A Founder Effect of c.257 + 2T > C Mutation in NCF2 Gene Underlies Severe Chronic Granulomatous Disease in Eleven Patients

Autor: Khaoula Ben-Farhat, Monia Khemiri, Zohra Fitouri, Sihem Barsaoui, Najla Mekki, Meriem Ben-Ali, Selim Abdelmoula, Mohamed-Neji Guediche, M. R. Barbouche, Samir Boukthir, Saber Hamami, Imen Ben-Mustapha, Amel Ben-Chehida, Jalel Chemli, Karen Rouault, Beya Larguèche
Přispěvatelé: Université de Tunis El Manar (UTM), Laboratoire de Transmission, Contrôle et Immunobiologie des Infections - Laboratory of Transmission, Control and Immunobiology of Infection (LR11IPT02), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Faculté de Médecine de Tunis, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Département pédiatrique [Hôpital Fattouma Bourguiba - Monastir], CHU Fattouma Bourguiba [Monastir] (HFB), Department of Pediatrics [Tunis], Hôpital La Rabta [Tunis], Béchir Hamza Children's Hospital, Hôpital Universitaire Sahloul (CHU Sahloul)
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
Neutrophils
[SDV]Life Sciences [q-bio]
DNA Mutational Analysis
Granulomatous Disease
Chronic
medicine.disease_cause
Severity of Illness Index
Consanguinity
0302 clinical medicine
Chronic granulomatous disease
MESH: Child
Immunology and Allergy
MESH: NADPH Oxidases/genetics
MESH: DNA Mutational Analysis
Child
MESH: Neutrophils/metabolism
MESH: Genetic Association Studies
Genetics
Mutation
MESH: Infant
Founder Effect
3. Good health
Phenotype
Child
Preschool
030220 oncology & carcinogenesis
Female
MESH: Tunisia
NCF2 gene
MESH: Alleles
MESH: Enzyme Activation
Tunisia
Immunology
Biology
MESH: Phenotype
03 medical and health sciences
MESH: Genetic Predisposition to Disease
MESH: Severity of Illness Index
MESH: Founder Effect
medicine
Humans
Genetic Predisposition to Disease
Allele
Gene
Alleles
Genetic Association Studies
MESH: Consanguinity
MESH: Granulomatous Disease
Chronic/diagnosis
MESH: Humans
MESH: Granulomatous Disease
Chronic/genetics
MESH: Child
Preschool
Haplotype
Infant
NADPH Oxidases
MESH: Granulomatous Disease
Chronic/metabolism
MESH: Haplotypes
medicine.disease
MESH: Male
Enzyme Activation
030104 developmental biology
Haplotypes
Genetic marker
MESH: Neutrophils/immunology
MESH: Mutation
MESH: NADPH Oxidases/metabolism
MESH: Female
Founder effect
Zdroj: Journal of Clinical Immunology
Journal of Clinical Immunology, Springer Verlag, 2016, 36 (6), pp.547-554. ⟨10.1007/s10875-016-0299-9⟩
ISSN: 1573-2592
0271-9142
Popis: International audience; 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.
Databáze: OpenAIRE
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