title: Novel Mutations Causing C5 Deficiency in Three North-African Families.
abstract: The complement system plays a central role in defense to encapsulated bacteria through opsonization and membrane attack complex (MAC) dependent lysis. The three activation pathways (classical, lectin, and alternative) converge in the cleavage of C5, which initiates MAC formation and target lysis. C5 deficiency is associated to recurrent infections by Neisseria spp. In the present study, complement deficiency was suspected in three families of North-African origin after one episode of invasive meningitis due to a non-groupable and two uncommon Meningococcal serotypes (E29, Y). Activity of alternative and classical pathways of complement were markedly reduced and the measurement of terminal complement components revealed total C5 absence. C5 gene analysis revealed two novel mutations as causative of the deficiency: Family A propositus carried a homozygous deletion of two adenines in the exon 21 of C5 gene, resulting in a frameshift and a truncated protein (c.2607_2608del/p.Ser870ProfsX3 mutation). Families B and C probands carried the same homozygous deletion of three consecutive nucleotides (CAA) in exon 9 of the C5 gene, leading to the deletion of asparagine 320 (c.960_962del/p.Asn320del mutation). Family studies confirmed an autosomal recessive inheritance pattern. Although sharing the same geographical origin, families B and C were unrelated. This prompted us to investigate this mutation prevalence in a cohort of 768 North-African healthy individuals. We identified one heterozygous carrier of the p.Asn320del mutation (allelic frequency = 0.065 %), indicating that this mutation is present at low frequency in North-African population.
authors.affiliation: Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain. rcolobran@vhebron.net.|Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Research Institute (VHIR), Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Edifici Laboratoris, planta baixa. Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain. rcolobran@vhebron.net.
authors.forename: Roger
authors.initials: R
authors.lastname: Colobran
authors.affiliation: Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Franco-Jarava
authors.affiliation: Pediatric Infectious Diseases and Immunodeficiencies Unit (UPIIP), Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Martín-Nalda
authors.affiliation: Genetic Laboratory UDIAT-Diagnostic Center, Corporació Sanitària Parc Taulí, Sabadell, Spain.
authors.forename: Neus
authors.initials: N
authors.lastname: Baena
authors.affiliation: Genetic Laboratory UDIAT-Diagnostic Center, Corporació Sanitària Parc Taulí, Sabadell, Spain.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Gabau
authors.affiliation: Research Unit in Translational Bioinformatics, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: Natàlia
authors.initials: N
authors.lastname: Padilla
authors.affiliation: Research Unit in Translational Bioinformatics, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: de la Cruz
authors.affiliation: Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Pujol-Borrell
authors.affiliation: Departament de Ciències Experimentals i de la Salut, Institut de Biologia Evolutiva (CSIC-UPF), Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Comas
authors.affiliation: Pediatric Infectious Diseases and Immunodeficiencies Unit (UPIIP), Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: Pere
authors.initials: P
authors.lastname: Soler-Palacín
authors.affiliation: Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hernández-González
mesh_terms: D000349:Africa; D002648:Child; D002675:Child, Preschool; D003182:Complement C5 / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D000081208:Hereditary Complement Deficiency Diseases; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000378:metabolism; D007223:Infant; D008297:Male; D009154:Mutation; D010375:Pedigree
chemical_list: D003182:Complement C5
keywords: African continental ancestry group; Complement system; complement 5 deficiency; meningococcal disease; mutation