title: Molecular characterization of patients with X-linked Hyper-IgM syndrome: description of two novel CD40L mutations.
abstract: Type 1, X-linked Hyper-IgM syndrome (HIGM1) is caused by mutations in the gene encoding the CD154 protein, also known as CD40 ligand (CD40LG). CD40L is expressed in activated T cells and interacts with CD40 receptor expressed on B lymphocytes and dendritic cells. Affected patients present cellular and humoral immune defects, with infections by intracellular, opportunistic and extracellular pathogens. In the present study we investigated the molecular defects underlying disease in four patients with HIGM1. We identified four distinct CD40L mutations, two of them which have not been previously described. P1 harboured the novel p.G227X mutation which abolished CD40L expression. P2 had a previously described frame shift deletion in exon 2 (p.I53fsX65) which also prevented protein expression. P3 demonstrated the previously known p.V126D change in exon 4, affecting the TNF homology (TNFH) domain. Finally, P4 evidenced the novel p.F229L mutation also located in the TNFH domain. In silico analysis of F229L predicted the change to be pathological, affecting the many hydrophobic interactions of this residue. Precise molecular diagnosis in HIGM syndrome allows reliable detection of carriers, making genetic counselling and prenatal diagnosis possible.
authors.affiliation: Dermatology Department, Laboratory of Medical Investigation Unit 56 (LIM-56), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: A
authors.initials: A
authors.lastname: Rangel-Santos
authors.forename: V L
authors.initials: VL
authors.lastname: Wakim
authors.forename: C M
authors.initials: CM
authors.lastname: Jacob
authors.forename: A C
authors.initials: AC
authors.lastname: Pastorino
authors.forename: J M
authors.initials: JM
authors.lastname: Cunha
authors.forename: A C
authors.initials: AC
authors.lastname: Collanieri
authors.forename: J E
authors.initials: JE
authors.lastname: Niemela
authors.forename: A S
authors.initials: AS
authors.lastname: Grumach
authors.forename: A J S
authors.initials: AJ
authors.lastname: Duarte
authors.forename: D
authors.initials: D
authors.lastname: Moraes-Vasconcelos
authors.forename: J B
authors.initials: JB
authors.lastname: Oliveira
mesh_terms: D000595:Amino Acid Sequence; D023201:CD40 Ligand / Q000032:analysis / Q000737:chemistry / Q000235:genetics*; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006801:Humans; D006942:Hypergammaglobulinemia / Q000235:genetics*; D007075:Immunoglobulin M / Q000097:blood*; D008969:Molecular Sequence Data; D009154:Mutation; D013601:T-Lymphocytes / Q000737:chemistry
chemical_list: D007075:Immunoglobulin M; D023201:CD40 Ligand