title: Organization of the human CD40L gene: implications for molecular defects in X chromosome-linked hyper-IgM syndrome and prenatal diagnosis.
abstract: Recently, CD40L has been identified as the gene responsible for X chromosome-linked hyper-IgM syndrome (HIGM1). CD40L on activated T cells from HIGM1 patients fails to bind B-cell CD40 molecules, and subsequent analysis of CD40L transcripts by reverse transcription PCR demonstrated coding region mutations in these patients. This approach, however, is of limited use for prenatal diagnosis of HIGM1 in the early-gestation fetus. In this report, we have defined the genomic structure of the CD40L gene, which is composed of five exons and four intervening introns. With this information, we have defined at the genomic level the CD40L gene abnormalities for three previously described HIGM1 patients who demonstrated clustered deletions in the CD40L coding region. These different deletions arose from three distinct mechanisms, including (i) a splice donor mutation with exon skipping, (ii) a splice acceptor mutation with utilization of a cryptic splice site, and (iii) a deletion/insertion event with the creation of a new splice acceptor site. In addition, we have performed prenatal evaluation of an 11-week-old fetus at risk for HIGM1. CD40L genomic clones provide a starting point for further studies of the genetic elements that control CD40L expression. Our knowledge of the CD40L gene structure will prove useful for the identification of additional mutations in HIGM1 and for performing genetic counseling about this disease.
authors.affiliation: Istituto di Tecnologie Biomediche Avanzate, Consiglio Nazionale delle Ricerche, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Villa
authors.forename: L D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: J P
authors.initials: JP
authors.lastname: Di Santo
authors.forename: P P
authors.initials: PP
authors.lastname: Macchi
authors.forename: D
authors.initials: D
authors.lastname: Strina
authors.forename: A
authors.initials: A
authors.lastname: Frattini
authors.forename: F
authors.initials: F
authors.lastname: Lucchini
authors.forename: C M
authors.initials: CM
authors.lastname: Patrosso
authors.forename: S
authors.initials: S
authors.lastname: Giliani
authors.forename: E
authors.initials: E
authors.lastname: Mantuano
mesh_terms: D001483:Base Sequence; D023201:CD40 Ligand; D004247:DNA; D005091:Exons; D005260:Female; D005315:Fetal Diseases / Q000175:diagnosis / Q000235:genetics*; D008040:Genetic Linkage; D006801:Humans; D006942:Hypergammaglobulinemia / Q000175:diagnosis / Q000235:genetics*; D007075:Immunoglobulin M / Q000097:blood*; D007438:Introns; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011296:Prenatal Diagnosis; D012333:RNA, Messenger / Q000235:genetics; D015183:Restriction Mapping; D017384:Sequence Deletion; D014960:X Chromosome
chemical_list: D007075:Immunoglobulin M; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D023201:CD40 Ligand; D004247:DNA