title: Three novel mutations reflect the variety of defects causing phenotypically diverse X-linked hyper-IgM syndrome.
abstract: X-linked hyper-IgM syndrome (HIGM1) (MIM musical sharp 308230), is a severe primary immunodeficiency caused by mutations in the gene coding for CD40 ligand (CD40L or CD154), a member of the tumour necrosis factor (TNF) superfamily. The interaction of this protein with its ligand, CD40, mediates crucial processes in the immune response. The variety of defects that have been described in HIGM1 patients range from a complete lack of CD40L protein expression to missense mutations that interfere with its interaction with CD40L. In this study we describe three families - a total of seven HIGM1 patients and carriers, presenting a spectrum of severity in clinical evolution. In two of these families, patient DNA samples were available for genetic studies. In the third, carrier detection was performed on female family members. The results of immunological studies - the different patterns of CD40L expression and binding capacity as measured by flow cytometry - and molecular diagnosis are presented. Three novel mutations were identified: an intron mutation that partially interferes with the splicing process (intron 3, position + 5 G/T); a missense mutation (Ser222 Phe) located in the molecular region which interacts with the receptor and which abrogates binding capacity; and a 14 base pair deletion leading to a frameshift and a premature truncated mutation (del I 171 X 195). An attempt to correlate protein expression and function of the CD40L mutants with clinical disease evolution is described.
authors.affiliation: Immunology Unit, Hospital La Paz, Madrid, Spain.
authors.forename: E
authors.initials: E
authors.lastname: López-Granados
authors.forename: R
authors.initials: R
authors.lastname: Cambronero
authors.forename: A
authors.initials: A
authors.lastname: Ferreira
authors.forename: G
authors.initials: G
authors.lastname: Fontán
authors.forename: M C
authors.initials: MC
authors.lastname: García-Rodríguez
mesh_terms: D001483:Base Sequence; D023201:CD40 Ligand / Q000737:chemistry / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X; D003461:Crystallography; D005260:Female; D005434:Flow Cytometry; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D006942:Hypergammaglobulinemia / Q000235:genetics* / Q000276:immunology; D007075:Immunoglobulin M; D007223:Infant; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D018807:Polymorphism, Single-Stranded Conformational; D020836:Protein Structure, Quaternary; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D007075:Immunoglobulin M; D023201:CD40 Ligand