CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency
Menno C. van Zelm, … , Jacques J.M. van Dongen, Mirjam van der Burg
Menno C. van Zelm, … , Jacques J.M. van Dongen, Mirjam van der Burg
Published March 8, 2010
Citation Information: J Clin Invest. 2010;120(4):1265-1274. https://doi.org/10.1172/JCI39748.
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CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency

Abstract

Antibody deficiencies constitute the largest group of symptomatic primary immunodeficiency diseases. In several patients, mutations in CD19 have been found to underlie disease, demonstrating the critical role for the protein encoded by this gene in antibody responses; CD19 functions in a complex with CD21, CD81, and CD225 to signal with the B cell receptor upon antigen recognition. We report here a patient with severe nephropathy and profound hypogammaglobulinemia. The immunodeficiency was characterized by decreased memory B cell numbers, impaired specific antibody responses, and an absence of CD19 expression on B cells. The patient had normal CD19 alleles but carried a homozygous CD81 mutation resulting in a complete lack of CD81 expression on blood leukocytes. Retroviral transduction and glycosylation experiments on EBV-transformed B cells from the patient revealed that CD19 membrane expression critically depended on CD81. Similar to CD19-deficient patients, CD81-deficient patients had B cells that showed impaired activation upon stimulation via the B cell antigen receptor but no overt T cell subset or function defects. In this study, we present what we believe to be the first antibody deficiency syndrome caused by a mutation in the CD81 gene and consequent disruption of the CD19 complex on B cells. These findings may contribute to unraveling the genetic basis of antibody deficiency syndromes and the nonredundant functions of CD81 in humans.

Authors

Menno C. van Zelm, Julie Smet, Brigitte Adams, Françoise Mascart, Liliane Schandené, Françoise Janssen, Alina Ferster, Chiung-Chi Kuo, Shoshana Levy, Jacques J.M. van Dongen, Mirjam van der Burg

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Figure 2

Homozygous CD81 splice site mutation results in alternative splicing and disruption of the CD19 complex on B cells.

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Homozygous CD81 splice site mutation results in alternative splicing and...
(A). Schematic representation of the CD81 gene, consisting of 8 exons. The patient was homozygous for a splice site mutation downstream of exon 6 (exon6+1 G>A) resulting in the use of a cryptic splice site 13 nucleotides downstream of exon 6. The 13-nucleotide insertion results in a frameshift and a premature stop codon upstream of the fourth transmembrane domain of the CD81 protein. TM, transmembrane domain; SEL, short extracellular loop; LEL, large extracellular loop. (B). Pedigree of the family of the CD81-deficient patient. Half-filled symbols denote known carriers of the mutation; the filled symbol represents the patient, who is homozygous for the mutation; gray symbols denote family members who were not tested for carriership of the mutation; squares denote male family members; circles denote female family members. The parents of the patient were consanguineous (double line). (C). Quantitative analysis of CD81 transcripts in blood mononuclear cells. Three PCR assays were developed to quantify total, wild-type, and alternatively spliced CD81 transcripts. Arrows indicate primers; blue bars denote TaqMan probes. Data represent mean ± SD. (D). Expression levels of CD19 complex members on B cells of the patient and a carrier of the CD81 mutation. CD19 and CD81 expression were absent on patient’s B cells and reduced in carriers of the mutation. CD21 and CD225 were normally expressed. Isotype controls are shown for CD81 and CD225 stains and CD20-negative lymphocytes for CD19 and CD21 stains.