title: A Founder Effect of c.257 + 2T > C Mutation in NCF2 Gene Underlies Severe Chronic Granulomatous Disease in Eleven Patients.
abstract: Chronic granulomatous disease (CGD) is the prototypic functional neutrophil disorder caused by genetic defects in one of the five genes encoding the superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase subunits of phagocytes. Mutations causing the most prevalent form of CGD in western populations are located in the X-linked-CYBB gene. The four remaining autosomal recessive (AR) forms collectively account for one-third of CGD cases. We investigated the clinical and molecular features of eleven patients with CGD from 6 consanguineous families, originating from contiguous regions in the west of Tunisia. The patients' clinical phenotype is characterized by a high incidence of mycobacterial infections. Five out of the eleven patients died despite treatment arguing in favor of a severe clinical form of CGD. These findings correlated with the absence of functional p67phox protein as well as the absence of residual reactive oxygen intermediates (ROI) production. Genetic analysis showed the presence, in all patients, of a unique mutation (c.257 + 2T > C) in NCF2 gene predicted to affect RNA splicing. Segregating analysis using nine polymorphic markers overlapping the NCF2 gene revealed a common haplotype spanning 4.1 Mb. The founder event responsible for this mutation was estimated to have arisen approximately 175 years ago. These findings will facilitate the implementation of preventive approaches through genetic counseling in affected consanguineous families.
authors.affiliation: Laboratory of Transmission, Control and Immunobiology of Infections (LTCII), LR11IPT02, Institut Pasteur de Tunis, Pasteur, 1002, Tunis-Belvedere, Tunisia.|University of Tunis El Manar, 1068, Tunis, Tunisia.
authors.forename: Khaoula
authors.initials: K
authors.lastname: Ben-Farhat
authors.affiliation: Laboratory of Transmission, Control and Immunobiology of Infections (LTCII), LR11IPT02, Institut Pasteur de Tunis, Pasteur, 1002, Tunis-Belvedere, Tunisia. imen.benmustapha@pasteur.tn.|University of Tunis El Manar, 1068, Tunis, Tunisia. imen.benmustapha@pasteur.tn.|Faculty of Medicine, Tunis, Tunisia. imen.benmustapha@pasteur.tn.
authors.forename: Imen
authors.initials: I
authors.lastname: Ben-Mustapha
authors.affiliation: Laboratory of Transmission, Control and Immunobiology of Infections (LTCII), LR11IPT02, Institut Pasteur de Tunis, Pasteur, 1002, Tunis-Belvedere, Tunisia.|University of Tunis El Manar, 1068, Tunis, Tunisia.
authors.forename: Meriem
authors.initials: M
authors.lastname: Ben-Ali
authors.affiliation: Inserm, UMR 1078, Brest, France.
authors.forename: Karen
authors.initials: K
authors.lastname: Rouault
authors.affiliation: Department of Pediatrics, Fattouma Bourguiba Hospital, 5000, Monastir, Tunisia.
authors.forename: Saber
authors.initials: S
authors.lastname: Hamami
authors.affiliation: Laboratory of Transmission, Control and Immunobiology of Infections (LTCII), LR11IPT02, Institut Pasteur de Tunis, Pasteur, 1002, Tunis-Belvedere, Tunisia.|University of Tunis El Manar, 1068, Tunis, Tunisia.|Faculty of Medicine, Tunis, Tunisia.
authors.forename: Najla
authors.initials: N
authors.lastname: Mekki
authors.affiliation: Department of Pediatrics, La Rabta Hospital, 1007, Tunis, Tunisia.
authors.forename: Amel
authors.initials: A
authors.lastname: Ben-Chehida
authors.affiliation: Laboratory of Transmission, Control and Immunobiology of Infections (LTCII), LR11IPT02, Institut Pasteur de Tunis, Pasteur, 1002, Tunis-Belvedere, Tunisia.
authors.forename: Beya
authors.initials: B
authors.lastname: Larguèche
authors.affiliation: Department of Emergency and Consultations, Children's Hospital, 1029, Tunis, Tunisia.
authors.forename: Zohra
authors.initials: Z
authors.lastname: Fitouri
authors.affiliation: Department of Pediatrics, La Rabta Hospital, 1007, Tunis, Tunisia.
authors.forename: Selim
authors.initials: S
authors.lastname: Abdelmoula
authors.affiliation: Department of Pediatrics A, Children's Hospital, 1029, Tunis, Tunisia.
authors.forename: Monia
authors.initials: M
authors.lastname: Khemiri
authors.affiliation: Department of Pediatrics, Fattouma Bourguiba Hospital, 5000, Monastir, Tunisia.
authors.forename: Mohamed-Neji
authors.initials: MN
authors.lastname: Guediche
authors.affiliation: Department of Pediatrics C, Children's Hospital, 1029, Tunis, Tunisia.
authors.forename: Samir
authors.initials: S
authors.lastname: Boukthir
authors.affiliation: Department of Pediatrics A, Children's Hospital, 1029, Tunis, Tunisia.
authors.forename: Sihem
authors.initials: S
authors.lastname: Barsaoui
authors.affiliation: Department of Pediatrics, Sahloul Hospital, 4011, Sousse, Tunisia.
authors.forename: Jalel
authors.initials: J
authors.lastname: Chemli
authors.affiliation: Laboratory of Transmission, Control and Immunobiology of Infections (LTCII), LR11IPT02, Institut Pasteur de Tunis, Pasteur, 1002, Tunis-Belvedere, Tunisia.|University of Tunis El Manar, 1068, Tunis, Tunisia.|Faculty of Medicine, Tunis, Tunisia.
authors.forename: Mohamed-Ridha
authors.initials: MR
authors.lastname: Barbouche
mesh_terms: D000483:Alleles; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D005260:Female; D018703:Founder Effect; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006105:Granulomatous Disease, Chronic / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D012720:Severity of Illness Index; D014416:Tunisia
chemical_list: D019255:NADPH Oxidases; C527764:NCF2 protein, human
keywords: Chronic granulomatous disease; NCF2 gene; Tunisia; consanguinity; founder effect