Clinical, functional and genetic analysis of twenty-four patients with chronic granulomatous disease - identification of eight novel mutations in CYBB and NCF2 genes.
Cécile Martel
(1)
,
Michelle Mollin
(1)
,
Sylvain Beaumel
(2)
,
Jean Paul Brion
(3, 4)
,
Charles Coutton
(5, 6)
,
Véronique Satre
(5)
,
Gaëlle Vieville
(6)
,
Mary Callanan
(1, 7)
,
Christine Lefebvre
(7)
,
Alexandra Salmon
(8)
,
Anne Pagnier
(9)
,
Dominique Plantaz
(9)
,
Cécile Bost-Bru
(9)
,
Laurence Eitenschenck
,
Isabelle Durieu
(10)
,
Daniel Floret
(11)
,
Claire Galambrun
(12)
,
Hervé Chambost
(12)
,
Gérard Michel
(12)
,
Jean-Louis Stephan
(13)
,
Olivier Hermine
(14, 15)
,
Stéphane Blanche
(16)
,
Nathalie Blot
(17)
,
Hervé Rubié
(18)
,
Guillaume Pouessel
(19)
,
Stephanie Drillon-Haus
(20)
,
Bernard Conrad
(21)
,
Klara M. Posfay-Barbe
(22)
,
Zuzana Havlicekova
(23)
,
Tamara Voskresenky-Baricic
(24)
,
Kelecic Jadranka
(25)
,
Maria Cristina Arriazu
(26)
,
Luis Alberto Garcia
(26)
,
Lamia Sfaihi Ben Mansour
(27)
,
Pierre Bordigoni
(28)
,
Marie José Stasia
(29)
1
UJF -
Université Joseph Fourier - Grenoble 1
2 TheREx
3 Maladie Infectieuse
4 Service de Médecine Interne et Maladies Infectieuses
5 AGIM - AGeing and IMagery
6 Laboratoire de biochimie et génétique moléculaire
7 INSERM U823 - Institut d'oncologie/développement Albert Bonniot de Grenoble
8 Service de Génétique [CHRU Nancy]
9 Service Hématologie Infantile
10 Service de Médecine Interne - Centre Hospitalier Lyon Sud
11 Services de Réanimation et d'urgences Pédiatriques
12 Service de pédiatrie spécialisée et médecine infantile (neurologie, pneumologie, maladies héréditaires du métabolisme) [Hôpital de la Timone - APHM]
13 Service d'hématologie pédiatrique
14 ERL 8254 - Equipe Inserm U1163 - Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications
15 CEREDIH - Centre de Référence Déficits Immunitaires Héréditaires
16 Service d'immuno-hématologie pédiatrique [CHU Necker]
17 Service de Pédiatrie Néonatologique
18 Sercice Hématologie, immunologie et oncologie pédiatrique [CHU Toulouse]
19 Service de Pédiatrie
20 Service de Pédiatrie et Onco-hématologie
21 DiaGena
22 Pediatric Infectious Diseases
23 Department of Pediatrics
24 Pediatric Clinic Klaiceva
25 Department of Pediatrics
26 Department of Pediatric and Pneumology
27 Service de pédiatrie
28 Service de Médecine Infantile II [CHRU Nancy]
29 TheREx
2 TheREx
3 Maladie Infectieuse
4 Service de Médecine Interne et Maladies Infectieuses
5 AGIM - AGeing and IMagery
6 Laboratoire de biochimie et génétique moléculaire
7 INSERM U823 - Institut d'oncologie/développement Albert Bonniot de Grenoble
8 Service de Génétique [CHRU Nancy]
9 Service Hématologie Infantile
10 Service de Médecine Interne - Centre Hospitalier Lyon Sud
11 Services de Réanimation et d'urgences Pédiatriques
12 Service de pédiatrie spécialisée et médecine infantile (neurologie, pneumologie, maladies héréditaires du métabolisme) [Hôpital de la Timone - APHM]
13 Service d'hématologie pédiatrique
14 ERL 8254 - Equipe Inserm U1163 - Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications
15 CEREDIH - Centre de Référence Déficits Immunitaires Héréditaires
16 Service d'immuno-hématologie pédiatrique [CHU Necker]
17 Service de Pédiatrie Néonatologique
18 Sercice Hématologie, immunologie et oncologie pédiatrique [CHU Toulouse]
19 Service de Pédiatrie
20 Service de Pédiatrie et Onco-hématologie
21 DiaGena
22 Pediatric Infectious Diseases
23 Department of Pediatrics
24 Pediatric Clinic Klaiceva
25 Department of Pediatrics
26 Department of Pediatric and Pneumology
27 Service de pédiatrie
28 Service de Médecine Infantile II [CHRU Nancy]
29 TheREx
Charles Coutton
- Fonction : Auteur
- PersonId : 764155
- ORCID : 0000-0002-8873-8098
- IdRef : 137277547
Laurence Eitenschenck
- Fonction : Auteur
Isabelle Durieu
- Fonction : Auteur
- PersonId : 1362869
- ORCID : 0000-0002-3874-5580
Olivier Hermine
- Fonction : Auteur
- PersonId : 1308844
- ORCID : 0000-0003-2574-3874
- IdRef : 069884927
Résumé
Chronic granulomatous disease is an inherited disorder in which phagocytes lack a functional NADPH oxidase and cannot produce superoxide anions. The most common form is caused by mutations in CYBB encoding gp91phox. We investigated 24 CGD patients and their families. Twenty-one mutations in CYBB were classified as X91(0), X91(+) or X91(-) variants according to cytochrome b (558) expression. Point mutations in encoding regions represented 50 % of the mutations found in CYBB, splice site mutations 27 %, deletions and insertions 23 %. Eight mutations in CYBB were novel leading to X91(0)CGD cases. Two of these were point mutations: c493G>T and a double mutation c625C>G in exon 6 and c1510C>T in exon 12 leading to a premature stop codon at Gly165 in gp91phox and missense mutations His209Arg/Thr503Ile respectively. Two novel splice mutations in 5'intronic regions of introns 1 and 6 were found. A novel deletion/insertion c1024_1026delCTG/insT results in a frameshift introducing a stop codon at position 346 in gp91phox. The last novel mutation was the insertion of a T at c1373 leading to a frameshift and a premature stop codon at position 484 in gp91phox. For the first time the precise size of two large mutations in CYBB was determined by array-comparative genomic hybridization and carriers' status were evaluated by multiplex ligation-dependent probe amplification assay. No clear correlation between clinical severity and CYBB mutations could be established. Of three mutations in CYBA, NCF1 and NCF2 leading to rare autosomal recessive CGD, one nonsense mutation c29G>A in exon 1 of NCF2 was new.