A Donor splice mutation and a single-base deletion produce two carboxyl-terminal variants of human serum albumin

At least 35 allelic variants of human serum
albumin have been sequenced at the protein level. All except
two COOH-terminal variants, Catania and Venezia, are
readily explainable as single-point substitutions. The two
chain-termination variants are clustered in certain locations in
Italy and are found in numerous unrelated individuals. In
order to correlate the protein change in these variants with the
corresponding DNA mutation, the two variant albumin genes
have been cloned, sequenced, and compared to normal albumin
genomic DNA. In the Catania variant, a single base deletion
and subsequent frameshift leads to a shortened and altered
COOH terminus. Albumin Venezia is caused by a mutation
that alters the first consensus nucleotide of the 5' donor splice
junction of intron 14 and the 3' end of exon 14, which is
shortened from 68 to 43 base pairs. This change leads to an exon
skipping event resulting in direct splicing of exon 13 to exon 15.
The predicted Venezia albumin product has a truncated amino
acid sequence (580 residues instead of 585), and the COOHterminal
sequence is altered after Glu-571. The variant COOH
terminus ends with the dibasic sequence Arg-Lys that is
apparently removed through stepwise cleavage by serum carboxypeptidase
B to yield several forms of circulating albumin.