Genomic alterations in a case of alpha heavy chain disease leading to the generation of composite exons from the JH region.

Human alpha heavy chain disease (HCD) is characterized by the presence in patient's serum of a short Ig alpha chain devoid of light chains. We analyzed the serum protein, the alpha HCD mRNA and the productive rearranged H chain gene from the leukemic cells of a new case (YAO) of alpha HCD. The abnormal YAO alpha 1 Ig was devoid of VH and CH1 domains and started at the beginning of the hinge region. The alpha HCD mRNA was shorter than normal alpha mRNA and the cDNA prepared from YAO mRNA encoded a leader sequence, an insert of 70 nucleotides and the CH2 and CH3 exons. The origin of the inserted sequence was assessed by cloning and sequence analysis of the alpha 1 productive gene. It started with a leader exon, a leader-VH intron and the first 11 bp of a VH exon. Then the VH region was deleted and replaced by a 19-nucleotide sequence that turned out to correspond to the 3' part of a modified JH5 exon. It was followed by a 221-bp sequence homologous to the JH5-psi JH3 intron and by an inserted sequence of unknown origin. The 3' part of this insertion and the remnant of a JH6 exon delineated a third exon that was followed by a relatively conserved JH6-C alpha intron. These two composite exons were flanked by splicing sites and accounted for the 70-nucleotide insert of the cDNA. The genomic nucleotide sequence also revealed a large deletion in the switch CH1 region which eliminated normal splicing sites and resulted in splicing of the third exon directly to the CH2 exon.