Project description
Advanced diagnosis for (severe) combined immune deficiency
Over 100 genes can cause (severe) combined immunodeficiency ((S)CID), but roughly one-third of cases remain undiagnosed. Mutations in the GTF3A gene, linked to T-cell differentiation issues, disrupt the nucleolar stress response, revealing a new disease mechanism. The ERC-funded project LYNCID will investigate transcription factor IIIA (TFIIIA)-deficient patients, along with cellular and zebrafish models, to explore the link between nucleolar stress and (S)CID. It will clarify TFIIIA’s role in T-cell development and the nucleolar stress response, and develop a diagnostic tool, the ‘Nucleolar Stress Index’, to detect altered nucleolar stress in patients with undefined (S)CID. By uncovering new pathways in (S)CID, the project will provide valuable insights into T-cell biology and nucleolar stress, as well as create advanced diagnostics.
Objective
LYNCID addresses critical gaps in our understanding of (severe) combined immune deficiencies ((S)CIDs), a group of debilitating inborn errors of immunity caused by T-cell dysfunction. Although over 100 (S)CID-causing genes are known, 30-40% of (S)CID patients remain molecularly undiagnosed, resulting in high mortality. Better knowledge and timely diagnosis of (S)CID represent critical unmet medical needs.
Recently, my team has identified biallelic mutations in GTF3A, encoding transcription factor IIIA (TFIIIA), in (S)CID patients with early T-cell differentiation block. TFIIIA plays a critical housekeeping role by transcribing 5S ribosomal RNA, essential for ribosome assembly and nucleolar stress regulation. Intriguingly, patient-derived cells experience increased G2/M cell cycle arrest during chemically induced nucleolar stress, evidencing an impaired stress response.
Based on this finding, I hypothesize that TFIIIA deficiency triggers (S)CID by impairing the nucleolar stress response, thus unveiling a completely novel disease mechanism still to be explored. Using TFIIIA-deficient patients as a model, alongside cellular and zebrafish models, LYNCID seeks to uncover the hidden interplay between nucleolar stress and (S)CID. We aim to 1) elucidate the role of TFIIIA in T-cell development and nucleolar stress response, 2) unravel nucleolar stress response in T-cell biology, and 3) develop the ‘Nucleolar Stress Index’, a diagnostic tool to detect altered nucleolar stress in molecularly undefined (S)CID patients.
LYNCID spearheads (S)CID research by uncovering new (S)CID pathways and providing unprecedented insights into T-cell biology and nucleolar stress. We will develop cutting-edge diagnostics to improve patient care. Overall, by revealing the role of nucleolar stress, LYNCID will substantially advance our understanding of immune disorders and can open new therapeutic avenues in other nucleolar stress-related diseases including cancer and neurodegeneration.
Fields of science (EuroSciVoc)
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CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences neurobiology
- social sciences sociology demography mortality
- natural sciences biological sciences genetics mutation
- medical and health sciences clinical medicine oncology
- natural sciences biological sciences genetics RNA
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2025-STG
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9000 Gent
Belgium
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