A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation

S. J. Tavernier; V. Athanasopoulos; P. Verloo; G. Behrens; J. Staal; D. J. Bogaert; L. Naesens; M. De Bruyne; S. Van Gassen; E. Parthoens; J. Ellyard; J. Cappello; L. X. Morris; H. Van Gorp; G. Van Isterdael; Y. Saeys; M. Lamkanfi; P. Schelstraete; J. Dehoorne; V. Bordon; R. Van Coster; B. N. Lambrecht; B. Menten; R. Beyaert; C. G. Vinuesa; V. Heissmeyer; M. Dullaers; F. Haerynck

doi:10.1038/s41467-019-12704-6

A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation

S. J. Tavernier, V. Athanasopoulos, P. Verloo, G. Behrens, J. Staal, D. J. Bogaert, L. Naesens, M. De Bruyne, S. Van Gassen, E. Parthoens, J. Ellyard, J. Cappello, L. X. Morris, H. Van Gorp, G. Van Isterdael, Y. Saeys, M. Lamkanfi, P. Schelstraete, J. Dehoorne, V. BordonR. Van Coster, B. N. Lambrecht, B. Menten, R. Beyaert, C. G. Vinuesa, V. Heissmeyer, M. Dullaers, F. Haerynck^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms. In the quintessential hyperinflammatory syndrome familial hemophagocytic lymphohistiocytosis (HLH), inborn errors of cytotoxicity result in effector cell accumulation, immune dysregulation and, if untreated, tissue damage and death. Here, we describe a human case with a homozygous nonsense R688* RC3H1 mutation suffering from hyperinflammation, presenting as relapsing HLH. RC3H1 encodes Roquin-1, a posttranscriptional repressor of immune-regulatory proteins such as ICOS, OX40 and TNF. Comparing the R688* variant with the murine M199R variant reveals a phenotypic resemblance, both in immune cell activation, hypercytokinemia and disease development. Mechanistically, R688* Roquin-1 fails to localize to P-bodies and interact with the CCR4-NOT deadenylation complex, impeding mRNA decay and dysregulating cytokine production. The results from this unique case suggest that impaired Roquin-1 function provokes hyperinflammation by a failure to quench immune activation.

Original language	English
Article number	4779
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12704-6
Publication status	Published - 1 Dec 2019

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Tavernier, S. J., Athanasopoulos, V., Verloo, P., Behrens, G., Staal, J., Bogaert, D. J., Naesens, L., De Bruyne, M., Van Gassen, S., Parthoens, E., Ellyard, J., Cappello, J., Morris, L. X., Van Gorp, H., Van Isterdael, G., Saeys, Y., Lamkanfi, M., Schelstraete, P., Dehoorne, J., ... Haerynck, F. (2019). A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation. Nature Communications, 10(1), Article 4779. https://doi.org/10.1038/s41467-019-12704-6

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title = "A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation",

abstract = "Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms. In the quintessential hyperinflammatory syndrome familial hemophagocytic lymphohistiocytosis (HLH), inborn errors of cytotoxicity result in effector cell accumulation, immune dysregulation and, if untreated, tissue damage and death. Here, we describe a human case with a homozygous nonsense R688* RC3H1 mutation suffering from hyperinflammation, presenting as relapsing HLH. RC3H1 encodes Roquin-1, a posttranscriptional repressor of immune-regulatory proteins such as ICOS, OX40 and TNF. Comparing the R688* variant with the murine M199R variant reveals a phenotypic resemblance, both in immune cell activation, hypercytokinemia and disease development. Mechanistically, R688* Roquin-1 fails to localize to P-bodies and interact with the CCR4-NOT deadenylation complex, impeding mRNA decay and dysregulating cytokine production. The results from this unique case suggest that impaired Roquin-1 function provokes hyperinflammation by a failure to quench immune activation.",

author = "Tavernier, {S. J.} and V. Athanasopoulos and P. Verloo and G. Behrens and J. Staal and Bogaert, {D. J.} and L. Naesens and {De Bruyne}, M. and {Van Gassen}, S. and E. Parthoens and J. Ellyard and J. Cappello and Morris, {L. X.} and {Van Gorp}, H. and {Van Isterdael}, G. and Y. Saeys and M. Lamkanfi and P. Schelstraete and J. Dehoorne and V. Bordon and {Van Coster}, R. and Lambrecht, {B. N.} and B. Menten and R. Beyaert and Vinuesa, {C. G.} and V. Heissmeyer and M. Dullaers and F. Haerynck",

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year = "2019",

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doi = "10.1038/s41467-019-12704-6",

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Tavernier, SJ, Athanasopoulos, V, Verloo, P, Behrens, G, Staal, J, Bogaert, DJ, Naesens, L, De Bruyne, M, Van Gassen, S, Parthoens, E, Ellyard, J, Cappello, J, Morris, LX, Van Gorp, H, Van Isterdael, G, Saeys, Y, Lamkanfi, M, Schelstraete, P, Dehoorne, J, Bordon, V, Van Coster, R, Lambrecht, BN, Menten, B, Beyaert, R, Vinuesa, CG, Heissmeyer, V, Dullaers, M & Haerynck, F 2019, 'A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation', Nature Communications, vol. 10, no. 1, 4779. https://doi.org/10.1038/s41467-019-12704-6

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T1 - A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation

AU - Tavernier, S. J.

AU - Athanasopoulos, V.

AU - Verloo, P.

AU - Behrens, G.

AU - Staal, J.

AU - Bogaert, D. J.

AU - Naesens, L.

AU - De Bruyne, M.

AU - Van Gassen, S.

AU - Parthoens, E.

AU - Ellyard, J.

AU - Cappello, J.

AU - Morris, L. X.

AU - Van Gorp, H.

AU - Van Isterdael, G.

AU - Saeys, Y.

AU - Lamkanfi, M.

AU - Schelstraete, P.

AU - Dehoorne, J.

AU - Bordon, V.

AU - Van Coster, R.

AU - Lambrecht, B. N.

AU - Menten, B.

AU - Beyaert, R.

AU - Vinuesa, C. G.

AU - Heissmeyer, V.

AU - Dullaers, M.

AU - Haerynck, F.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms. In the quintessential hyperinflammatory syndrome familial hemophagocytic lymphohistiocytosis (HLH), inborn errors of cytotoxicity result in effector cell accumulation, immune dysregulation and, if untreated, tissue damage and death. Here, we describe a human case with a homozygous nonsense R688* RC3H1 mutation suffering from hyperinflammation, presenting as relapsing HLH. RC3H1 encodes Roquin-1, a posttranscriptional repressor of immune-regulatory proteins such as ICOS, OX40 and TNF. Comparing the R688* variant with the murine M199R variant reveals a phenotypic resemblance, both in immune cell activation, hypercytokinemia and disease development. Mechanistically, R688* Roquin-1 fails to localize to P-bodies and interact with the CCR4-NOT deadenylation complex, impeding mRNA decay and dysregulating cytokine production. The results from this unique case suggest that impaired Roquin-1 function provokes hyperinflammation by a failure to quench immune activation.

AB - Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms. In the quintessential hyperinflammatory syndrome familial hemophagocytic lymphohistiocytosis (HLH), inborn errors of cytotoxicity result in effector cell accumulation, immune dysregulation and, if untreated, tissue damage and death. Here, we describe a human case with a homozygous nonsense R688* RC3H1 mutation suffering from hyperinflammation, presenting as relapsing HLH. RC3H1 encodes Roquin-1, a posttranscriptional repressor of immune-regulatory proteins such as ICOS, OX40 and TNF. Comparing the R688* variant with the murine M199R variant reveals a phenotypic resemblance, both in immune cell activation, hypercytokinemia and disease development. Mechanistically, R688* Roquin-1 fails to localize to P-bodies and interact with the CCR4-NOT deadenylation complex, impeding mRNA decay and dysregulating cytokine production. The results from this unique case suggest that impaired Roquin-1 function provokes hyperinflammation by a failure to quench immune activation.

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U2 - 10.1038/s41467-019-12704-6

DO - 10.1038/s41467-019-12704-6

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VL - 10

JO - Nature Communications

JF - Nature Communications

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ER -

A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation

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