CHARACTERIZATION OF 9 NOVEL MUTATIONS IN THE CD40 LIGAND GENE IN PATIENTS WITH X-LINKED HYPER IGM SYNDROME OF VARIOUS ANCESTRY

X-linked immunodeficiency with hyper-IgM (HIGMX-1) is a rare disorder caused by defective expression of the CD40 ligand (CD40L) by activated T lymphocytes, resulting in inefficient T-B cell cooperation and fail ure of B cells to undergo immunoglobulin isotype switch. In the presen t work, we describe nine patients of various ancestry who bear differe nt mutations in the X chromesome-specific CD40L gene. Two of the mutat ions were nonsense mutations, one each resulting in premature stop cod ons at amino acid residues 39 and 140. Three patients had single point missense mutations, one each at codons 126, 140, and 144. Another pat ient had a 4-bp genomic deletion in exon 2, resulting in a frameshift and premature termination. Three patients showed insertions, one each of 1, 2, and 4 nt, probably because of polymerase slippage, resulting in frameshift mutation and premature termination. Overall, these obser vations confirm the heterogeneity of mutations in HIGMX-1. However, th e identification of two patients whose mutation involves codon 140 (pr eviously shown to be altered in two other unrelated subjects) suggests that this may be a hotspot of mutation in HIGMX-1. In two additional patients with clinical and immunological features indistinguishable fr om canonical HIGMX-1, no mutation was detected in the coding sequence, in the 5' flanking region, or in the 3' UTR.