Standing, AS;
Hong, Y;
Paisan-Ruiz, C;
Omoyinmi, E;
Medlar, A;
Stanescu, H;
Kleta, R;
... Brogan, PA; + view all
(2020)
TRAP1 chaperone protein mutations and autoinflammation.
Life Science Alliance
, 3
(2)
, Article e201900376. 10.26508/lsa.201900376.
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Abstract
We identified a consanguineous kindred, of three affected children with severe autoinflammation, resulting in the death of one sibling and allogeneic stem cell transplantation in the other two. All three were homozygous for MEFV p.S208C mutation; however, their phenotype was more severe than previously reported, prompting consideration of an oligogenic autoinflammation model. Further genetic studies revealed homozygous mutations in TRAP1, encoding the mitochondrial/ER resident chaperone protein tumour necrosis factor receptor associated protein 1 (TRAP1). Identification of a fourth, unrelated patient with autoinflammation and compound heterozygous mutation of TRAP1 alone facilitated further functional studies, confirming the importance of this protein as a chaperone of misfolded proteins with loss of function, which may contribute to autoinflammation. Impaired TRAP1 function leads to cellular stress and elevated levels of serum IL-18. This study emphasizes the importance of considering digenic or oligogenic models of disease in particularly severe phenotypes and suggests that autoinflammatory disease might be enhanced by bi-allelic mutations in TRAP1.
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