Point substitutions in albumin genetic variants from Asia.

Abstract

Despite their rarity and physiologically neutral character, more inherited structural variants of serum albumin (alloalbumins) are known than for any other human protein except hemoglobin. Including three previously unreported examples described here, we have identified 13 different point substitutions in alloalbumins of Japanese origin. Of these only albumin B and two proalbumins have been reported in other ethnic groups, and these are the most common variants of European origin. Some alloalbumins of Asiatic origin, but not yet identified in Japanese, are present in diverse ethnic groups. An alloalbumin found in indigenes of New Guinea (lysine -* asparagine at position 313) is also present in Caucasians of various European descents. Albumin Lambadi, occurring in a tribal group in south India, has a mutation (glutamic acid -* lysine at position 501) also found as a rare variant in individuals of diverse ethnic origin resident on four continents. These results suggest that some alloalbumins with the same substitution may have originated by independent mutations in various populations. This, together with the apparent clustering of point substitutions in the protein structure, may reflect hypermutability of the albumin gene.Because of recent studies (1-17) more heritable structural variants of serum albumin (alloalbumins) are known than for any other human protein except hemoglobin. However, unlike the situation with hemoglobin variants, no adverse effect on molecular function has been attributed to alloalbumins. Alloalbuminemia is rare and has a cumulative frequency of only 1:3000 to 1:10,000 in most populations (18-25); thus, it is usually expressed in a heterozygous fashion. More than 100 alloalbumins that have been given geographical or tribal names have been identified by genetic screening (18)(19)(20), by blood donor surveys (21), or by clinical electrophoresis (22, 23), and at least 20 different sites of structural change have been determined (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Four types of alloalbumins have been identified: (i) a series of single-point mutants (1-7, 12-14, 16), (ii) several chain-termination mutants (10, 11), (iii) proalbumins (variants that retain a basic amino-terminal hexapeptide because of a mutation in the Arg-Arg propeptide sequence required for post-transcriptional processing) (8,15), and (iv) arginyl-albumin, a variant that begins with arginine followed by a polypeptide sequence of the usual length (585 amino acid residues) (ref. 17; C. B. Laurell and F.W.P., unpublished results).Recently we have undertaken a series of collaborative studies on alloalbumins from populations throughout the world (1-3, 5, 6). Our objectives have been to determine the structural changes and to correlate these with the molecular properties ofalbumin and with such genetic characteristics as the site and type of mutation, heritability, and frequency. In this paper we report structural studies on alloalbumins from eight unrelated Japanese residents of Japan or Hawaii and a...

Hypermutability of CpG dinucleotides in the propeptide-encoding sequence of the human albumin gene.

“…Many rare genetic variants of human serum albumin (alloalbumins) have recently been studied because of interest in their population distribution, site of mutation, and structural change (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Three types of alloalbumins have been identified: (i) more than 20 different point mutants that have a single substitution in the mature processed albumin molecule, which contains 585 amino acid residues (for a list with references see ref.…”

cDNA and protein sequence of polymorphic macaque albumins that differ in bilirubin binding.

“…It is a paradox that although analbuminemia is extremely rare but apparently tolerable (1,11), genetic variants of albumin (alloalbumins) are also extremely rare in humans and other species (11)(12)(13)(14)(15)(16)(17). More than 40 different human alloalbumins have been identified by protein or DNA sequence analysis, many of them in our laboratory (11)(12)(13)(14)(15)(16)(17); however, their cumulative frequency worldwide is only of the order of 1 in 3000.…”

“…More than 40 different human alloalbumins have been identified by protein or DNA sequence analysis, many of them in our laboratory (11)(12)(13)(14)(15)(16)(17); however, their cumulative frequency worldwide is only of the order of 1 in 3000. Occasional reports of albumin polymorphism in domestic animals that are based on electrophoretic analysis have appeared, but none of these has apparently been substantiated by structural study.…”

“…The albumin of each phenotype was purified by HPLC on a preparative DEAE-5-PW column (21.5 x 150 mm; Bio-Rad) with use of a 20 mM sodium acetate buffer with a pH gradient from 5.2 to 4.0 at a flow rate of 5.0 ml/min for 40 min (14)(15)(16). The general strategy for protein structural study of the purified macaque albumins was similar to that described for human alloalbumins (12)(13)(14)(15)(16)(17). However, because the amino acid sequence of the macaque albumin and its methionine content were unknown, purification and sequence analysis of the CNBr fragments of each phenotype was required to identify them by homology to human albumin.…”

“…However, because the amino acid sequence of the macaque albumin and its methionine content were unknown, purification and sequence analysis of the CNBr fragments of each phenotype was required to identify them by homology to human albumin. The general procedure consisted of (i) analytical isoelectric focusing of a CNBr digest of reduced and carboxymethylated albumin to identify the CNBr fragments and to ascertain which differed for the two phenotypes, (ii) purification of all CNBr fragments by size-exclusion and reversedphase HPLC (12)(13)(14)(15), (iii) HPLC peptide mapping of Staphylococcus aureus V8 protease or lysyl endopeptidase digests of the purified CNBr fragment, and (iv) automated sequence determination of the CNBr fragments and ofpeptides purified from the enzymatic digests (14)(15)(16). Contrary to our previous experience (12,15), the V8 protease was not specific for glutamic residues and gave unexpected cleavage after glycine and alanine residues.…”