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Blood, Vol. 92 No. 7 (October 1), 1998:
pp. 2421-2434
Mutations of the CD40 Ligand Gene and Its Effect on CD40
Ligand Expression in Patients With X-Linked Hyper IgM Syndrome
Kuniaki Seyama,
Shigeaki Nonoyama,
Ingvild Gangsaas,
Diane Hollenbaugh,
Henry F. Pabst,
Alejandro Aruffo, and
Hans D. Ochs
From the Department of Pediatrics and Biological Structure,
University of Washington Medical School, Seattle, WA; the Department of
Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan;
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA;
and the Department of Pediatrics, University of Alberta, Alberta,
Canada.
X-linked hyper IgM syndrome (XHIM) is a primary immunodeficiency
disorder caused by mutations of the gene encoding CD40 ligand (CD40L).
We correlated mutations of the CD40L gene, CD40L
expression, and the clinical manifestations observed in XHIM patients
from 30 families. The 28 unique mutations identified included 9 missense, 5 nonsense, 9 splice site mutations, and 5 deletions/insertions. In 4 of 9 splice site mutations, normally spliced
and mutated mRNA transcripts were simultaneously expressed. RNase
protection assay demonstrated that 5 of 17 mutations tested resulted in
decreased levels of transcript. The effect of the mutations on CD40L
expression by activated peripheral blood mononuclear cells (PBMC) and
T-cell lines or clones was assessed using one polyclonal and four
monoclonal antibodies and a CD40-Ig fusion protein. In most patients,
the binding of at least one antibody but not of CD40-Ig was observed, suggesting nonfunctional CD40L. However, activated PBMC from three patients and activated T-cell lines from two additional patients, each
with different genotype, bound CD40-Ig at low intensity, suggesting
functional CD40L. Thus, failure of activated PBMC to bind CD40-Ig is
not an absolute diagnostic hallmark of XHIM and molecular analysis of
the CD40L gene may be required for the correct diagnosis.
Patients with genotypes resulting in diminished expression of wild-type
CD40L or mutant CD40L that can still bind CD40-Ig appear to have milder
clinical consequences.
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