Scientists Discover Genetic Cause of Lupus, a Chronic Autoimmune Disease

Genetic Disease Research Concept

Scientists carried out whole genome sequencing on the DNA of a child with lupus and discovered a suspicious gene mutation. They then ran experiments on mice to confirm that the mutation does indeed cause lupus.

An international team of researchers has discovered DNA mutations in a gene that senses viral RNA as a cause of the autoimmune disease lupus, paving the way for the development of new treatments.

Lupus is a chronic autoimmune disease that causes inflammation in joints and organs, affects movement and the skin, and causes fatigue. Symptoms can be debilitating in extreme cases, and consequences can be deadly.

Currently, there is no cure for the condition, which affects around 50,000 people in the UK. Available treatments are predominantly immuno-suppressors, which act by suppressing the immune system to ameliorate symptoms.

Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body’s immune system mistakenly attacks healthy tissue in many different parts of the body. Symptoms vary from one person to the next and can range from mild to severe. Painful and swollen joints, hair loss, fever, mouth ulcers, chest discomfort, swollen lymph nodes, fatigue, and a red rash, most typically on the face, are all common symptoms.

In their study, published in the journal Nature on April 27, 2022, the scientists carried out whole genome sequencing on the DNA of a Spanish child named Gabriela, who was diagnosed with severe lupus when she was 7 years old. Such a severe case with early onset of symptoms is rare and indicates a single genetic cause.

In their genetic analysis, carried out at the Centre for Personalised Immunology at the Australian National University, the researchers found a single point mutation in the TLR7 gene. Via referrals from the US and the China Australia Centre of Personalised Immunology (CACPI) at Shanghai Renji Hospital, they identified other cases of severe lupus where this gene was also mutated.

To confirm that the mutation causes lupus, the team used CRISPR gene-editing to introduce it into mice. These mice went on to develop the disease and showed similar symptoms, providing evidence that the TLR7 mutation was the cause. The mouse model and the mutation were both named ‘kika’ by Gabriela, the young girl central to this discovery.

Carola Vinuesa, senior author and principal investigator at the Centre for Personalised Immunology in Australia, co-director of CACPI, and now group leader at the Crick says: “It has been a huge challenge to find effective treatments for lupus, and the immune-suppressors currently being used can have serious side effects and leave patients more susceptible to infection. There has only been a single new treatment approved by the FDA in about the last 60 years.

“This is the first time a TLR7 mutation has been shown to cause lupus, providing clear evidence of one way this disease can arise.”

Professor Nan Shen, co-director of CACPI adds: “While it may only be a small number of people with lupus who have variants in TLR7 itself, we do know that many patients have signs of overactivity in the TLR7 pathway. By confirming a causal link between the gene mutation and the disease, we can start to search for more effective treatments.”

The mutation the researchers identified causes the TLR7 protein to bind more easily to a nucleic acid component called guanosine and become more active. This increases the sensitivity of the immune cell, making it more likely to incorrectly identify healthy tissue as foreign or damaged and mount an attack against it.

Interestingly, other studies have shown mutations that cause TLR7 to become less active are associated with some cases of severe COVID-19 infection, highlighting the delicate balance of a healthy immune system.*

The work may also help explain why lupus is about 10 times more frequent in females than in males. As TLR7 sits on the X chromosome, females have two copies of the gene while males have one. Usually, in females one of the X chromosomes is inactive, but in this section of the chromosome, silencing of the second copy is often incomplete. This means females with a mutation in this gene can have two functioning copies.

Dr. Carmen de Lucas Collantes, a co-author of this study says: “Identification of TLR7 as the cause of lupus in this unusually severe case ended a diagnostic odyssey and brings hope for more targeted therapies for Gabriela and other lupus patients likely to benefit from this discovery.”

Gabriela, who remains in touch with the research team and is now a teenager, says: “I hope this finding will give hope to people with lupus and make them feel they are not alone in fighting this battle. Hopefully, the research can continue and end up in a specific treatment that can benefit so many lupus warriors who suffer from this disease.”

The researchers are now working with pharmaceutical companies to explore the development of, or the repurposing of existing treatments, which target the TLR7 gene. And they hope that targeting this gene could also help patients with related conditions.

Carola adds: “There are other systemic autoimmune diseases, like rheumatoid arthritis and dermatomyositis, which fit within the same broad family as lupus. TLR7 may also play a role in these conditions.”

Carola has started a new laboratory at the Francis Crick Institute to further understand the disease-causing mechanisms that occur downstream of key mutations like the one found on the TLR7 gene.


* Examples of studies on TLR7 and COVID-19:

“X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19” by Takaki Asano, Bertrand Boisson, Fanny Onodi, Daniela Matuozzo, Marcela Moncada-Velez, Majistor Raj Luxman Maglorius Renkilaraj, Peng Zhang, Laurent Meertens, Alexandre Bolze, Marie Materna, Sarantis Korniotis, Adrian Gervais, Estelle Talouarn, Benedetta Bigio, Yoann Seeleuthner, Kaya Bilguvar, Yu Zhang, Anna-Lena Neehus, Masato Ogishi, Simon J. Pelham, Tom Le Voyer, Jérémie Rosain, Quentin Philippot, Pere Soler-Palacín, Roger Colobran, Andrea Martin-Nalda, Jacques G. Rivière, Yacine Tandjaoui-Lambiotte, Khalil Chaïbi, Mohammad Shahrooei, Ilad Alavi Darazam, Nasrin Alipour Olyaei, Davood Mansouri, Nevin Hatipoğlu, Figen Palabiyik, Tayfun Ozcelik, Giuseppe Novelli, Antonio Novelli, Giorgio Casari, Alessandro Aiuti, Paola Carrera, Simone Bondesan, Federica Barzaghi, Patrizia Rovere-Querini, Cristina Tresoldi, Jose Luis Franco, Julian Rojas, Luis Felipe Reyes, Ingrid G. Bustos, Andres Augusto Arias, Guillaume Morelle, Christèle Kyheng, Jesús Troya, Laura Planas-Serra, Agatha Schlüter, Marta Gut, Aurora Pujol, Luis M. Allende, Carlos Rodriguez-Gallego, Carlos Flores, Oscar Cabrera-Marante, Daniel E. Pleguezuelo, Rebeca Pérez de Diego, Sevgi Keles, Gokhan Aytekin, Ozge Metin Akcan, Yenan T. Bryceson, Peter Bergman, Petter Brodin, Daniel Smole, C. I. Edvard Smith, Anna-Carin Norlin, Tessa M. Campbell, Laura E. Covill, Lennart Hammarström, Qiang Pan-Hammarström, Hassan Abolhassani, Shrikant Mane, Nico Marr, Manar Ata, Fatima Al Ali, Taushif Khan, András N. Spaan, Clifton L. Dalgard, Paolo Bonfanti, Andrea Biondi, Sarah Tubiana, Charles Burdet, Robert Nussbaum, Amanda Kahn-Kirby, Andrew L. Snow, COVID Human Genetic Effort, COVID-STORM Clinicians, COVID Clinicians, Imagine COVID Group, French COVID Cohort Study Group, CoV-Contact Cohort, Amsterdam UMC Covid-19 Biobank, NIAID-USUHS COVID Study Group, Jacinta Bustamante, Anne Puel, Stéphanie Boisson-Dupuis, Shen-Ying Zhang, Vivien Béziat, Richard P. Lifton, Paul Bastard, Luigi D. Notarangelo, Laurent Abel, Helen C. Su, Emmanuelle Jouanguy, Ali Amara, Vassili Soumelis, Aurélie Cobat, Qian Zhang and Jean-Laurent Casanova, 20 August 2021, Science Immunology.
DOI: 10.1126/sciimmunol.abl4348

“Presence of Genetic Variants Among Young Men With Severe COVID-19” by Caspar I. van der Made, MD; Annet Simons, PhD; Janneke Schuurs-Hoeijmakers, MD, PhD; Guus van den Heuvel, MD; Tuomo Mantere, PhD; Simone Kersten, MSc; Rosanne C. van Deuren, MSc; Marloes Steehouwer, BSc; Simon V. van Reijmersdal, BSc; Martin Jaeger, PhD; Tom Hofste, BSc; Galuh Astuti, PhD; Jordi Corominas Galbany, PhD; Vyne van der Schoot, MD, PhD; Hans van der Hoeven, MD, PhD; Wanda Hagmolen of ten Have, MD, PhD; Eva Klijn, MD, PhD; Catrien van den Meer, MD; Jeroen Fiddelaers, MD; Quirijn de Mast, MD, PhD; Chantal P. Bleeker-Rovers, MD, PhD; Leo A. B. Joosten, PhD; Helger G. Yntema, PhD; Christian Gilissen, PhD; Marcel Nelen, PhD; Jos W. M. van der Meer, MD, PhD; Han G. Brunner, MD, PhD; Mihai G. Netea, MD, PhD; Frank L. van de Veerdonk, MD, PhD and Alexander Hoischen, PhD, 24 July 2020, JAMA.
DOI: 10.1001/jama.2020.13719

Reference: “TLR7 gain-of-function genetic variation causes human lupus” by Grant J. Brown, Pablo F. Cañete, Hao Wang, Arti Medhavy, Josiah Bones, Jonathan A. Roco, Yuke He, Yuting Qin, Jean Cappello, Julia I. Ellyard, Katharine Bassett, Qian Shen, Gaetan Burgio, Yaoyuan Zhang, Cynthia Turnbull, Xiangpeng Meng, Phil Wu, Eun Cho, Lisa A. Miosge, T. Daniel Andrews, Matt A. Field, Denis Tvorogov, Angel F. Lopez, Jeffrey J. Babon, Cristina Aparicio López, África Gónzalez-Murillo, Daniel Clemente Garulo, Virginia Pascual, Tess Levy, Eric J. Mallack, Daniel G. Calame, Timothy Lotze, James R. Lupski, Huihua Ding, Tomalika R. Ullah, Giles D. Walters, Mark E. Koina, Matthew C. Cook, Nan Shen, Carmen de Lucas Collantes, Ben Corry, Michael P. Gantier, Vicki Athanasopoulos and Carola G. Vinuesa, 27 April 2022, Nature.
DOI: 10.1038/s41586-022-04642-z

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