Journal of Clinical Immunology

, Volume 32, Issue 5, pp 942–958 | Cite as

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
  • Michelle Mollin
  • Sylvain Beaumel
  • Jean Paul Brion
  • Charles Coutton
  • Véronique Satre
  • Gaëlle Vieville
  • Mary Callanan
  • Christine Lefebvre
  • Alexandra Salmon
  • Anne Pagnier
  • Dominique Plantaz
  • Cécile Bost-Bru
  • Laurence Eitenschenck
  • Isabelle Durieu
  • Daniel Floret
  • Claire Galambrun
  • Hervé Chambost
  • Gérard Michel
  • Jean-Louis Stephan
  • Olivier Hermine
  • Stéphane Blanche
  • Nathalie Blot
  • Hervé Rubié
  • Guillaume Pouessel
  • Stephanie Drillon-Haus
  • Bernard Conrad
  • Klara M. Posfay-Barbe
  • Zuzana Havlicekova
  • Tamara Voskresenky-Baricic
  • Kelecic Jadranka
  • Maria Cristina Arriazu
  • Luis Alberto Garcia
  • Lamia Sfaihi Ben Mansour
  • Pierre Bordigoni
  • Marie José Stasia
Article

Abstract

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 X910, X91+ or X91 variants according to cytochrome b558 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 X910CGD 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.

Keywords

Chronic granulomatous disease NADPH oxidase Nox mutation 

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Cécile Martel
    • 1
  • Michelle Mollin
    • 1
  • Sylvain Beaumel
    • 1
    • 2
  • Jean Paul Brion
    • 3
  • Charles Coutton
    • 4
    • 5
  • Véronique Satre
    • 4
    • 5
  • Gaëlle Vieville
    • 4
  • Mary Callanan
    • 6
    • 7
  • Christine Lefebvre
    • 6
  • Alexandra Salmon
    • 8
  • Anne Pagnier
    • 9
  • Dominique Plantaz
    • 9
  • Cécile Bost-Bru
    • 9
  • Laurence Eitenschenck
    • 10
  • Isabelle Durieu
    • 11
  • Daniel Floret
    • 12
  • Claire Galambrun
    • 13
  • Hervé Chambost
    • 13
  • Gérard Michel
    • 13
  • Jean-Louis Stephan
    • 14
  • Olivier Hermine
    • 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
    • 8
  • Marie José Stasia
    • 1
    • 2
  1. 1.Chronic Granulomatous Disease Diagnosis and Research Centre (CDiReC), Pôle Biologie, CHU de GrenobleGrenobleFrance
  2. 2.CDiReC, Therex-TIMC/Imag, UMR CNRS 5525GrenobleFrance
  3. 3.Service d’infectiologie, Pôle Médecine Aigue et Communautaire, CHU GrenobleGrenobleFrance
  4. 4.Laboratoire de Génétique Chromosomique, Pôle Couple/Enfants, CHU de GrenobleGrenobleFrance
  5. 5.Equipe “Génétique, Infertilité et Thérapeutiques” Laboratoire AGIM, CNRS FRE3405La Tronche, F-38700, Université Joseph FourierGrenobleFrance
  6. 6.Laboratoire Génétique et Onco-Hematologie, Pôle Biologie, CHU GrenobleGrenobleFrance
  7. 7.Ontogenèse et Oncogenèse Moléculaire - Inserm U823Institut A. BonniotGrenobleFrance
  8. 8.Département d‘Oncologie et d’Hématologie Pédiatriques et de Thérapie CellulaireHôpital d’Enfants, CHU de NancyVandoeuvre-Lès-NancyFrance
  9. 9.Département de PédiatriePôle Couple/Enfant, CHU de GrenobleGrenobleFrance
  10. 10.Service de PédiatrieCentre Hospitalier de VoironGrenobleFrance
  11. 11.Service de Médecine Interne et Pathologie VasculaireCentre Hospitalier Lyon-SudLyonFrance
  12. 12.Université Claude Bernard Lyon1- Service d’Urgences et Réanimation Pédiatrique Hôpital Femme Mère EnfantBronFrance
  13. 13.Service de Pédiatrie et Hématologie PédiatriqueCHU Hôpital d’Enfants, La TimoneMarseilleFrance
  14. 14.Service de Pédiatrie, Hôpital NordSaint-EtienneFrance
  15. 15.Service d’Hématologie AdulteHôpital Necker-Enfants Malades, AP-HPParisFrance
  16. 16.Unité d’Immunologie et d’Hématologie Pédiatrique, Hôpital Necker–Enfants Malades, AP-HPParisFrance
  17. 17.Service de Pédiatrie Néonatologique, CH SallanchesSallanchesFrance
  18. 18.Service Pédiatrie - HématologieOncologie Pôle Enfants Hôpital des EnfantsToulouseFrance
  19. 19.Service de PédiatrieCH de RoubaixRoubaixFrance
  20. 20.Service de Pédiatrie et Onco-hématologieHôpital de Hautepierre, CHU StrasbourgStrasbourgFrance
  21. 21.DiaGena, MCL NiederwangenNiederwangenSwitzerland
  22. 22.Pediatric Infectious Diseases, Children’s HospitalUniversity Hospital of GenevaGenevaSwitzerland
  23. 23.Department of Pediatrics, Center of Experimental and Clinical Respirology IIComenius University, Jessenius School of MedicineMartinSlovakia
  24. 24.Pediatric Clinic KlaicevaClinical Hospital Center Sestre milosrdnice ZagrebZagrebCroatia
  25. 25.Department of PediatricsUniversity Hospital Center ZagrebZagrebCroatia
  26. 26.Department of Pediatric and PneumologyHospital Privado ComunidadMar del PlataArgentina
  27. 27.Service de pédiatrie, CHU Hédi ChakerSfaxTunisia

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