RT Journal Article
SR Electronic
T1 TRAP1 chaperone protein mutations and autoinflammation
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900376
DO 10.26508/lsa.201900376
VO 3
IS 2
A1 Standing, Ariane SI
A1 Hong, Ying
A1 Paisan-Ruiz, Coro
A1 Omoyinmi, Ebun
A1 Medlar, Alan
A1 Stanescu, Horia
A1 Kleta, Robert
A1 Rowcenzio, Dorota
A1 Hawkins, Philip
A1 Lachmann, Helen
A1 McDermott, Michael F
A1 Eleftheriou, Despina
A1 Klein, Nigel
A1 Brogan, Paul A
YR 2020
UL http://www.life-science-alliance.org/content/3/2/e201900376.abstract
AB 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.