Inherited human TFIIIA deficiency disrupts T cell development

Résumé fourni par la source

ABSTRACT Molecular characterization of human monogenic inborn errors of T cell immunity provides both biological insights and medical progress. We report rare biallelic deleterious variants in GTF3A , encoding transcription factor IIIA (TFIIIA), a zinc-finger protein required for transcription and chaperoning of 5S ribosomal RNA (rRNA). These variants were identified in ten patients from eight unrelated families and eight countries presenting with either T - B + NK + severe combined immunodeficiency (SCID) or combined immune deficiency (CID), characterized by T cell lymphopenia and variable antibody deficiency. The GTF3A variants disrupt TFIIIA function through distinct mechanisms, including defective DNA binding, aberrant nuclear localization, and reduced protein stability compromising TFIIIA-mediated transcription and chaperoning of 5S rRNA. Using artificial thymic organoids derived from TFIIIA-deficient CD34⁺ progenitors, an early developmental arrest at the T cell commitment stage was documented in vitro . Zebrafish deficient for gtf3aa recapitulated the impaired thymocyte development in vivo . Together, these findings establish TFIIIA deficiency as a novel cause of (S)CID, expanding the genetic and mechanistic landscape of inborn errors of T cell immunity and uncovering an essential role for TFIIIA in human adaptive immunity. One-sentence summary Biallelic GTF3A variants causing TFIIIA deficiency, which disrupts 5S rRNA transcription, represent a novel monogenic cause of (S)CID, unveiling a crucial role of TFIIIA in T cell development.

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