Researchers at the University Medical Centre Ulm discovered mutations in the KIF5A gene which can trigger the hereditary variant of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). One of them is the most commonly detected genetic factor in patients that contributes to the development of ALS. The study, which was published by the renowned journal Brain, also supports the hypothesis that the fatal disease has a combination of several gene defects at its base.

ALS is a complex and currently incurable neurodegenerative disease which causes the decay of motor neurons and consequently progressing paralyses. The relatively rare disease - about three out of 100,000 people are newly affected every year - gained publicity through famous patients like the physics professor Stephen Hawking and the 'Ice Bucket Challenge' in the summer of 2014. ALS frequently leads to death within three to five years after the onset of the illness. The hereditary ('familial') form, as opposed to the sporadic variant, makes up only about 10 percent of all cases. The development of the disease is not yet completely understood in both variants. Thanks to recent progress in DNA sequencing technology, scientists were able to identify several genes whose mutations pose a predisposition for ALS. However, these mutations explain less than 25 percent of all cases.

Researchers at the University Clinic for Neurology in Ulm (Rehabilitation and University Medical Centre Ulm) and the Swedish University in Umeå compared the genome of 426 ALS patients who had at least one other diseased relative with that of a healthy control group (via a process called whole exome sequencing). The researchers around Professor Jochen Weishaupt and Professor Peter Andersen were able to identify in the ALS patients three 'splice site mutations' in the C-terminal domain of the KIF5A gene, which cause the loss of function of the respective gene. In three of the researched families, the inheritance of the illness was linked to one of those mutations across several generations. The authors also found in numerous familial ALS patients an enrichment of the single nucleotide polymorphism (SNP) rs113247976, which also affects the KIF5A gene. 'We found this polymorphism in six percent of familial ALS patients and 50 percent of those had at least one mutation in another known ALS gene. This indicates an interrelation of several genetic defects in the heredity of the disease,' explain Professor Weishaupt and first author Dr. David Brenner. Among all genetic mutations found in ALS patients worldwide since 1993, rs113247976 is the most prevalent genetic factor contributing to the development of the illness.

The KIF5A gene is the blueprint for a protein that is involved in the transport of substances in the axon of nerve cells. The study results therefore emphasise the importance of intracellular transport processes in ALS pathogenesis. Other neurological diseases are also associated with various mutations in the KIF5A gene (hereditary spastic paraplegia, Charcot-Marie-Tooth diseases type 2, neonatal intractable myoclonus). The published findings could contribute to new approaches in molecular therapy.

'In summary, this study adds KIF5A to a constantly growing list of genes that cause ALS and expands the spectrum of mutations in this gene,' asserts Professor Albert Ludolph, Medical Director of the University Clinic for Neurology in Ulm. The high prevalence of the SNP KIF5A rs113247976 in familial ALS patients also supports the hypothesis of an interplay of a variety of genetic defects in a patient. This could also genetically explain some of the sporadic, non-hereditary ALS cases.

The German side of the study received funding predominantly from the Federal Ministry of Education and Research (BMBF), German Society for Patients with Neuromuscular Disease (DGM), the German Research Association (ALS Register Schwaben), the German ALS network (MND-NET) as well as the Baden-Württemberg Foundation.

Text and media contact: Annika Bingmann

Literature reference:
David Brenner, Rüstem Yilmaz, Kathrin Müller, Torsten Grehl, Susanne Petri, Thomas Meyer, Julian Grosskreutz, Patrick Weydt, Wolfgang Ruf, Christoph Neuwirth, Markus Weber, Susana Pinto, Kristl G. Claeys, Berthold Schrank, Berit Jordan, Antje Knehr, Kornelia Günther, Annemarie Hübers, Daniel Zeller, The German ALS network MND-NET, Christian Kubisch, Sibylle Jablonka, Michael Sendtner, Thomas Klopstock, Mamede de Carvalho, Anne Sperfeld, Guntram Borck, Alexander E. Volk, Johannes Dorst, Joachim Weis, Markus Otto, Joachim Schuster, Kelly del Tredici, Heiko Braak, Karim M. Danzer, Axel Freischmidt, Thomas Meitinger, Tim M. Strom, Albert C. Ludolph, Peter M. Andersen and Jochen H. Weishaupt. Hot-spot KIF5A mutations cause familial ALS. Brain. DOI: 10.1093/brain/awx370