Mutations in genetic variants of human serum albumin found in Italy.

Abstract

A long-term electrophoretic survey of genetic variants of serum albumin has identified an alloalbumin in 589 unrelated individuals in Italy. The alloalbumins were classified electrophoretically into 17 types. The number of unrelated carriers for each type varied from 1 for several variants reported here to 103 for albumin B. The structural change in 8 of these types has previously been determined, and the amino acid substitutions in 3 additional types are reported here. Albumin Varese has a substitution, -2 arginine to histidine (-2 Arg----His), the same as that reported for proalbumin Lille; albumin Torino has the substitution 60 Glu----Lys; and albumin Vibo Valentia has the substitution 82 Glu----Lys. The ability to distinguish so many alloalbumin types by electrophoresis at several pH values indicates that similar substitutions at different sites produce variants with different electrophoretic mobilities. Except for chain terminations in two Italian variants, all the mutations thus far determined for alloalbumins are attributable to a single-base change in the structural gene, and there is a preponderance of transitions and purine mutations. Seven alloalbumins for which the structural change has been established have been ascertained only in Italy. Several of these are clustered in specific geographic regions of Italy, which suggests an origin through a founder individual. Other variants that occur worldwide are nonetheless clustered in geographic regions within Italy. In these cases an independent mutation probably occurred at a hypermutable site such as a CpG dinucleotide.

Interaction with Both Domain I and III of Albumin Is Required for Optimal pH-dependent Binding to the Neonatal Fc Receptor (FcRn)

“…Furthermore, we were intrigued by the fact that two rare naturally occurring HSA variants exist with single amino acid substitutions within the DI loops (38,39). We expressed these as recombinant molecules and demonstrated that they bound with reduced FcRn affinity.…”

“…Two of these are missense mutants in which a single nucleotide change resulted in an amino acid substitution within the Dl loops; one in loop I (Vibo Valentia, E82K), and one in loop II (Yanomama-2, R114G) (38,39). We produced these two variants as recombinant GST-fusions that migrated with a profile similar to WT HSA (Fig.…”

A nucleotide insertion and frameshift cause analbuminemia in an Italian family.

“…Nor has it been reported in Sweden, where about one million electrophoretic analyses have been made (Carl-Bertil Laurell, personal communication). The paradox is that the albumin gene is subject to many neutral mutations (11)(12)(13)(14)(15)(16)); yet, analbuminemia, though tolerable, is extremely rare. It has been postulated (17) that the presence of albumin may be critical in fetal life and only a few analbuminemic individuals survive past the neonatal state; this could explain why analbuminemia is so rare in adults.…”

Structural Characterization of Four Genetic Variants of Human Serum Albumin Associated with Alloalbuminemia in Italy

“…In addition, four cases of unrelated subjects with analbuminemia have been found. Our laboratories have previously identified the molecular defect in 19 of the 28 variants and in two cases of analbuminemia [3,4,[6][7][8][9][10][11][12][13][14]. Here we report the structural characterization of four Italian alloalbumins, albumins Tregasio, Bergamo, Maddaloni, and Besana Brianza.…”