described exactly what BAF-1 does, since mutations in this gene can create so much turmoil.
The research has been published in the EMBO Journal.
“Unfortunately, this study is not going to affect the lives of the three people identified as having NGPS. Instead, we can learn more about the role of BAF-1 in the cell nuclear envelope, since these individuals age faster. This is basic research that can expand long-term knowledge on both progeria and the ageing process as a whole – even for healthy people,” explains a researcher behind the study, Peter Askjær, a biologist and principal investigator at the Andalusian Center for Developmental Biology, Seville, Spain.
NGPS is caused by a mutation
Peter Askjær aims to understand how chromosomes and the genes in the cell nuclear envelope are organised. The cell nucleus contains two metres of DNA, which requires it to be folded carefully around itself.
In some diseases, including progeria, the folding does not take place normally, and studies on misfolding associated with disease can expand researchers’ knowledge on how chromosomes and genes should fold correctly.
When Peter Askjær and colleagues heard that two individuals in Spain had been diagnosed with NGPS, they set out to investigate how a dysfunctional BAF-1 protein affects chromosome folding.
“Classic progeria is often caused by a mutation in LMNA that encodes lamin A and C protein located in the cell membrane that helps to organise the chromosomes and genes. When LMNA mutates, the protein cannot perform its role, and this leads to genes not being read correctly and many cells in the body ageing more rapidly than normal. In our research, we aimed to determine the role of BAF-1, since the symptoms of progeria are very similar in both types,” says Peter Askjær.
Studied mutant worms
The researchers mutated BAF-1 in the Caenorhabditis elegans worm and investigated how this affects the organisation of the chromosomes in the cell nucleus of the skin and intestinal system of C. elegans.
The skin often shows clear signs of ageing when people have progeria – thin and fragile like an older person. The intestines have a major role in metabolism and also show these clear signs of ageing.
The results revealed the role of BAF-1 in the cell nucleus and in relation to lamin A and progeria.
A mutation in BAF-1 changes how it binds to the chromosomes and the presence of lamin A in the nuclear membrane.
Less lamin A is present in the nuclear membrane, and this may explain the link between the symptoms associated with classic progeria (Hutchinson-Gilford progeria syndrome) and the symptoms associated with NGPS.
“Envision that mutations change the composition of proteins in the nuclear membrane and that proteins can no longer bind optimally to each other or to the chromosomes. This results in various genes changing gene expression, which leads to the premature ageing symptoms in both types of progeria,” notes Peter Askjær.
He elaborates that when lamin A and BAF-1 anchor the chromosomes to the nuclear membrane, the genes located in the relevant regions are often not expressed very strongly. But when this anchoring is missing, the genes are overexpressed.
“The hypodermal and intestinal cells showed the typical signs that they had aged more rapidly than normal because we had mutated BAF-1,” says Peter Askjær.
Knowledge about what causes progeria
Peter Askjær says that the clinical symptoms of the two types of progeria have many similarities.
Worldwide, about 400 people have classic progeria. However, people with classic progeria differ from the three individuals identified with BAF-1 mutations.
Individuals with classic progeria often have heart problems, which do not affect the three people with BAF-1 mutations. Nevertheless, they have very severe osteoporosis.
“Naturally, we hope that we can eventually help these people. However, this is not possible until we understand NGPS better, and this study is a step in this direction. We now know the role of BAF-1 in the nuclear membrane and how mutations in BAF-1 lead to incorrect gene expression in all cells, resulting in symptoms of progeria,” concludes Peter Askjær.
