TRAP1 chaperone protein mutations and autoinflammation.

Autor:	Standing AS; University College London and Great Ormond Street Institute of Child Health, London, UK ariane.standing@ucl.ac.uk.; The Natural History Museum, London, UK., Hong Y; University College London and Great Ormond Street Institute of Child Health, London, UK., Paisan-Ruiz C; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York City, NY, USA., Omoyinmi E; University College London and Great Ormond Street Institute of Child Health, London, UK., Medlar A; University College London Division of Medicine, London, UK., Stanescu H; University College London Division of Medicine, London, UK., Kleta R; University College London Division of Medicine, London, UK., Rowcenzio D; National Amyloidosis Centre and Royal Free Hospital, London, UK., Hawkins P; National Amyloidosis Centre and Royal Free Hospital, London, UK., Lachmann H; National Amyloidosis Centre and Royal Free Hospital, London, UK., McDermott MF; Leeds Institute of Rheumatic and Musculoskeletal Medicine, St James's University Hospital, Leeds, UK., Eleftheriou D; University College London and Great Ormond Street Institute of Child Health, London, UK., Klein N; University College London and Great Ormond Street Institute of Child Health, London, UK., Brogan PA; University College London and Great Ormond Street Institute of Child Health, London, UK.
Jazyk:	angličtina
Zdroj:	Life science alliance [Life Sci Alliance] 2019 Dec 27; Vol. 3 (2). Date of Electronic Publication: 2019 Dec 27 (Print Publication: 2020).
DOI:	10.26508/lsa.201900376
Abstrakt:	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 . (© 2019 Standing et al.)
Databáze:	MEDLINE
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