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Mutations in the human lambda5/14.1 gene result in B cell deficiency and agammaglobulinemia.

Minegishi Y, Coustan-Smith E, Wang YH, Cooper MD, Campana D, Conley ME - J. Exp. Med. (1998)

Bottom Line: The three substitutions correspond to the sequence in the lambda5/14. 1 pseudogene 16.1 and result in an amino acid substitution at an invariant proline.When expressed in COS cells, the allele carrying the pseudogene sequence resulted in defective folding and secretion of mutant lambda5/14.1.These findings indicate that expression of the functional lambda5/14.1 is critical for B cell development in the human.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennesse 38105, USA.

ABSTRACT
B cell precursors transiently express a pre-B cell receptor complex consisting of a rearranged mu heavy chain, a surrogate light chain composed of lambda5/14.1 and VpreB, and the immunoglobulin (Ig)-associated signal transducing chains, Igalpha and Igbeta. Mutations in the mu heavy chain are associated with a complete failure of B cell development in both humans and mice, whereas mutations in murine lambda5 result in a leaky phenotype with detectable humoral responses. In evaluating patients with agammaglobulinemia and markedly reduced numbers of B cells, we identified a boy with mutations on both alleles of the gene for lambda5/14.1. The maternal allele carried a premature stop codon in the first exon of lambda5/14.1 and the paternal allele demonstrated three basepair substitutions in a 33-basepair sequence in exon 3. The three substitutions correspond to the sequence in the lambda5/14. 1 pseudogene 16.1 and result in an amino acid substitution at an invariant proline. When expressed in COS cells, the allele carrying the pseudogene sequence resulted in defective folding and secretion of mutant lambda5/14.1. These findings indicate that expression of the functional lambda5/14.1 is critical for B cell development in the human.

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Comparison of the normal and mutant λ5/14.1 genes. (A)  Partial DNA sequence of the first (left) and third (right) exon of λ5/14.1 in  the patient and in a normal control. The basepair substitutions are indicated by an asterisk. (B) Sequence alignment of the third exon of the  functional λ5/14.1 gene, the patient's λ5/14.1 gene, and the 16.1  pseudogene. Only the basepairs at which λ5/14.1 and the pseudogene  16.1 differ are indicated. The basepairs at which the patient's λ5/14.1  gene correspond to the 16.1 gene are shown in bold type.
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Figure 1: Comparison of the normal and mutant λ5/14.1 genes. (A) Partial DNA sequence of the first (left) and third (right) exon of λ5/14.1 in the patient and in a normal control. The basepair substitutions are indicated by an asterisk. (B) Sequence alignment of the third exon of the functional λ5/14.1 gene, the patient's λ5/14.1 gene, and the 16.1 pseudogene. Only the basepairs at which λ5/14.1 and the pseudogene 16.1 differ are indicated. The basepairs at which the patient's λ5/14.1 gene correspond to the 16.1 gene are shown in bold type.

Mentions: The patient's exon 1 sequence revealed a C to T transition at codon 22, resulting in the substitution of a premature stop codon for the wild-type glutamine (Fig. 1). In exon 3, there were three basepair substitutions: T to C at nucleotide 393 (codon 131), T to C at nucleotide 420 (codon 140), and C to T at nucleotide 425 (codon 142). The first two substitutions do not change the coding sequence; however, the third results in the replacement of the wild-type proline with leucine. The proline at this site, which occurs in the loop linking the second and third strands of one of the two beta pleated sheets that compose the immunoglobulin domain (33), is conserved not only in lambda constant region domains in all species evaluated, but also in most immunoglobulin domains (11). SSCP analysis of exon 3 of λ5/14.1 in DNA from 100 individuals did not demonstrate the pattern seen in the patient's paternal allele in any other samples.


Mutations in the human lambda5/14.1 gene result in B cell deficiency and agammaglobulinemia.

Minegishi Y, Coustan-Smith E, Wang YH, Cooper MD, Campana D, Conley ME - J. Exp. Med. (1998)

Comparison of the normal and mutant λ5/14.1 genes. (A)  Partial DNA sequence of the first (left) and third (right) exon of λ5/14.1 in  the patient and in a normal control. The basepair substitutions are indicated by an asterisk. (B) Sequence alignment of the third exon of the  functional λ5/14.1 gene, the patient's λ5/14.1 gene, and the 16.1  pseudogene. Only the basepairs at which λ5/14.1 and the pseudogene  16.1 differ are indicated. The basepairs at which the patient's λ5/14.1  gene correspond to the 16.1 gene are shown in bold type.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199185&req=5

Figure 1: Comparison of the normal and mutant λ5/14.1 genes. (A) Partial DNA sequence of the first (left) and third (right) exon of λ5/14.1 in the patient and in a normal control. The basepair substitutions are indicated by an asterisk. (B) Sequence alignment of the third exon of the functional λ5/14.1 gene, the patient's λ5/14.1 gene, and the 16.1 pseudogene. Only the basepairs at which λ5/14.1 and the pseudogene 16.1 differ are indicated. The basepairs at which the patient's λ5/14.1 gene correspond to the 16.1 gene are shown in bold type.
Mentions: The patient's exon 1 sequence revealed a C to T transition at codon 22, resulting in the substitution of a premature stop codon for the wild-type glutamine (Fig. 1). In exon 3, there were three basepair substitutions: T to C at nucleotide 393 (codon 131), T to C at nucleotide 420 (codon 140), and C to T at nucleotide 425 (codon 142). The first two substitutions do not change the coding sequence; however, the third results in the replacement of the wild-type proline with leucine. The proline at this site, which occurs in the loop linking the second and third strands of one of the two beta pleated sheets that compose the immunoglobulin domain (33), is conserved not only in lambda constant region domains in all species evaluated, but also in most immunoglobulin domains (11). SSCP analysis of exon 3 of λ5/14.1 in DNA from 100 individuals did not demonstrate the pattern seen in the patient's paternal allele in any other samples.

Bottom Line: The three substitutions correspond to the sequence in the lambda5/14. 1 pseudogene 16.1 and result in an amino acid substitution at an invariant proline.When expressed in COS cells, the allele carrying the pseudogene sequence resulted in defective folding and secretion of mutant lambda5/14.1.These findings indicate that expression of the functional lambda5/14.1 is critical for B cell development in the human.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennesse 38105, USA.

ABSTRACT
B cell precursors transiently express a pre-B cell receptor complex consisting of a rearranged mu heavy chain, a surrogate light chain composed of lambda5/14.1 and VpreB, and the immunoglobulin (Ig)-associated signal transducing chains, Igalpha and Igbeta. Mutations in the mu heavy chain are associated with a complete failure of B cell development in both humans and mice, whereas mutations in murine lambda5 result in a leaky phenotype with detectable humoral responses. In evaluating patients with agammaglobulinemia and markedly reduced numbers of B cells, we identified a boy with mutations on both alleles of the gene for lambda5/14.1. The maternal allele carried a premature stop codon in the first exon of lambda5/14.1 and the paternal allele demonstrated three basepair substitutions in a 33-basepair sequence in exon 3. The three substitutions correspond to the sequence in the lambda5/14. 1 pseudogene 16.1 and result in an amino acid substitution at an invariant proline. When expressed in COS cells, the allele carrying the pseudogene sequence resulted in defective folding and secretion of mutant lambda5/14.1. These findings indicate that expression of the functional lambda5/14.1 is critical for B cell development in the human.

Show MeSH
Related in: MedlinePlus