A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection

Emmanuelle Jouanguy; Salma Lamhamedi-Cherradi; David Lammas; Susan E. Dorman; Marie Claude Fondanèche; Stéphanie Dupuis; Rainer Döffinger; Frédéric Altare; John Girdlestone; Jean François Emile; Henri Ducoulombier; David Edgar; Jane Clarke; Vivi Anne Oxelius; Melchiorre Brai; Vas Novelli; Klaus Heyne; Alain Fischer; Steven M. Holland; Dinakantha S. Kumararatne; Robert D. Schreiber; Jean Laurent Casanova

doi:10.1038/7701

A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection

Emmanuelle Jouanguy, Salma Lamhamedi-Cherradi, David Lammas, Susan E. Dorman, Marie Claude Fondanèche, Stéphanie Dupuis, Rainer Döffinger, Frédéric Altare, John Girdlestone, Jean François Emile, Henri Ducoulombier, David Edgar, Jane Clarke, Vivi Anne Oxelius, Melchiorre Brai, Vas Novelli, Klaus Heyne, Alain Fischer, Steven M. Holland, Dinakantha S. KumararatneRobert D. Schreiber, Jean Laurent Casanova

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Abstract

The immunogenetic basis of severe infections caused by bacille Calmette- Guerin vaccine and environmental mycobacteria in humans remains largely unknown. We describe 18 patients from several generations of 12 unrelated families who were heterozygous for 1 to 5 overlapping IFNGR1 frameshift small deletions and a wild-type IFNGR1 allele. There were 12 independent mutation events at a single mutation site, defining a small deletion hotspot. Neighbouring sequence analysis favours a small deletion model of slipped mispairing events during replication. The mutant alleles encode cell-surface IFNγ receptors that lack the intra-cytoplasmic domain, which, through a combination of impaired recycling, abrogated signalling and normal binding to IFNγ exert a dominant-negative effect. We thus report a hotspot for human IFNGR1 small deletions that confer dominant susceptibility to infections caused by poorly virulent mycobacteria.

Original language	English
Pages (from-to)	370-378
Number of pages	9
Journal	Nature Genetics
Volume	21
Issue number	4
DOIs	https://doi.org/10.1038/7701
State	Published - Apr 1999

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Jouanguy, E., Lamhamedi-Cherradi, S., Lammas, D., Dorman, S. E., Fondanèche, M. C., Dupuis, S., Döffinger, R., Altare, F., Girdlestone, J., Emile, J. F., Ducoulombier, H., Edgar, D., Clarke, J., Oxelius, V. A., Brai, M., Novelli, V., Heyne, K., Fischer, A., Holland, S. M., ... Casanova, J. L. (1999). A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection. Nature Genetics, 21(4), 370-378. https://doi.org/10.1038/7701

@article{a11d2b1828bc4b01a8e29a1eebfa60cb,

title = "A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection",

abstract = "The immunogenetic basis of severe infections caused by bacille Calmette- Guerin vaccine and environmental mycobacteria in humans remains largely unknown. We describe 18 patients from several generations of 12 unrelated families who were heterozygous for 1 to 5 overlapping IFNGR1 frameshift small deletions and a wild-type IFNGR1 allele. There were 12 independent mutation events at a single mutation site, defining a small deletion hotspot. Neighbouring sequence analysis favours a small deletion model of slipped mispairing events during replication. The mutant alleles encode cell-surface IFNγ receptors that lack the intra-cytoplasmic domain, which, through a combination of impaired recycling, abrogated signalling and normal binding to IFNγ exert a dominant-negative effect. We thus report a hotspot for human IFNGR1 small deletions that confer dominant susceptibility to infections caused by poorly virulent mycobacteria.",

author = "Emmanuelle Jouanguy and Salma Lamhamedi-Cherradi and David Lammas and Dorman, {Susan E.} and Fondan{\`e}che, {Marie Claude} and St{\'e}phanie Dupuis and Rainer D{\"o}ffinger and Fr{\'e}d{\'e}ric Altare and John Girdlestone and Emile, {Jean Fran{\c c}ois} and Henri Ducoulombier and David Edgar and Jane Clarke and Oxelius, {Vivi Anne} and Melchiorre Brai and Vas Novelli and Klaus Heyne and Alain Fischer and Holland, {Steven M.} and Kumararatne, {Dinakantha S.} and Schreiber, {Robert D.} and Casanova, {Jean Laurent}",

note = "Funding Information: Lipscombe, who referred patients from kindred A for immunological assessment; and R.A. Thompson, who carried out the initial immunologic assessment. J.-L.C. thanks P. Even for encouragement and support. This work was supported by institutional grants from INSERM, AFM, PHRC, PNRFMMIP, MRC (UK) and West-Midland Regional Research Fund. E.J. is supported by the Ligue Nationale Contre le Cancer, S.L. by the Association Recherche et Partage, R.D. by the INSERM, F.A. by the AFM and D.L. by the Glaxo-Wellcome Action TB programme.",

year = "1999",

month = apr,

doi = "10.1038/7701",

language = "English",

volume = "21",

pages = "370--378",

journal = "Nature Genetics",

issn = "1061-4036",

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Jouanguy, E, Lamhamedi-Cherradi, S, Lammas, D, Dorman, SE, Fondanèche, MC, Dupuis, S, Döffinger, R, Altare, F, Girdlestone, J, Emile, JF, Ducoulombier, H, Edgar, D, Clarke, J, Oxelius, VA, Brai, M, Novelli, V, Heyne, K, Fischer, A, Holland, SM, Kumararatne, DS, Schreiber, RD & Casanova, JL 1999, 'A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection', Nature Genetics, vol. 21, no. 4, pp. 370-378. https://doi.org/10.1038/7701

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T1 - A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection

AU - Jouanguy, Emmanuelle

AU - Lamhamedi-Cherradi, Salma

AU - Lammas, David

AU - Dorman, Susan E.

AU - Fondanèche, Marie Claude

AU - Dupuis, Stéphanie

AU - Döffinger, Rainer

AU - Altare, Frédéric

AU - Girdlestone, John

AU - Emile, Jean François

AU - Ducoulombier, Henri

AU - Edgar, David

AU - Clarke, Jane

AU - Oxelius, Vivi Anne

AU - Brai, Melchiorre

AU - Novelli, Vas

AU - Heyne, Klaus

AU - Fischer, Alain

AU - Holland, Steven M.

AU - Kumararatne, Dinakantha S.

AU - Schreiber, Robert D.

AU - Casanova, Jean Laurent

N1 - Funding Information: Lipscombe, who referred patients from kindred A for immunological assessment; and R.A. Thompson, who carried out the initial immunologic assessment. J.-L.C. thanks P. Even for encouragement and support. This work was supported by institutional grants from INSERM, AFM, PHRC, PNRFMMIP, MRC (UK) and West-Midland Regional Research Fund. E.J. is supported by the Ligue Nationale Contre le Cancer, S.L. by the Association Recherche et Partage, R.D. by the INSERM, F.A. by the AFM and D.L. by the Glaxo-Wellcome Action TB programme.

PY - 1999/4

Y1 - 1999/4

N2 - The immunogenetic basis of severe infections caused by bacille Calmette- Guerin vaccine and environmental mycobacteria in humans remains largely unknown. We describe 18 patients from several generations of 12 unrelated families who were heterozygous for 1 to 5 overlapping IFNGR1 frameshift small deletions and a wild-type IFNGR1 allele. There were 12 independent mutation events at a single mutation site, defining a small deletion hotspot. Neighbouring sequence analysis favours a small deletion model of slipped mispairing events during replication. The mutant alleles encode cell-surface IFNγ receptors that lack the intra-cytoplasmic domain, which, through a combination of impaired recycling, abrogated signalling and normal binding to IFNγ exert a dominant-negative effect. We thus report a hotspot for human IFNGR1 small deletions that confer dominant susceptibility to infections caused by poorly virulent mycobacteria.

AB - The immunogenetic basis of severe infections caused by bacille Calmette- Guerin vaccine and environmental mycobacteria in humans remains largely unknown. We describe 18 patients from several generations of 12 unrelated families who were heterozygous for 1 to 5 overlapping IFNGR1 frameshift small deletions and a wild-type IFNGR1 allele. There were 12 independent mutation events at a single mutation site, defining a small deletion hotspot. Neighbouring sequence analysis favours a small deletion model of slipped mispairing events during replication. The mutant alleles encode cell-surface IFNγ receptors that lack the intra-cytoplasmic domain, which, through a combination of impaired recycling, abrogated signalling and normal binding to IFNγ exert a dominant-negative effect. We thus report a hotspot for human IFNGR1 small deletions that confer dominant susceptibility to infections caused by poorly virulent mycobacteria.

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U2 - 10.1038/7701

DO - 10.1038/7701

M3 - Article

C2 - 10192386

AN - SCOPUS:0032948177

SN - 1061-4036

VL - 21

SP - 370

EP - 378

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection

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