The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve.
For the first time mutations in a newly identified disease gene, VWA1, explain the frequent falling and late learning to walk in some young children. Those affected previously lacked diagnosis.
Also suffering from the gene mutation is a patient whose childhood data had been recorded in a database programmed 30 years ago by medical informaticist Dr. Radu Wirth. After 21 years, the human geneticist Prof. Dr. Brunhilde Wirth, University Medicine Cologne, and her team have now solved this previously unsolved case and unraveled the genetic cause of the disease. This medical "detective story" has now been published in the scientific journal "Brain" with the following titel: An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy (Brain, Online Brain, awaa420, https://doi.org/10.1093/brain/awaa420)
A 10 base pair (bp) insertion in a very difficult to sequence region of the VWA1 gene occurs in about 1 in 1000 people in the European population. Genome sequencing and new analyzing software made the detection of the mutation possible.
Professor Henry Houldon of University College London and a group of international researchers including a research group from Cologne have uncovered mutations in the VWA1 gene in patients with a mild course of a condition similar to spinal muscular atrophy (SMA).
Advanced genome sequencing techniques and new evaluation programs have enabled the discovery of a mutation located in a very difficult to sequence region of the genome that occurs in 1:500 to 1:1000 Europeans. The disease is inherited in an autosomal recessive manner, meaning that mutations must be present on both parental VWA1 genes for the neuromuscular disease to develop. This mutation destroys the function of the protein, which plays an important role in the extracellular matrix, the area between cells. The preliminary results were presented by Dr. Alistair Pagnamenta of the University of Oxford at the Virtual European Meeting on Human Genetics in June 2020.
Professor Brunhilde Wirth (Institute of Human Genetics, Center for Molecular Medicine Cologne (CMMC) and Center for Rare Diseases Cologne at the University of Cologne) contacted the English group and informed them about the "treasure " of unsolved SMA cases in Cologne. Dr. Radu Wirth programmed a rapid query of the database and uncovered about 2,000 unresolved SMA cases. Postdoctoral researcher Marlen Lauffer and master's student Isabell Brusius from Wirth's research group sequenced the VWA1 gene for mutations in more than 1,000 patients with suspected SMA in just a few weeks. This database now lists more than 3500 patients with suspected SMA; about half of the cases are still genetically unsolved.
After only a few days, the first patient was found with this very defect - a 10 base pair insertion and a second mutation in a different VWA1 gene segment. The patient's blood sample was sent to Brunhilde Wirth at the Institute of Human Genetics in Bonn 21 years ago, when she habilitated there. While Brunhilde Wirth was allowed to transfer all samples from patients with suspected SMA to Cologne after she accepted her appointment, the files remained in Bonn. This made it difficult to clarify the identity of the patient. A call to Bonn was unsuccessful. However, the sender of the blood sample was still noted in the database: an inquiry with the pediatrician, however, also came to nothing.
Professor Wirth then searched the Internet for the patient's name and place of residence, hoping to find a telephone entry - again without success. But she surprisingly found a news item reporting on an accident involving a young woman who had lost a limb and was now teaching a course to sensitize young people to the tragic consequences of a car accident. The name, date of birth, and region of the patient described matched the affected person with the VWA1 mutations. A call to the trauma surgery department there revealed that it was very likely the patient they were looking for, but there was no longer access to the electronic record. Wirth then asked to be put in touch with a senior physician in charge, whom she informed by e-mail of her research in the service of science. A few minutes later, the doctor wrote that he knew the patient and would contact the family right away.
Ten minutes later, the family contacted Professor Wirth by phone, amazed that after more than 20 years the cause of the disease could finally be discovered. The affected woman, who now works as a physiotherapist, made her thoroughly stored medical records available to the researchers. They were of great use: A detailed account of the course of the illness was added to the current publication in "Brain."
After another three days, the patient came in person to the Center for Rare Diseases at the University Hospital of Cologne. The center combines diagnostics, therapy and research of rare diseases in its subcenters. It combines interdisciplinary cooperation and the close connection of patient care and research. The patient received extensive human genetic counseling from Dr. Mert Karakaya (Human Genetics, University Hospital Cologne) and neurological examinations from Dr. Gilbert Wunderlich (Neurology, University Hospital Cologne). After more than 20 years, a targeted therapy can now finally begin. In addition, videos and pictures were made and attached to the publication.
Wirth comments: "This case shows that in rare diseases it is extremely important not to destroy medical records or DNA samples. Bioinformatics also plays a major role, she says, with a database enabling rapid selection of DNA samples suitable for a scientific question. Only in this way patients will have the chance to clarify their disease for themselves and their relatives, and that also retrospectively after many years." "Only after the diagnosis targeted therapy can begin in the best case," Wirth adds. Her message is: a declaration of consent for the long-term storage of samples and data, as well as participation in scientific investigations is of importance to enable progress in the understanding of molecular mechnisms of diseases and targeted therapies.
An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy
Alistair T Pagnamenta*, Rauan Kaiyrzhanov*, Yaqun Zou*, Sahar I Da'as,* Reza Maroofian*, Sandra Donkervoort, Natalia Dominik, Marlen Lauffer, Matteo P Ferla, Andrea Orioli, Adam Giess, Arianna Tucci, Christian Beetz, Maryam Sedghi, Behnaz Ansari, Rita Barresi, Keivan Basiri, Andrea Cortese, Greg Elgar, Miguel A Fernandez-Garcia, Janice Yip, A Reghan Foley, Nicholas Gutowski, Heinz Jungbluth, Saskia Lassche, Tim Lavin, Carlo Marcelis, Peter Marks, Chiara Marini-Bettolo, Livija Medne, Ali-Reza Moslemi, Anna Sarkozy, Mary M Reilly, Francesco Muntoni, Francisca Millan, Colleen C Muraresku, Anna C Need, Andrea H Nemeth, Sarah B Neuhaus, Fiona Norwood, Marie O'Donnell, Mary O’Driscoll, Julia Rankin, Sabrina W Yum, Zarazuela Zolkipli-Cunningham, Isabell Brusius, Gilbert Wunderlich, Genomics England Research Consortium , Mert Karakaya, Brunhilde Wirth, Khalid A Fakhro, Homa Tajsharghi, Carsten G Bönnemann*, Jenny C Taylor*, Henry Houlden* (2021) Brain, Online Brain, awaa420, published January 18, 2021 https://doi.org/10.1093/brain/awaa420
* authors contributed equally to this work, Cologne authors are indicated in bold
Univ.-Prof. Dr. Brunhilde Wirth
Institute for Human Genetics / Center of Rare Diseases Cologne, University Hospital Cologne / Center for Molecular Medicine Cologne University of Cologne
Original press release: https://portal.uni-koeln.de/universitaet/aktuell/presseinformationen/detail/erkrankungsursache-mit-21-jahre-alter-blutprobe-geklaert
StephanieWolff - Communication - Medical Faculty, University of Cologne - firstname.lastname@example.org
Modified press release by:
Dr. Debora Grosskopf-Kroiher - CMMC - debora.grosskopf.kroiher[at]uni-koen.de