Nerve disease: The most common genetic factor of familial ALS discovered so far
The rare nerve disease amyotrophic lateral sclerosis (ALS) has been known to many people since the so-called "Ice Bucket Challenge". As part of the campaign, thousands of people around the world poured ice water over their heads to raise money for ALS research. Researchers have now identified the most common genetic factor in familial ALS.
Incurable nerve disease
The neurodegenerative disease ALS, which can include violent muscle twitches and severe swallowing problems, leads to the demise of the motor nerve cells and thus to progressively progressive paralysis. The relatively rare disease - about three out of 100,000 people are affected every year - has not yet been curable. Although prominent patients such as physics professor Stephen Hawking and the “Ice Bucket Challenge” made ALS better known in summer 2014, treatment is still difficult, mainly because the actual causes have not yet been identified. But researchers have now discovered the most common genetic factor of familial ALS.
Interaction of several genetic defects
Researchers at Ulm University Medical Center have discovered mutations in the KIF5A gene that can trigger the hereditary variant of the neurodegenerative disease amyotrophic lateral sclerosis (ALS).
According to a message, this is the most commonly identified genetic factor in patients to date that contributes to the development of ALS.
The study, now published in the renowned journal "Brain", also underpins the assumption that the fatal disease is based on the interaction of several genetic defects.
Illness leads to death within a few years
As a rule, the complex and currently incurable neurodegenerative disease ALS leads to death within three to five years after the onset of the disease.
The sporadic variant is distinguished from the hereditary (“familial”) form, which only makes up about ten percent of the diseases. In both cases, the origin of the disease is not yet fully understood.
Advances in DNA sequencing technology have enabled scientists to identify multiple genes whose mutation predisposes to ALS.
However, these mutations only explain the cause of less than 25 percent of all illnesses.
Several genetic changes are likely to interact when the disease develops
Now researchers from the Ulm University Clinic for Neurology (Rehabilitation and University Clinic Ulm) and the Swedish University of Umeå have compared the genome of 426 ALS patients who had at least one other relatives with a healthy control group (using so-called “total exome sequencing ").
The scientists led by Professor Jochen Weishaupt and Professor Peter Andersen were able to identify three so-called splice site mutations in the C-terminal domain of the KIF5A gene in ALS patients, which lead to a loss of function of the corresponding gene.
In three families examined, the inheritance of the disease was linked to such a mutation over several generations.
In addition, the authors found an accumulation of the single nucleotide polymorphism (Single Nucleotide Polymorphism / SNP) rs113247976, which also affects the KIF5A gene, in several patients with familial ALS.
“We were able to detect this polymorphism in six percent of familial ALS patients and again 50 percent of them had at least one mutation in another known ALS gene. This suggests that multiple genetic defects often interact when the disease is inherited, ”explain Professor Weishaupt and first author Dr. David Brenner.
Of all the genetic changes that have been found in ALS patients worldwide since 1993, rs113247976 is the most common genetic factor that contributes to the development of the disease.
Other neurological disorders associated with the affected gene
The KIF5A gene is the blueprint for a protein that is involved in the transport of substances in the axon of a nerve cell. The study results thus underline the importance of intracellular transport processes in the development of ALS.
In addition, other neurological diseases are associated with different changes in the KIF5A gene (hereditary spastic paraplegia, Charcot-Marie-Tooth disease type 2, neonatally intractable myoclonus).
In the future, the findings that have now been published could contribute to new molecular therapeutic approaches.
"In summary, this study adds KIF5A to a growing list of genes that cause ALS and expands the spectrum of mutations in this gene," said Professor Albert Ludolph, medical director of the Ulm University Hospital for Neurology.
The high prevalence of the SNP KIF5A rs113247976 in familial ALS patients also fueled the hypothesis that different genetic defects interacted in one patient. This could also explain part of the sporadic, non-familial ALS cases genetically.
New insights into the causes of ALS
Other researchers have also gained important insights into the causes of ALS in recent years.
For example, Australian scientists have found new gene variants that contribute to the disease in many cases.
According to a release published on the ScienceDaily portal, Professor Naomi Wray of the University of Queensland said: “These three new genes open up new opportunities for research to understand a complex and debilitating disease that it is currently against is not yet an effective treatment. "
The study results of Dutch researchers are also interesting. As the experts from Utrecht University reported in the journal "Occupational & Environmental Medicine", electromagnetic fields can obviously also trigger ALS. (ad)