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Two Different Forms of Inherited Human Tcrα Chain Deficiency Publisher



Materna M ; Seyedpour S ; Le Voyer T ; Parvaneh N ; Yazdanpanah N ; Hamidieh AA ; Mehdizadeh M ; Roknizadeh H ; Changiashtiani M ; Amarajeeva K ; Momenilandi M ; Casanova JL ; Shahrooei M ; Bustamante J Show All Authors
Authors
  1. Materna M
  2. Seyedpour S
  3. Le Voyer T
  4. Parvaneh N
  5. Yazdanpanah N
  6. Hamidieh AA
  7. Mehdizadeh M
  8. Roknizadeh H
  9. Changiashtiani M
  10. Amarajeeva K
  11. Momenilandi M
  12. Casanova JL
  13. Shahrooei M
  14. Bustamante J
  15. Rezaei N
  16. Beziat V

Source: Journal of Human Immunity Published:2025


Abstract

Genetic defects that result in the absence of all T cells, including both αβ and γδ T cells, are classified as severe combined immunodeficiency (SCID), a life-threatening condition requiring immediate hematopoietic stem cell transplantation (HSCT) in affected newborns. Previously, patients with a homozygous c.*+1G>A splice variant in the T cell receptor (TCR) α constant chain (TRAC) were found to lack only αβ T cells and demonstrated longer survival compared with SCID patients lacking both αβ and γδ T cells. This observation suggested that γδ T cells might partially compensate for the absence of αβ T cells. Here, we describe two children with biallelic premature stop codons in TRAC. These mutations result in a complete loss of TCRαβ expression on the cell surface and an absence of αβ T cells, leading to severe immunodeficiency and early death. Additionally, we demonstrate that the previously reported c.*+1G>A TRAC variant retains partial activity in vitro, enabling low-level expression of functional TCRαβ. This residual expression likely explains the milder phenotype and extended survival observed in patients carrying this variant. In conclusion, we clarify the nonredundant role of αβ T cells in humans. Our findings show that complete TCRα deficiency causes a SCID-like clinical presentation, whereas partial TCRα deficiency is associated with milder clinical outcomes and longer survival. © 2025 Materna et al. T.