Researchers identify new gene responsible for liver disease.


Acute liver failure is a rare yet life-threatening disease for young children. It often occurs extremely rapidly, for example, when a child has a fever. Yet in around 50 percent of cases it is unclear as to why this happens. Now, a team of researchers working on an international research project headed by Technische Universität München (TUM), the Helmholtz Zentrum Munich and Heidelberg University Hospital have discovered a link between the disease and mutations in a specific gene. The researchers used whole genome sequencing to uncover the mutations, which affect transport processes in cells.  The opensource study is published in the American Journal of Human Genetics.

According to the European Union, a disease such as acute liver failure is classified as rare if it affects less than five in 10,000 people. Yet despite low patient numbers, research into rare diseases has been on the rise in recent years. Previous studies show that the reason for this is that many of these illnesses have a genetic cause that researchers can pinpoint. The findings could also provide important insights into metabolic processes in healthy people or serve as a model for other diseases.

The team has spent 20 years caring for several patients who have suffered from recurrent acute liver failure since childhood. They state that the similarities in the progression of the disease led them to suspect that there might be a common cause.  To investigate this the current study examined four children suffering from recurrent, fever-dependent liver failure in a bid to identify a genetic cause. The researchers initially focused on the genetic similarities in these children to determine a possible cause for their disease.

The current study used exome sequencing to do this, a process that involves sequencing all subsets of a patient’s DNA that contain information on creating protein. The team also examined the DNA of close family members. In multiple instances, they discovered mutations in one specific gene. The results identified mutations in the NBAS gene in a total of 11 patients. The team state that to their knowledge this is the first time a link has been established between this gene and liver disease. They go on to add that this discovery could also be interesting for other illnesses.

The researchers state that they were also keen to find out exactly how these mutations affect cellular processes. To do this, they carried out a number of molecular biology experiments. The data findings showed that when the mutations were present in the NBAS gene, only small amounts of the NBAS protein were created. NBAS is involved in cell transport processes that pack proteins in vesicles and transport them from one cell compartment to another.  The team state that they were able to show that the faulty protein is more susceptible to heat. They go on to explain that this means that when an individual has a fever, there are fewer proteins available for coordinating the transport processes. This, in turn, can have a negative impact on metabolic processes in the liver in an acute situation.

The researchers surmise that the primary aim is to improve the diagnosis of rare diseases such as acute liver failure in childhood and pave the way for targeted treatment. They go on to add that when a child suffers from liver failure triggered by fever, they can now specifically investigate the NBAS gene.

The team note that over the years they have been able to empirically develop a therapy that uses specific drugs as well as sugar and fat infusions. They conclude that these can be immediately administered once a patient is diagnosed and that they can now use the latest findings to further improve therapeutic approaches.

Source:  Technische Universität München (TUM)

NBAS Structure and Conservation of Identified Mutations.  Gene structure of NBAS with known protein domains of the gene product and localization and conservation of amino acid residues affected by mutations. Mutation c.5741G>A (p.Arg1914His) in exon 45 in the C-terminal domain of unknown function is associated with SOPH syndrome.17 Amino acids 90–371 form a quinoprotein aminedehydrogenase, beta chain like domain (IPR011044) and amino acids 725–1,376 form a secretory pathway sec39 domain (IPR013244). Intronic regions are not drawn to scale.  Biallelic Mutations in NBAS Cause Recurrent Acute Liver Failure with Onset in Infancy.  Prokisch et al 2015.

NBAS Structure and Conservation of Identified Mutations. Gene structure of NBAS with known protein domains of the gene product and localization and conservation of amino acid residues affected by mutations. Mutation c.5741G>A (p.Arg1914His) in exon 45 in the C-terminal domain of unknown function is associated with SOPH syndrome.17 Amino acids 90–371 form a quinoprotein aminedehydrogenase, beta chain like domain (IPR011044) and amino acids 725–1,376 form a secretory pathway sec39 domain (IPR013244). Intronic regions are not drawn to scale. Biallelic Mutations in NBAS Cause Recurrent Acute Liver Failure with Onset in Infancy. Prokisch et al 2015.

 

 

 

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