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The productive gene for alpha-H chain disease protein MAL is highly modified by insertion-deletion processes
A Tsapis1, M Bentaboulet, P Pellet
1Laboratoire d'Immunochimie et d'Immunopathologie, INSERM U.108, Paris, France.
Insights
Alpha-H chain diseases (HCD) involve producing shortened alpha-immunoglobulin heavy chains. This study details genetic alterations in a patient with HCD, revealing deletions and insertions that create abnormal mRNA and proteins.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Alpha-H chain diseases (HCD) are lymphoproliferative disorders.
- Characterized by truncated alpha-immunoglobulin (Ig) heavy chains lacking light chains.
Purpose of the Study:
- Analyze serum protein, alpha-HCD mRNA, and rearranged alpha-HCD gene in a patient (MAL) with HCD.
- Characterize the molecular basis of alpha-HCD.
Main Methods:
- Serum protein analysis
- mRNA sequencing
- Gene sequencing of leukemic cells
- cDNA analysis
Main Results:
- Abnormal serum Ig contained short alpha 1-chains (CH2 and CH3 domains only).
- Alpha-HCD mRNA was truncated (1.2 kb vs. 2 kb), containing leader, an 84-bp alien exon, and CH2/CH3 exons.
- Gene sequencing revealed deletions of VH and CH1 regions, altered JH region, and two large inserts (INS1 and Insert2) of non-Ig origin.
- INS1 replaced the VH region and contained the 84-bp alien exon.
Conclusions:
- Genetic alterations in alpha-HCD include deletions and non-Ig inserts.
- These mutations lead to the production of truncated alpha-H chains and abnormal mRNA.
- The findings provide molecular insights into the pathogenesis of alpha-H chain disease.
Abstract:
alpha-H chain diseases (HCD) is a human lymphoproliferative disorder, characterized by the production of truncated alpha-Ig H chains, without associated L chains. In this study, we have analysed the serum protein, the alpha-HCD mRNA and the rearranged alpha-HCD gene from the leukemic cells of a patient (MAL) with alpha-HCD. The abnormal MAL serum Ig consisted of short alpha 1-chains, lacking VH and CH1 domains (only CH2 and CH3 domains were present). The alpha-HCD mRNA (1.2 kb) was shorter than a normal alpha-mRNA (2 kb); the corresponding cDNA had sequences for the leader, a 84-bp sequence of unknown origin and the CH2 and CH3 exons. The establishment of the sequence of the productive alpha-HCD MAL allele revealed two major deletions; that of the VH region as well as that of the CH1 region. The JH region is altered by multiple mutations, small insertions and a duplication of the psi JH3 region. A large insert (INS1), of 360 bp (containing the 84 bp exon found in the cDNA), replaces the deleted VH region. INS1 is non-Ig related and apparently of nongenomic origin. A large second insert (509 bp), is located between the enhancer and the switch region. Insert2 contains repetitive non-Ig-related sequences and a small Ig-related sequence. All these alterations resulted in an abnormal mRNA, which comprises the leader, a 84-bp alien exon derived from INS1 and the CH2 and CH3 exons of the alpha 1-gene.