Clinical and molecular analysis of patients with defects in micro heavy chain gene

Abstract

Autosomal recessive disorders of B cell development are rare and heterogeneous. To determine the proportion of affected patients who have defects in the micro heavy chain (IGHM) gene, we used single-stranded conformational polymorphism analysis to screen genomic DNA from 40 unrelated patients with early onset infections, profound hypogammaglobulinemia, and absent B cells. All of the patients were genotypically normal in BTK, the gene that underlies X-linked agammaglobulinemia. Eight different mutations in the micro heavy chain were identified in 19 members of 12 unrelated families. Four of the mutations were large deletions that removed more than 40 kb of DNA in the IGHM locus. In six of the 12 families, the affected patients had an identical single base pair substitution, a G-->A, at the -1 position of the alternative splice site. Immunoglobulin haplotype analysis showed that this mutation occurred on at least three different haplotypes, indicating that this is a hot spot for mutations. Compared with patients with mutations in Btk, patients with defects in the micro heavy chain had an earlier onset of disease and more complications. Our study indicates that at least 20-30% of patients with autosomal recessive defects in B cell development have mutations in the micro heavy chain.

Figure 1

The pedigrees of the families with known consanguinity or more than one affected family member are shown. Males and females are indicated with squares and circles respectively. A line is drawn through the symbol for an individual who is no longer living.

Figure 2

Schematic diagram of the μ heavy chain gene. The exons common to the membrane and secretory form of μ heavy chain are shown in open boxes, the 3′ segment of the secretory form of μ heavy chain is shown as a hatched pattern, and the two exons that form the membrane exons are shown in filled boxes. The mutations are shown above the gene, and the polymorphic sites are shown below the gene with asterisks. The polymorphic sites that were used to define the haplotypes in patients with shared mutations are marked with a filled circle.