title: Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM.
abstract: CD40 is a member of the tumor necrosis factor receptor superfamily, expressed on a wide range of cell types including B cells, macrophages, and dendritic cells. CD40 is the receptor for CD40 ligand (CD40L), a molecule predominantly expressed by activated CD4(+) T cells. CD40/CD40L interaction induces the formation of memory B lymphocytes and promotes Ig isotype switching, as demonstrated in mice knocked-out for either CD40L or CD40 gene, and in patients with X-linked hyper IgM syndrome, a disease caused by CD40L/TNFSF5 gene mutations. In the present study, we have identified three patients with an autosomal recessive form of hyper IgM who fail to express CD40 on the cell surface. Sequence analysis of CD40 genomic DNA showed that one patient carried a homozygous silent mutation at the fifth base pair position of exon 5, involving an exonic splicing enhancer and leading to exon skipping and premature termination; the other two patients showed a homozygous point mutation in exon 3, resulting in a cysteine to arginine substitution. These findings show that mutations of the CD40 gene cause an autosomal recessive form of hyper IgM, which is immunologically and clinically undistinguishable from the X-linked form.
authors.affiliation: Istituto di Medicina Molecolare "Angelo Nocivelli," Clinica Pediatrica, Università di Brescia, Piazzale Spedali Civili 1, 25123 Brescia, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Ferrari
authors.forename: S
authors.initials: S
authors.lastname: Giliani
authors.forename: A
authors.initials: A
authors.lastname: Insalaco
authors.forename: A
authors.initials: A
authors.lastname: Al-Ghonaium
authors.forename: A R
authors.initials: AR
authors.lastname: Soresina
authors.forename: M
authors.initials: M
authors.lastname: Loubser
authors.forename: M A
authors.initials: MA
authors.lastname: Avanzini
authors.forename: M
authors.initials: M
authors.lastname: Marconi
authors.forename: R
authors.initials: R
authors.lastname: Badolato
authors.forename: A G
authors.initials: AG
authors.lastname: Ugazio
authors.forename: Y
authors.initials: Y
authors.lastname: Levy
authors.forename: N
authors.initials: N
authors.lastname: Catalan
authors.forename: A
authors.initials: A
authors.lastname: Durandy
authors.forename: A
authors.initials: A
authors.lastname: Tbakhi
authors.forename: L D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: A
authors.initials: A
authors.lastname: Plebani
mesh_terms: D019013:CD40 Antigens / Q000032:analysis / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005091:Exons; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007075:Immunoglobulin M / Q000097:blood*; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D008297:Male; D009154:Mutation; D014960:X Chromosome
chemical_list: D019013:CD40 Antigens; D007075:Immunoglobulin M