Molecular analysis of the pre-BCR complex in a large cohort of patients affected by autosomal-recessive agammaglobulinemia

Abstract

Autosomal-recessive agammaglobulinemia is a rare and heterogeneous disorder, characterized by early-onset infections, profound hypogammaglobulinemia of all immunoglobulin isotypes and absence of circulating B lymphocytes. To investigate the molecular basis of the disease, 23 patients with early-onset disease and no mutations in Bruton tyrosine kinase, the gene responsible for X-linked agammaglobulinemia, were selected and analyzed by direct sequencing of candidate genes. Two novel mutations in the m heavy chain (mHC) gene (IGHM) were identified in three patients belonging to two unrelated families. A fourth patient carries a previously described G4A nucleotide substitution at the À1 position of an alternative splice site in IGHM; here, we demonstrate that this mutation is indeed responsible for aberrant splicing. Comparison of bone marrow cytofluorimetric profiles in two patients carrying different mutations in the IGHM gene suggests a genotype-phenotype correlation with the stage at which B-cell development is blocked. Several new single nucleotide polymorphisms (SNPs) both in the mHC and in the l5-like/VpreB-coding genes were identified. Two unrelated patients carry compound heterozygous variations in the VpreB1 gene that may be involved in disease ethiology.

Antibody deficiency diseases

“…This mutation has occurred on at least three different Ig haplotypes, indicating that this is a hot spot for mutations. The study indicated that at least 20-30% of patients with autosomal recessive defects in B cell development have mutations in the l heavy chain and multiple additional patients have recently been described [16][17][18].…”

“…Interestingly, in one of the latter studies [16], two patients with compound heterozygous variations in the pre-B lymphocyte gene 1 (VpreB1) were also described. Although it cannot be ruled out that these variations represent low-frequency polymorphisms, they may be the first cases suggesting that VpreB mutations are indeed involved in the etiology of agammaglobulinemia in humans.…”

“…This mutation has occurred on at least three different Ig haplotypes, indicating that this is a hot spot for mutations. The study indicated that at least 20-30% of patients with autosomal recessive defects in B cell development have mutations in the l heavy chain and multiple additional patients have recently been described [16][17][18].Interestingly, in one of the latter studies [16], two patients with compound heterozygous variations in the pre-B lymphocyte gene 1 (VpreB1) were also described. Although it cannot be ruled out that these variations represent low-frequency polymorphisms, they may be the first cases suggesting that VpreB mutations are indeed involved in the etiology of agammaglobulinemia in humans.…”

Gastrectomy with isoperistaltic jejunal parallel pouch in a 15-year-old adolescent boy with gastric adenocarcinoma and autosomal recessive agammaglobulinemia

“…Autosomal recessive agammaglobulinemia represents 5% of all patients with agammaglobulinemia [2,3]. In 20% to 30% of this small patient group, mutations in the gene for the μ heavy-chain gene are found [4].…”

The Novel Patient with BLNK Gene Type of Agammaglobulinemia

“…Abnormal laboratory parameters include low Ig levels and low or absent peripheral blood mature B lymphocytes [5] [9]. For determine the genetic defect and to confirm the diagnosis, should be performed molecular genetic testing.…”