Discovery of a frequent genetic cause of autoimmunity From rare to frequent variants: the case of pre-TCRα deficiency

The work carried out at Institut Imagine (Inserm, AP-HP, Université Paris Cité) focuses on rare and common genetic diseases. One of the aims of the Institute's teams is to use and apply the knowledge gained from studying rare diseases to common diseases. Vivien Béziat's team in the "Human Genetics of Infectious Diseases" laboratory, co-directed by Jean-Laurent Casanova and Laurent Abel, has identified rare and frequent mutations in the PTCRA gene. The frequent mutations affect hundreds of thousands of individuals in the Middle East and South Asia, greatly increasing their risk of developing an autoimmune disease. This work has been published in the scientific journal Science.

Published on 06.03.2024

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The PTCRA gene was identified in the 1990s by Professor Harald Von Boehmer's team at the Hôpital Necker-Enfants Malades. It was quickly shown that this gene plays a major role in the maturation of T lymphocyte-type immune cells; mice mutant for this gene show a sharp reduction in thymus cells at a very early age, a vital organ in the immune response and an area where immune cells are produced. On this basis, the researchers anticipated that a disease involving a loss of function of this gene would be associated with an absence of T lymphocytes and a fatal disease if not treated from birth.

Marie Materna, as part of her thesis project under the supervision of Vivien Béziat, in the "Human Genetics of Infectious Diseases" laboratory, looked at mutations in the PTCRA gene in humans. In collaboration with laboratories and clinical services in 12 countries on 3 continents, she has identified 10 patients aged between 1 and 65 with rare mutations that completely inactivate the PTCRA gene. Four of these patients were identified through newborn screening for severe genetic diseases. However, to the great surprise of the researchers, 6 patients, mostly children, had no symptoms. The remaining 4 patients, all adults, suffered from severe infections, autoimmunity and blood cell cancers. The researchers explain the late onset of symptoms in these patients by their ability to produce a small but sufficient quantity of T lymphocytes capable of protecting them during childhood. This work suggests the existence of as yet unknown compensatory mechanisms enabling the production of T lymphocytes in the absence of PTCRA. Thus, contrary to all expectations, loss of the PTCRA gene only has clinical consequences in adolescence or young adulthood.

Even more surprisingly, using public genetic databases, the team also identified another mutation in the PTCRA gene, present in a homozygous state (on each of the 2 copies of the gene) in 1 in 4,000 individuals in the Middle East and South Asia. This second mutation has less of an impact on the expression of the PTCRA gene. However, in carriers of this mutation, autoimmune diseases (such as hypothyroidism, vitiligo, rheumatoid arthritis or coagulation anomalies) are up to 5 times more frequent than in the rest of the population. These individuals also have abnormal lymphocyte populations, but to a lesser extent than patients with a complete PTCRA defect.

These results show that the frequency of mutations in genes considered essential is sometimes greatly underestimated. This may be explained by the late onset of clinical manifestations in adulthood. This research also demonstrates the need to continue work on understanding rare genetic diseases in order to gain a better understanding of common genetic diseases and develop personalised medicine based on patient needs.


Reference : The immunopathological landscape of human pre-TCRa deficiency: From rare to common variants

Corresponding authors: Vivien Béziat

DOI: 10.1126/science.adh4059