Almost 6000 of the estimated 9000 genetic diseases have been unraveled, more than two thirds through the new exome and genome sequencing technologies. The search for disease-causing genes has become faster and more efficient thanks to the sequencing of exomes and genomes.
For several years now, scientists have been able to store newly identified, potential disease genes in a database, the GeneMatcher. As soon as another patient appears worldwide with a mutation in the same gene, both parties are notified and a cooperation can begin. The functional analysis of these variants and the analysis if their consequences in cells and the organism, remains complex and requires a wide range of experimental expertise.
The research group around Professor Dr. Brunhilde Wirth at the Institute for Human Genetics, the Center for Molecular Medicine Cologne (CMMC) and the Center for Rare Diseases at the University Hospital Cologne has now identified mutations in the GBF1 gene that cause a new type of motor neuropathy. The scientists published their results in the prestigious journal, The American Journal of Human Genetics.
Peripheral neuropathies often have a genetic cause. The first clinical symptoms of this disease often appear after the fourth to fifth decade of life. While the search for causal genes in genetic diseases that manifest in childhood can be made easier through family analysis, the search for peripheral neuropathies is complicated in several ways. On the one hand, the late onset of the disease makes it difficult to find out whether it is an acquired or an inherited disease; on the other hand, access to parental samples is often no longer possible.
Dr. Mert Karakaya from the working group of Prof. Dr. Brunhilde Wirth found a new causative disease gene, GBF1, through the exome analysis of a 58-year-old affected person and his parents. The exome comprises all approx. 20,000 genes of our genetic material, but only corresponds to approx. 2% of the entire genome (the entire genetic material in one nucleus of a cell). The exome can be sequenced in just a few hours using next-generation sequencing technology. A new mutation in the GBF1 gene was found through the parallel analysis of the affected person and his parents. GBF1 stands for Golgi Brefeldin-A Resistant Guanine Nucleotide Exchange Factor 1, a protein with important functions in the Golgi apparatus, the mitochondria but also in the context of infection with corona and other viruses. Working with scientists around the world and the GeneMatcher database, additional families and patients with mutations in GBF1 have been identified. A total of seven affected people were identified in four families.
The loss of the function of GBF1 leads to an impairment of the motor neurons in the spinal cord. Motor neurons are nerve cells whose cell bodies are located in the spinal cord and which form projections over 1 m long, called axons, to the muscles in order to control trigger contractions. The neuromuscular synapse, the largest synapse between two cells, is located at the junction between the nerve ending and the muscle fiber.
The postdoc Dr. Natalia Mendoza-Ferreira and other members of the Wirth research group found that the GBF1 mutations lead to a fragmentation of the Golgi apparatus, which impairs its function. The Golgi apparatus is an important organelle in our cells that, among other things, ensures the formation of secretory vesicles, lysosomes and plasma membranes as well as the modification of proteins. Since nerve cells do not divide, transport along the axons is very important, and the Golgi apparatus plays an important role in this. A disturbed function of the Golgi apparatus ultimately leads to degeneration of the motor neurons causing the peripheral neuropathy.
In the future, the scientists in Cologne hope to contribute to the elucidation of further of the approx. 3000 remaining disease-causing genes. The Institute of Human Genetics has identified and published over 70 new disease genes since it was founded in 2004. Vigorous research is already underway to elucidate several new disease genes.
Mendoza-Ferreira N *, Karakaya M *, Cengiz N, Beijer D, Brigatti KW, Gonzaga-Jauregui C, Fuhrmann N, Hölker I, Thelen MP, Zetzsche S, Rombo R, Puffenberger EG, De Jonghe P, Deconinck T, Zuchner SL, Strauss KA, Carson V, Cabinet B, Wunderlich G, Baets J, Wirth B. De Novo and Inherited Variants in GBF1 are Associated with Axonal Neuropathy caused by Golgi Fragmentation
Am J Hum Genet., online 15.09.2020
* First authors with equal participation
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