The research group of Prof. Brunhilde Wirth from the Institute of Human Genetics (Univ. Hospital of Cologne) and the Center for Molecular Medicine Cologne (CMMC), in collaboration with the research group of Prof. Henry Houlden from the Department of Molecular Neuroscience of the University College London, identified mutations in the VAMP1 gene as cause of a new type of congenital myasthenic syndrome.
This work has been published in the prestigious journal Annals of Neurology on March 2, 2017.
Both PIs are in the Neuromics project (Integrated European-Omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases).
“Myasthenic” is the medical adjective referring to muscular weakness.
Patients affected by myasthenic disorders show impairments in muscular contraction and, consequently, muscular weakness. The main structure affected in myasthenic disorders is the neuromuscular junction, which is the largest synapse in our body. This is a highly-specialized interface between the nervous system and the muscle. Here, electric impulses from the nerves trigger the release of chemical neurotransmitters from storage vesicles into the synaptic space. These molecules are then able to bind specific muscular receptors, leading to the muscular contraction. The disruption of this crucial process therefore leads to myasthenic disorders.
PhD students Andrea Delle Vedove and Dr. Markus Storbeck from the research group of Prof. Wirth and Dr. Vincenzo Salpietro from the research group of Prof. Houlden independently identified and characterized mutations in the VAMP1 gene in individuals affected by a congenital myasthenic disorder. Both groups are part of a large European research program called NEUROMICS, aimed to identify at least 100 novel disease genes for neuromuscular and neurodegenerative disorders within a 5-year funding period.
Whole genome sequencing of the affected siblings and their parents was used to unravel VAMP1 as the disease-causing gene. The two groups shared their data in a very early stage, which led to this successful story. The researchers are particularly proud of this open-minded strategy from which people with rare disorders have an immediate benefit. In this case, the new finding allowed the treatment of the patients with pyridostigmin, a drug known to be effective in other types of myasthenic syndromes. All patients improved under therapy.
VAMP1 is essential for docking of synaptic vesicles to the plasma membrane in order to release the neurotransmitter acetylcholine and induce muscle contracture on the postsynaptic side. Lack of VAMP1 causes reduced stimulation of the muscle and weaker contraction. Mice lacking this protein show a progressive lack of movements, which leads to premature death.
Salpietro V*, Lin W*, Delle Vedove A*, Storbeck M, Liu Y, Efthymiou S, Manole A, Wiethoff S, Ye Q, Saggar A, McElreavey K, Krishnakumar S, Pitt M, Bello O, Rothman JE, Basel-Vanagaite L, Hubshman MW, Aharoni S, Manzur AY, Wirth B#, Houlden H#. Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome.
Ann Neurol, 2017 Mar 2. DOI: 10.1002/ana.24905.
* equally contributing first authors, # equally contributing senior authors
Press release - University Hospital Cologne
Brunhilde Wirth - CMMC Project C16 (funding period 01/2017-12/2019
Unraveling the molecular and cellular mechanism underlying spinal muscular atrophy by use of genetic modifiers
For further information, please contact
Prof. Dr. Brunhilde Wirth
Director of the Institute for Human Genetics and
associated with the Center for Molecular Medicine Cologne (CMMC)