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Clinical, functional and genetic characterization of Sixteen Patients Suffering from Chronic Granulomatous Disease variants - Identification of Twelve Novel Mutations in CYBB
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  • Marie josé STASIA,
  • Michelle Mollin,
  • Sylvain Beaumel,
  • Benedicte Vigne,
  • Julie Brault,
  • Nathalie Roux-Buisson,
  • John Rendu,
  • Vincent Barlogis,
  • Gaud Catho,
  • Claire Dumeril,
  • Fanny Fouyssac,
  • Delphine Monnier,
  • Virginie Gandemer,
  • Matthieu Revest,
  • Jean-Paul Brion,
  • Cecile Bost-Bru,
  • Eric Jeziorski,
  • Laurence Eitenschenck,
  • Clemence Jarrasse,
  • Stephanie Drillon Haus
Marie josé STASIA
Université Grenoble Alpes
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Michelle Mollin
Centre Hospitalier Universitaire Grenoble Alpes Institut de Biologie et de Pathologie
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Sylvain Beaumel
Centre Hospitalier Universitaire Grenoble Alpes Institut de Biologie et de Pathologie
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Benedicte Vigne
Centre Hospitalier Universitaire Grenoble Alpes Institut de Biologie et de Pathologie
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Julie Brault
Centre Hospitalier Universitaire Grenoble Alpes Institut de Biologie et de Pathologie
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Nathalie Roux-Buisson
Centre Hospitalier Universitaire Grenoble Alpes Institut de Biologie et de Pathologie
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John Rendu
Centre Hospitalier Universitaire Grenoble Alpes Institut de Biologie et de Pathologie
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Vincent Barlogis
AP-HM
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Gaud Catho
Hospices Civils de Lyon
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Claire Dumeril
Centre Hospitalier Annecy Genevois
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Fanny Fouyssac
Centre Hospitalier Universitaire de Nancy
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Delphine Monnier
Centre Hospitalier Universitaire de Rennes
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Virginie Gandemer
Centre Hospitalier Universitaire de Rennes
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Matthieu Revest
Centre Hospitalier Universitaire de Rennes
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Jean-Paul Brion
Centre Hospitalier Universitaire Grenoble Alpes
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Cecile Bost-Bru
Centre Hospitalier Universitaire Grenoble Alpes Pole Couple Enfant
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Eric Jeziorski
Centre Hospitalier Universitaire de Montpellier
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Laurence Eitenschenck
Centre Hospitalier Annecy Genevois
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Clemence Jarrasse
Centre Hospitalier Annecy Genevois
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Stephanie Drillon Haus
Centre Hospitalier Universitaire de Strasbourg
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Abstract

Chronic Granulomatous Disease (CGD) is a rare inherited disorder in which phagocytes lack NADPH oxidase activity. The most common form is the X-linked CGD (X-CGD), caused by mutations in the CYBB gene. Clinical, functional and genetic characterizations of 16 CGD cases of male patients and their relatives were done. We classified them as suffering from different variants of CGD (X910, X91− or X91+) according to NOX2 expression and NADPH oxidase activity in neutrophils. Twelve mutations were novel (10 X910-CGD and 2 X91− -CGD). One X910-CGD was due to a new and extremely rare double missense mutation Thr208Arg-Thr503Ile. We investigated the pathological impact of each single using stable transfection of each mutated cDNA in the NOX2 knock-out PLB-985 cell line. Both mutations leading to X91−-CGD were also novel; one deletion -67delT was localized in the promoter region of CYBB, the second one c.253-1879A>G mutation activates a splicing donor site, which unveils a cryptic acceptor site, leading to the inclusion of a 124-nucleotide pseudo-exon between exons 3 and 4 and responsible for the partial loss of NOX2 expression. Both X91−-CGD mutations were characterized by a low cytochrome b558 expression and a faint NADPH oxidase activity. The functional impact of new missense mutations is discussed in the context of a new 3D-model of the dehydrogenase domain of NOX2. Our study demonstrates that low NADPH oxidase activity found in both X91−-CGD patients correlates with mild clinical forms of CGD whereas X910-CGD and X91+-CGD cases remain the most clinically severe forms.

Peer review status:ACCEPTED

01 Jul 2020Submitted to Clinical & Experimental Immunology
01 Jul 2020Submission Checks Completed
01 Jul 2020Assigned to Editor
03 Jul 2020Reviewer(s) Assigned
02 Aug 2020Review(s) Completed, Editorial Evaluation Pending
10 Aug 2020Editorial Decision: Revise Major
24 Aug 20201st Revision Received
25 Aug 2020Reviewer(s) Assigned
04 Sep 2020Review(s) Completed, Editorial Evaluation Pending
07 Sep 2020Editorial Decision: Accept