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\begin{document}

\title{Clinical, functional and genetic characterization of Sixteen Patients
Suffering from Chronic Granulomatous Disease variants - Identification
of Twelve Novel Mutations in CYBB}



\author[1]{Marie josé STASIA}%
\author[2]{Michelle Mollin}%
\author[2]{Sylvain Beaumel}%
\author[2]{Benedicte Vigne}%
\author[2]{Julie Brault}%
\author[2]{Nathalie Roux-Buisson}%
\author[2]{John Rendu}%
\author[3]{Vincent Barlogis}%
\author[4]{Gaud Catho}%
\author[5]{Claire Dumeril}%
\author[6]{Fanny Fouyssac}%
\author[7]{Delphine Monnier}%
\author[7]{Virginie Gandemer}%
\author[7]{Matthieu Revest}%
\author[8]{Jean-Paul Brion}%
\author[9]{Cecile Bost-Bru}%
\author[10]{Eric Jeziorski}%
\author[5]{Laurence Eitenschenck}%
\author[5]{Clemence Jarrasse}%
\author[11]{Stephanie Drillon Haus}%
\affil[1]{Université Grenoble Alpes}%
\affil[2]{Centre Hospitalier Universitaire Grenoble Alpes Institut de Biologie et de Pathologie}%
\affil[3]{AP-HM}%
\affil[4]{Hospices Civils de Lyon}%
\affil[5]{Centre Hospitalier Annecy Genevois}%
\affil[6]{Centre Hospitalier Universitaire de Nancy}%
\affil[7]{Centre Hospitalier Universitaire de Rennes}%
\affil[8]{Centre Hospitalier Universitaire Grenoble Alpes}%
\affil[9]{Centre Hospitalier Universitaire Grenoble Alpes Pole Couple Enfant}%
\affil[10]{Centre Hospitalier Universitaire de Montpellier}%
\affil[11]{Centre Hospitalier Universitaire de Strasbourg}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\begin{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\textgreater{}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.%
\end{abstract}%



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