• Scientists find a genetic cause of lupus

    From ScienceDaily@1:317/3 to All on Wednesday, April 27, 2022 22:30:48
    Scientists find a genetic cause of lupus

    Date:
    April 27, 2022
    Source:
    The Francis Crick Institute
    Summary:
    An international team of researchers has identified DNA mutations
    in a gene that senses viral RNA, as a cause of the autoimmune
    disease lupus, with the finding paving the way for the development
    of new treatments.



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


    ========================================================================== Lupus is a chronic autoimmune disease which causes inflammation in organs
    and joints, affects movement and the skin, and causes fatigue. In severe
    cases, symptoms can be debilitating and complications can be fatal.

    There is no cure for the disease, which affects around 50,000 people
    in the UK, and current treatments are predominantly immune-suppressors
    which work by dialling down the immune system to alleviate symptoms.

    In their study, published in Naturetoday (27 April), 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 TLR7gene. 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 TLR7itself, 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 TLR7sits 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 TLR7as 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 TLR7gene. 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.

    Notes * Examples of studies on TLR7 and COVID-19:
    * Asano, T. et al. (2021). X-linked recessive TLR7 deficiency in ~1%
    of men
    under 60 years old with life-threatening COVID-19. Science
    Immunology.

    DOI 10.1126/sciimmunol.abl4348
    * Van der Made, C.I. et al(2020). Presence of Genetic Variants
    Among Young
    Men With Severe COVID-19. JAMA. DOI 10.1001/jama.2020.13719

    ========================================================================== Story Source: Materials provided by The_Francis_Crick_Institute. Note:
    Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Grant J. Brown, Pablo F. Can~ete, 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 Lo'pez, A'frica
    Go'nzalez-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,
    Carola G.

    Vinuesa. TLR7 gain-of-function genetic variation causes human lupus.

    Nature, 2022; DOI: 10.1038/s41586-022-04642-z ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/04/220427115727.htm

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