HGNC Approved Gene Symbol: ALB
SNOMEDCT: 237547004;
Cytogenetic location: 4q13.3 Genomic coordinates (GRCh38): 4:73,404,287-73,421,482 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q13.3 | ?[Dysalbuminemic hypertriiodothyroninemia] | 615999 | Autosomal dominant; Autosomal recessive | 3 |
| [Dysalbuminemic hyperthyroxinemia] | 615999 | Autosomal dominant; Autosomal recessive | 3 | |
| Analbuminemia | 616000 | Autosomal recessive | 3 |
Albumin is the major protein of the blood plasma, amounting to 60 to 65% of its total protein. The principal functions of albumin are to support the oncotic pressure, which aids in keeping the blood within the circulation, and to sequester and transport many metabolites within the body, particularly less soluble, hydrophobic ones. It is also an important circulating antioxidant and possesses enzymatic properties (summary by Minchiotti et al., 2008).
Albumin is a globular unglycosylated serum protein of molecular weight 65,000 Da. The albumin variant first described by Fraser et al. (1959) in a Welsh family was characterized as a dimer by Jamieson and Ganguly (1969). The amino acid sequence has been determined in fragments of serum albumin of man (Dayhoff, 1972).
Albumin is synthesized in the liver as preproalbumin, which has an N-terminal peptide that is removed before the nascent protein is released from the rough endoplasmic reticulum. The product, proalbumin, is in turn cleaved in the Golgi vesicles to give the secreted albumin (summary by Brennan and Carrell, 1978).
Weitkamp et al. (1966) concluded that the albumin locus (ALB) is closely linked with the GC locus (139200). Using the Naskapi variant, Kaarsalo et al. (1967) found close linkage of the ALB and GC loci.
Harper and Dugaiczyk (1983) mapped the albumin gene to chromosome 4 by in situ hybridization. Dextran sulfate was used to enhance labeling, and their technique permitted G-banding of the chromosomes with Wright's stain on the same preparations used for autoradiography without pretreatment. The regional localization (to 4q11-q13) agreed remarkably with that arrived at by indirect methods. Kao et al. (1982) assigned the albumin locus to chromosome 4 by use of a human albumin cDNA probe in human/Chinese hamster somatic cell hybrids. The ALB and alpha-fetoprotein (AFP; 104150) genes are within 50 kb of each other (Urano et al., 1984) and show strong linkage disequilibrium (Murray et al., 1984).
Magenis et al. (1989) used in situ hybridization to localize the ALB and AFP genes to orangutan chromosome 3q11-q15 and gorilla chromosome 3q11-q12 which are considered homologous to 4q11-q13.
As reviewed by Shibata and Abe (1996), vitamin D-binding protein (GC) and serum protease inhibitor are linked not only in humans, but also in horse, cattle, and sheep in mammals, and chicken in avian species. They added the Japanese quail to the group.
The characteristic 3-domain structure of albumin and alpha-fetoprotein has been conserved throughout mammalian evolution. Thus, 35.2% amino acid homology is found between bovine serum albumin and murine AFP. Ohno (1981) addressed the vexing question of why this conservation occurs despite the nonessential nature of serum albumin as indicated by cases of analbuminemia. Minghetti et al. (1985) found a high rate of both silent substitutions and effective substitutions with amino acid changes in serum albumin. Although the rates of effective substitution in amino acid changes were not as high in albumin as in alpha-fetoprotein, they were still faster than those of either hemoglobin or cytochrome c. This high evolutionary change rate for albumin may be consistent with the fact that inherited analbuminemia produces surprisingly few symptoms despite the virtually complete absence of albumin.
Minghetti et al. (1986) found that the human albumin gene is 16,961 nucleotides long from the putative 'cap' site to the first poly(A) addition site. It is split into 15 exons which are symmetrically placed within the 3 domains that are thought to have arisen by triplication of a single primordial domain.
Pinkert et al. (1987) used transgenic mice to locate a cis-acting DNA element, an enhancer, important for efficient, tissue-specific expression of the mouse albumin gene in the adult. Chimeric genes with up to 12 kb of mouse albumin 5-prime flanking region fused to a human growth hormone 'reporter' gene were tested. Whereas a region located 8.5 to 10.4 kb upstream of the albumin promoter was essential for high-level expression in adult liver, the region between -8.5 and 0.3 kb was dispensable.
Wandzioch and Zaret (2009) investigated how bone morphogenetic protein (BMP4; 112262), transforming growth factor-beta (TGF-beta; 190180), and fibroblast growth factor signaling pathways converge on the earliest genes, among them ALB1, that elicit pancreas and liver induction in mouse embryos. The inductive network was found to be dynamic; it changed within hours. Different signals functioned in parallel to induce different early genes, and 2 permutations of signals induced liver progenitor domains, which revealed flexibility in cell programming. Also, the specification of pancreas and liver progenitors was restricted by the TGF-beta pathway.
Bisalbuminemia or Alloalbuminemia
On 2-dimensional electrophoresis (paper first, followed by starch), Fraser et al. (1959) found an anomalous plasma protein in 6 persons in 2 generations of a family. The electrophoretic properties on paper were the same in the anomalous albumin and in normal albumin. This distinguishes the protein from that in bisalbuminemia, as does the fact that the amount of the anomalous protein is much less than that of the normal albumin in presumably heterozygous persons. That the same locus as that which determines bisalbuminemia is involved here is suggested by the finding of Weitkamp et al. (1967) that the Fraser anomalous albumin is also linked to the GC locus.
Bisalbuminemia is an asymptomatic variation in serum albumin. Heterozygotes have 2 species of albumin, a normal type and one that migrates abnormally rapidly or slowly on electrophoresis. Acrocyanosis was present in 2 and probably 3 successive generations of the family reported by Williams and Martin (1960) but 4 other bisalbuminemic persons did not show acrocyanosis.
The term 'paralbuminemia' was suggested by Earle et al. (1959) as preferable to 'bisalbuminemia' because it was unclear whether the anomalous albumin fractions were chemically identical in the unrelated families reported with 'double albumin.'
Tarnoky and Lestas (1964) described a 'new' type of bisalbuminemia in 2 sibs and the son of one of them. The usual type was demonstrable by filter paper electrophoresis. The new type was demonstrable by electrophoresis on cellulose acetate at pH 8.6, but not on filter paper or starch gel.
Blumberg et al. (1968) suggested the term 'alloalbuminemia' for the condition in which an individual has an albumin variant different from the common albumin (albumin A). Various alloalbuminemias occur relatively frequently in various American Indians (Arends et al., 1969). Melartin and Blumberg (1966) found an electrophoretic variant of albumin in high frequency in Naskapi Indians of Quebec and in lower frequency in other North American Indians. Homozygotes were found.
Using 2 electrophoretic systems, Weitkamp et al. (1967) compared the serum albumin variants of 19 unrelated families. Five distinct classes were found. One class of variants was found only in North American Indians. The others were found only in persons of European descent.
By 1980, at least 2 dozen electrophoretic variants of serum albumin had been reported, but only 2 of them had been characterized with respect to their primary structure: albumin A (the common form) and albumin B (the variant found mainly in Europeans) (summary by Franklin et al., 1980).
In Punjab, North India, Kaur et al. (1982) found, by electrophoresis, 4 cases of alloalbuminemia among 550 persons. Two appeared to be new variants. Another was albumin Naskapi. Since this variant has been found also in North American Indians and Eti Turks, the authors suggested that albumin Naskapi existed in a common ancestral population before the migrations eastward and westward.
Rochu and Fine (1986) described a new method for identifying genetic variants of human proalbumin. Two genetic variants of proalbumin, proalbumin Christchurch (Brennan and Carrell, 1978) and proalbumin Lille (Abdo et al., 1981), have been shown to result from a substitution at 1 of the 2 arginyl residues at the dibasic site at which the normal propeptide is cleaved. Both of these mutations prevent excision of this basic propeptide, and thus each of these proalbumin variants has a slower electrophoretic mobility than that of normal albumin. Two genetic variants, previously described as albumin Gainesville and albumin Pollibauer, were shown to be identical with proalbumin Christchurch (Fine et al., 1983) and proalbumin Lille (Galliano et al., 1984), respectively.
In describing a new human albumin variant, albumin Carlisle, Hutchinson et al. (1986) stated that more than 80 genetically inherited variants of human albumin were known. Fine et al. (1987) found a frequency of alloalbuminemia in the French population of 0.0004. There was a high occurrence of albumin B and of 2 proalbumin variants, Christchurch and Lille.
Takahashi et al. (1987) identified the amino acid substitutions in 3 different types of proalbumins designated Gainesville, Taipei, and Takefu. The first 2 proalbumins were found to be identical to previously described proalbumins, Christchurch and Lille types, respectively. All of the variant proalbumins contain a basic propeptide that is not removed during posttranscriptional processing because of a mutation in the site of excision, an arg-arg sequence. Takefu resists tryptic cleavage because of the substitution of proline for arginine at the -1 position. The substitution of glutamine for histidine at position 3 in the variant albumin Nagasaki-3 decreases metal-binding affinity; mutations farther down the polypeptide chain do not affect metal-binding affinity, nor is there any reduction of copper-binding affinity in albumin from patients with Wilson disease (277900). The variant proalbumins show a characteristically lowered metal-binding affinity.
Takahashi et al. (1987) reported the amino acid substitution in 4 albumin variants detected by 1-dimensional electrophoresis in population surveys involving tribal Amerindians and Japanese children. Albumin Maku, discovered in a Maku Indian woman living among the Yanomama, showed a substitution of glutamine for lysine at position 541. Albumin Yanomama-2 appears to represent a true private polymorphism, i.e., it is the product of an apparently unique allele within a single tribe that has a frequency well above the 1% allele minimum for a polymorphism. It has been found only in Yanomama Indians, was present in 491 of 3,504 persons studied, and had the highest frequency of any polypeptide variant identified in 21 South American Indian tribes. It was found to have a substitution of glycine for arginine at position 114. This appears to represent a change from codon CGA to GGA. Albumin Nagasaki-2 showed a substitution of asparagine for aspartic acid at position 375, corresponding to a single base change in codon GAT to AAT. Albumin Nagasaki-3 was found to have substitution of glutamine for histidine at position 3, corresponding with a 1-base change in the codon CAC to either CAA or CAG.
Takahashi et al. (1987) pointed out that about one-half of the known mutations in the coding sections in the large albumin gene border an exonic junction, raising the possibility that hypermutable 'hot spots' may be clustered there. In Japan, surveys showed that hemoglobin and albumin variants were of roughly equal frequency and neither protein appeared exceptionally variable. Since albumin is a much larger protein, one might expect more genetic variability than in hemoglobin. This might suggest that selection is relatively active against variants of this molecule; yet total absence of this protein (analbuminemia) is consistent with apparently satisfactory health.
Takahashi et al. (1987) tabulated the 13 amino acid substitutions identified at that time and pointed out that they are unequally distributed throughout the polypeptide chain. The slower delineation of the nature of point mutations in albumin variants as compared to hemoglobin variants can be attributed to 2 primary factors: first, alloalbumins are not associated with disease or a significant effect on physiologic function, and most are rare; second, the albumin molecule consists of a single polypeptide chain with 585 amino acids and 17 disulfide bridges, a circumstance that magnifies the difficulty of determining the presence of a single substitution.
Arai et al. (1989) found that the 2 types of proalbumins most common in Europe (Lille type, arginine-to-histidine at position -2; Christchurch type, arginine-to-glutamic acid at position -1) also occur in Japan. The clustering of these and of several other amino acid exchanges in certain regions of the albumin molecule, arising as independent mutations, suggests that certain sites are hypermutable and/or that mutants involving certain sites are more subject to selection than mutants involving others.
In a study of 15,581 unrelated children in Hiroshima and Nagasaki, Arai et al. (1989) found 5 rare albumin variants and determined the single amino acid substitution in each. All of these were inherited and therefore unrelated to parental exposure at the time of the bombing. The 5 substitutions were: Nag-1, asp269-to-gly; Nag-2, asp375-to-asn; Nag-3, his3-to-gln; Hir-1, glu354-to-lys; and Hir-2, glu382-to-lys. Two of the substitutions (Nag-1 and Nag-2) had previously been reported (Takahashi et al., 1987). No instances of proalbumin variants or of albumin B (glu570-to-lys), which are the most common Caucasian alloalbumins, were found in the Hiroshima-Nagasaki study. Arai et al. (1989) found 2 instances of albumin B and 1 example of a variant proalbumin in Japanese from the vicinity of Tokyo. In a review of all reported mutations, Arai et al. (1989) noted that 7 independent substitution sites have been identified in the alloalbumins of diverse populations in a sequence of only 29 amino acids as compared to a total of 5 sites (excluding proalbumin variants) reported thus far for the first 353 amino acids. Such a cluster of substitutions may reflect vulnerability of the albumin gene to mutation in this region or the ease of accommodation to structural changes in the affected area of the protein. Arai et al. (1990) studied the albumin genetic variants that have been reported in Asian populations and listed a total of 26 point substitutions in diverse ethnic groups.
Madison et al. (1994) provided a tabulation of the molecular changes in albumin variants. Asymptomatic increases in the concentration of zinc in the blood, hyperzincemia (194470), may be due to a variant structure of albumin with consequent increased binding of zinc. If true, this would be dysalbuminemic hyperzincemia by a mechanism similar to that involved in dysalbuminemic hyperthyroxinemia.
Minchiotti et al. (2008) provided a detailed review of variants in the albumin gene and noted that variants are generally benign. Even the rare condition analbuminemia, which causes edema and hyperlipidemia, does not appear to be life-threatening. The majority of mutations are detected upon clinical electrophoretic studies.
Acquired Bisalbuminemia
A phenocopy of hereditary bisalbuminemia, acquired bisalbuminemia, occurs with overdose of beta-lactam antibiotics (Arvan et al., 1968) and with pancreatic pseudocyst associated with pleural or ascitic effusion (Shashaty and Atamer, 1972). The anomalous albumin is anodal to the normal albumin in its electrophoretic mobility. Vaysse et al. (1981) described acquired trisalbuminemia in a patient with familial bisalbuminemia and pancreatic pseudocyst.
Analbuminemia
In a Native American girl with analbuminemia (ANALBA; 616000), Ruffner and Dugaiczyk (1988) identified a homozygous splice site mutation in the albumin gene (103600.0027).
In an Italian woman with analbuminemia, Watkins et al. (1994) identified a homozygous mutation in the albumin gene (c.9156dupA; 103600.0040). In 3 other patients with analbuminemia, an Italian man reported by Di Guardo et al. (1977), an American woman (patient G.M.) reported by Gordon et al. (1959), and a Canadian neonate reported by Cormode et al. (1975), Watkins et al. (1994) identified homozygous mutations in the ALB gene (103600.0059, 103600.0060, and 103600.0061, respectively).
In a male newborn of Iraqi extraction with analbuminemia, Campagnoli et al. (2002) identified a homozygous splice site mutation in the ALB gene (103600.0057).
In 2 sibs, born to consanguineous Algerian parents, with analbuminemia, Caridi et al. (2019) identified a homozygous frameshift mutation in the ALB gene (c.1098dupT; 103600.0058).
Familial Dysalbuminemic Hyperthyroxinemia
In 2 unrelated patients with dysalbuminemic hyperthyroxinemia (615999), Petersen et al. (1994) identified a heterozygous mutation in the ALB gene (R218H; 103600.0041). During the preparation of the manuscript, a third patient with the same mutation was found, suggesting that R218H may be a frequent cause of this disorder.
Sunthornthepvarakul et al. (1994) identified the R218H mutation in affected members of 8 unrelated families with dysalbuminemic hyperthyroxinemia.
Wada et al. (1997) documented 6 members of a Japanese family with the FDH phenotype. All were heterozygous for a missense mutation in the ALB gene (R218P; 103600.0055). Wada et al. (1997) proposed the existence of a distinct ethnic phenotype of FDH characterized by extremely elevated serum total T4 levels and relatively elevated serum total T3 and rT3 levels in the Japanese.
Petitpas et al. (2003) characterized the structure of the interaction between thyroxine and albumin. Using crystallographic analyses, they identified 4 binding sites for thyroxine on albumin distributed in subdomains IIA, IIIA, and IIIB. Mutations of arg218 within subdomain IIA--i.e., arg218 to his (R218H; 103600.0041) and arg218 to pro (R218P; 103600.0055)--greatly enhanced the affinity for thyroxine and caused the elevated serum thyroxine levels associated with FDH. Structural analyses of these 2 mutants showed that this effect arises because substitution of arg218, which contacts the hormone bound in subdomain IIA, produces localized conformational changes to relax steric restrictions on thyroxine binding at this site. Petitpas et al. (2003) also found that, although fatty acid binding competes with thyroxine at all 4 sites, it induces conformational changes that create a fifth hormone-binding site in the cleft between domains I and III, at least 9 angstroms from arg218. These structural observations were consistent with binding data showing that albumin retains a high-affinity site for thyroxine in the presence of excess fatty acid that is insensitive to FDH mutations.
Familial Dysalbuminemic Hypertriiodothyroninemia
In a Thai family that presented with high serum total T3 but not T4 when measured by radioimmunoassay, Sunthornthepvarakul et al. (1998) identified a heterozygous missense mutation in the ALB gene (L66P; 103600.0056). The authors called the disorder familial dysalbuminemic hypertriiodothyroninemia (see 615999).
Substitution of histidine for arginine at position -2 was found in albumin Lille by Abdo et al. (1981) and Galliano et al. (1988), in albumin Fukuoka-2 by Arai et al. (1989), in albumin Taipei by Takahashi et al. (1987), and in albumin Varese by Galliano et al. (1990). A CGT-to-CAT change is responsible for the substitution.
Proalbumin Christchurch has also been called proalbumin Gainesville, proalbumin Fukuoka-3, and albumin Honolulu-2.
This albumin has an arg(-1)-to-gln change in the preproprotein (Arai et al., 1990; Brennan and Carrell, 1978). Brennan and Carrell (1978) found a family with a circulating variant of proalbumin in members of 4 generations. No clinical abnormality was discernible in any of them. The variant represents 50% of total albumin and shows an additional N-terminal sequence, arg-gly-val-phe-arg-gln. Called 'proalbumin Christchurch,' the variant appears to have a mutation of arginine to glutamine at the last amino acid of this sequence. Thus, 2 basic amino acids must be necessary for cleavage of proalbumin in the Golgi vesicles. Copper binding is expected to be absent in the variant albumin because of blocking of the high affinity binding site. This is a situation comparable to Ehlers-Danlos syndrome type VII-A (130060) in which an amino acid substitution at the site of cleavage of procollagen results in persistence of procollagen and, in that case, clinically important abnormalities in collagen fiber formation.
Proalbumin Takefu has also been called albumin Honolulu-1. Substitution of proline for arginine at position -1 (Takahashi et al., 1987).
This variant has also been called albumin Honolulu-1.
Albumin Blenheim has also been called albumin Bremen and Albumin Iowa City-2. See Arai et al. (1990) and Brennan et al. (1990). Brennan et al. (1990) suggested that hypermutability of 2 CpG dinucleotides in the codons for the diarginyl sequence may account for the frequency of mutations in the propeptide. Madison et al. (1991) showed that this mutation is caused by a GAT-to-GTT change.
See Takahashi et al. (1987).
See Takahashi et al. (1987).
See Arai et al. (1990).
This variant has also been called albumin Nagasaki-1. See Arai et al. (1989).
This variant has also been called albumin New Guinea and albumin Cooperstown. Huss et al. (1988) described an electrophoretically fast alloalbumin in a family in New York State and called it albumin Cooperstown. It was found to have a substitution of asparagine for lysine at residue 313 and was shown to be the same as albumins found in Italy and in New Zealand. A change from AAG to AAY is responsible for the substitution; Y = either T or C. Galliano et al. (1990) found this albumin variant in 49 individuals in the Abruzzo region of Italy.
Brennan et al. (1990) characterized albumin Redhill, an albumin variant that does not bind nickel and has a molecular mass 2.5 kD higher than normal albumin. Its inability to bind nickel was explained by the finding of an additional residue of arginine at position -1 of the mature protein, but this did not explain the molecular basis of the increase in apparent molecular mass. Further studies showed an ala320-to-thr change, which introduced an asn-tyr-thr oligosaccharide attachment sequence centered at asn318 and explained the increase in molecular mass. DNA sequencing of PCR-amplified genomic DNA encoding the prepro sequence of albumin indicated an additional mutation at position -2 from arg to cys. Brennan et al. (1990) proposed that the new phe-cys-arg sequence (replacing -phe-arg-arg-) in the propeptide serves as an aberrant signal peptidase cleavage site and that the signal peptidase cleaves the propeptide of albumin Redhill in the lumen of the endoplasmic reticulum before it reaches the Golgi vesicles, which is the site of the diarginyl-specific proalbumin convertase. Thus, albumin Redhill is longer than normal by 1 amino acid at its NH2-terminus. The ARG-2CYS mutation is the basis of proalbumin Malmo (103600.0030), a relatively frequent variant.
Galliano et al. (1988) demonstrated that albumin Roma has a substitution of lysine for glutamic acid at position 321. A GAG-to-AAG change is responsible for the substitution. Galliano et al. (1990) found this albumin variant in 25 individuals from various parts of Italy.
See Arai et al. (1989).
Arai et al. (1989) reported on amino acid substitutions in albumin variants found in Brazil. A previously unreported amino acid substitution was found in albumins Coari I and Porto Alegre I (glu358-to-lys).
See Brennan (1985).
Franklin et al. (1980) demonstrated apparent identity between the polymorphic albumin variants Naskapi, found chiefly in the Naskapi Indians of Quebec, and Mersin, found in the Eti Turks of southeastern Turkey. They suggested that these were derived from the same mutation occurring in Asia and spreading with the progenitors of the American Indians to the North American continent and with Asiatic invaders to Asia Minor. Takahashi et al. (1987) found that lysine-372 of normal (common) albumin A was changed to glutamic acid both in albumin Naskapi and in albumin Mersin. Identity of these albumins may have originated through descent from a common mid-Asiatic founder of the 2 migrating ethnic groups, or it may represent identical but independent mutations of the albumin gene. This variant has also been called albumin Mexico-1.
See Takahashi et al. (1987) and Arai et al. (1989).
See Arai et al. (1989).
See Arai et al. (1989).
Franklin et al. (1980) found a new variant in Eti Turks, which they termed albumin Adana. By improved methods, Huss et al. (1988) identified a substitution of lysine for glutamic acid at position 501 in albumins Vancouver and Birmingham, both from families that migrated from northern India, and also in albumin Adana from Turkey. This is the first substitution reported in an alloalbumin originating from the Indian subcontinent. Albumin Porto Alegre II also contains a glutamic acid-to-lysine substitution at position 501. This variant has also been called albumin Lambadi and albumin Manaus-1.
See Takahashi et al. (1987). The substitution in albumin Oriximina I is the same as that found in albumin Maku (lysine to glutamic acid at position 541) (Arai et al., 1989). This variant has also been called albumin Maku(Wapishana).
Franklin et al. (1980) showed that albumin Mexico is in fact 2 separate, electrophoretically similar variants and that albumin Mexico-2 contains a substitution of glycine for aspartic acid at position 550. Substitution of aspartic acid-550 by glycine was found in albumin Mexico-2 from 4 persons of the Pima tribe (Takahashi et al., 1987).
See Arai et al. (1990).
See Arai et al. (1990).
Albumin B has also been called albumin Oliphant, albumin Phnom Penh, albumin Nagano, albumin Osaka-2, and albumin Verona B.
Arai et al. (1989) identified the amino acid substitution characteristic of albumin B (glutamic acid-to-lysine at position 570) in alloalbumins from 6 unrelated persons of 5 different European descents and also in 2 Japanese and 1 Cambodian. A GAG-to-AAG change is responsible for this substitution. Galliano et al. (1990) found this variant in 103 individuals in the Veneto area of Italy.
This variant has also been called albumin Ghent. An AAA-to-GAA change is responsible for this substitution. Galliano et al. (1990) found this variant in 80 individuals from the Lombardy area of Italy. Homozygotes have been identified.
See Galliano et al. (1988).
Ruffner and Dugaiczyk (1988) identified a structural defect in the serum albumin gene in a Native American girl with analbuminemia (ANALBA; 616000). Sequence determination of 1.1 kb of the 5-prime regulatory region and of 6 kb across exonic regions revealed a single AG-to-GG mutation within the 3-prime splice site of intron 6 in the defective gene of the analbuminemic person. In an in vitro assay on the RNA transcript, this mutation caused a defect in out-splicing of the intron 6 sequence and in the subsequent ligation of the exon 6/exon 7 sequences. Using polymerase-amplified genomic DNA and allele-specific oligodeoxynucleotide probes, Ruffner and Dugaiczyk (1988) also showed that the sequence of this intron 6/exon 7 splice junction was normal in a different, unrelated analbuminemic person.
Minchiotti et al. (1989) described the molecular defect of an electrophoretically fast alloalbumin named Venezia, found in about 90 seemingly unrelated families in Italy, mainly in the Veneto region. In heterozygous subjects the total albumin content was in the normal range, with the variant accounting for about 30% of the total protein. Reduced stability of the mutant was thought to account for the lower-than-expected percentage. Minchiotti et al. (1989) found that albumin Venezia possesses a shortened polypeptide chain, 578 residues instead of 585, completely variant from residue 572 to the COOH-terminus: 572 pro-thr-met-arg-ile-arg-578 glu. This extensive modification can be accounted for by deletion of exon 14 and translation to the first terminator codon of exon 15, which normally does not code for protein. The absence of a basic COOH-terminal dipeptide in the mature molecule can be explained by the probable action of serum carboxypeptidase N. The low serum level of the variant in heterozygous subjects suggests that the carboxy-terminus of the molecule is critical for albumin stability. Galliano et al. (1990) found this variant in 105 individuals, particularly in the region of Veneto in Italy.
An AAG-to-GAG change is responsible for this substitution. Galliano et al. (1990) found this variant in 1 individual in Italy.
In a collaborative effort involving laboratories at Malmo, Sweden; Bloomington, Indiana; Christchurch, New Zealand; Saitama, Japan; and Pavia, Italy, Brennan et al. (1990) studied the most common Swedish albumin variant, which is expressed in plasma as a broadened electrophoretic band indicative of a slow component at pH 8.6. Present in about 1 per 1,000 persons in Sweden, it was also found in a family of Scottish descent from Kaikoura, New Zealand, and in 5 families in Tradate, Italy. The major variant component was found to be arginyl-albumin, in which arginine at the -1 position of the propeptide is still attached to the processed albumin. A minor component with the amino-terminal sequence of proalbumin was also present as 3 to 6% of the total albumin. The mutation was found to involve a change of arginine to cysteine at the -2 position. (In albumin Redhill (103600.0010), the Malmo mutation is combined with another.) A CGT-to-TGT change is responsible for the substitution. This variant has also been called albumin Tradate.
In a note added in proof, Brennan et al. (1990) stated that because of the similarity of the electrophoretic pattern of an anomalous albumin reported in a family by Laurell and Nilehn (1966), they obtained the plasma from one of the original subjects from that family and determined that it was the same as albumin Malmo.
In 2 members of a Tamil family from Jaffna (northern Sri Lanka), Galliano et al. (1989) found an electrophoretically slow-moving variant of serum albumin. Sequence analysis demonstrated that the variant is an abnormal proalbumin arising from a substitution of leucine for arginine at position -1, which prevents the proteolytic removal of the N-terminal hexapeptide and allows the mutated proalbumin to enter the circulation.
This variant has also been called albumin GE/CT.
This was the fourth albumin variant to be characterized structurally. Galliano et al. (1986) found a shortened chain with deletion of a cytosine in codon 580, causing frameshift and termination after amino acid 582. The COOH-terminal sequence is leu-val-ala-ala-ser-lys-leu-pro. Galliano et al. (1990) found this mutation in 62 individuals in Sicily.
Galliano et al. (1990) found a substitution of lysine for glutamic acid at position 60 resulting from a GAA-to-AAA change in a single Italian patient.
In 2 Italian individuals Galliano et al. (1990) found a GAA-to-AAA change in codon 82 leading to substitution of lysine for glutamic acid.
In albumin Casebrook, an electrophoretically slow albumin variant with a relative molecular mass of 2.5 kD higher than normal albumin, Peach and Brennan (1991) identified substitution of asparagine for aspartic acid-494. The mutation introduced an asn-glu-thr N-linked oligosaccharide attachment sequence centered on asn494, which explained the increase in molecular mass. The mutant albumin was associated with no apparent pathology and was detected in 2 unrelated individuals of Anglo-Saxon descent.
In a survey of alloalbumins in patients at 2 major medical centers in the United States and nearly 20,000 blood donors in Japan, Madison et al. (1991) identified 2 previously unreported alloalbumin types. In one type, found in a Caucasian family and designated Iowa City-1, aspartic acid at position 365 was replaced by valine. This was the second reported mutation at position 365; see albumin Parklands (103600.0014). The codon change was GAT-to-GTT. In the second type, found in a Japanese blood donor, histidine-128 was replaced by arginine (103600.0037). The codon change was CAT-to-CGT.
See 103600.0036.
Peach et al. (1992) found that 3 members of a family were heterozygous for an electrophoretically fast albumin variant, designated albumin Rugby Park, which constituted only 8% of total serum albumin. Isoelectric focusing indicated an increased negative charge on the C-terminal CNBr peptide. Sequencing of PCR-amplified DNA indicated a G-to-C transversion at position 1 of the intron 13. The replacement of the obligate GT sequence by CT at the exon/intron boundary prevented splicing of intron 13, and translation continued for 21 nucleotides until a stop codon was reached. The new protein lacked the 14 amino acids encoded in exon 14, but these were replaced by 7 new residues, giving a truncated albumin of 578 residues.
Minchiotti et al. (1993) found that albumin Herborn, a variant discovered in Germany, had a point mutation in codon 240 changing AAA (lys) to GAA (glu). The mutation was in the region implicated in bilirubin binding, but Minchiotti et al. (1993) found that the binding of bilirubin and biliverdin to albumin Herborn was not significantly reduced.
Watkins et al. (1994) investigated analbuminemia (ANALBA; 616000) in an Italian family by analysis of DNA from a mother and her daughter. The mother, whose parents were first cousins, was homozygous for the trait and had a serum albumin value of less than 0.01 g/dl (about 1/500 normal); the daughter was heterozygous for the trait and had a nearly normal albumin value. Molecular cloning and sequence analysis showed that the mutation, called analbuminemia Roma, was a nucleotide insertion in exon 8, producing a frameshift that led to a premature stop 7 codons downstream. Watkins et al. (1994) used heteroduplex hybridization and single-strand conformation polymorphism to compare the DNA of these 2 individuals with the DNA of 2 unrelated analbuminemic persons, 1 Italian (103600.0059) and 1 American (patient G.M.; 103600.0060) and showed that each patient had a different mutation. These mutations also differed from the mutation identified in a Native American (103600.0027). Whereas the normal serum albumin gene has 4 A residues as nucleotides 9156-9159, the Roma allele had 5 A residues encompassing 9156-9160. The predicted translation product from the Roma allele would consist of only 273 amino acids instead of the normal 585 amino acid residues found in mature serum albumin. The insertion of the additional adenine changed codon 267 from AAT (asn) to AAA (lys) and changed the reading frame in such a way that codon 274 was changed from AAA (lys) to TAA (stop).
In 2 unrelated patients with dysalbuminemic hyperthyroxinemia (FDAH; 615999), Petersen et al. (1994) identified an arg218-to-his substitution that was caused by a G (CGC)-to-A (CAG) transition at nucleotide 653 in the ALB gene. Abnormal affinity of the albumin from these patients for a thyroxine analog was verified by an adaptation of the procedure used in routine free T4 measurement. Both subjects were heterozygous. During the preparation of the manuscript, a third patient with the same mutation was found, suggesting that R218H may be the most frequent cause of this disorder. The mutation created a new HphI restriction site in exon 7, which was used diagnostically.
Sunthornthepvarakul et al. (1994) identified R218H mutation in affected members of 8 unrelated families with dysalbuminemic hyperthyroxinemia.
Pohlenz et al. (2001) reported a 5-month-old boy with familial dysalbuminemic hyperthyroxinemia and congenital hypothyroidism who had a blood thyrotropin (TSH) level of 479 mU/L but normal T4 and elevated T3 levels. The patient and his euthyroid father and brother all carried the R218H mutation.
Madison et al. (1994) stated that of the more than 50 different genetic variants of human serum albumin that had been characterized by amino acid or DNA sequence analysis, almost half had been identified in Italy through a long-term electrophoretic survey of serum. They reported 4 other Italian alloalbumins not previously recorded: Larino, his3-to-tyr; Tradate-2, lys225-to-gln (103600.0043); Caserta, lys276-to-asn (103600.0044); and Bazzano, a carboxyl-terminal variant (103600.0045). The first 3 had point mutations that produced a single amino acid substitution; a nucleotide deletion caused a frameshift and an altered and truncated carboxy-terminal sequence in albumin Bazzano. In these 4 instances, the expression of the alloalbumin was variable, ranging from 10 to 70% of the total albumin, in contrast to the usual 50% each for the normal and mutant albumin. Madison et al. (1994) commented that the distribution of point mutations in the albumin gene is nonrandom; most of the 47 reported point substitutions involved charged amino acid residues on the surface of the molecule that are not concerned with ligand-binding sites.
See 103600.0042. In a patient from Tradate (Lombardy region), Madison et al. (1994) demonstrated a substitution of glutamine for lysine-225. An AAA-to-CAA change is responsible for the substitution. Albumin Tradate-2 was present in equimolar ratio with albumin A and had a fast mobility.
See 103600.0042. In 3 members of a family from Caserta near Naples, Madison et al. (1994) demonstrated a substitution of asparagine for lysine-276. An AAG-to-AAC change is responsible for the substitution. The alloalbumin was identified by its fast mobility. The 3 subjects were heterozygous, but the variant/normal ratio was 1.5/1 in the serum of the mother, whereas it was about 2/1 in both sibs. In all 3 cases, an increased total albumin content was observed.
See 103600.0042. Madison et al. (1994) found albumin Bazzano in several families from Bazzano, a small town close to Bologna. At pH 8.6 the variant was much slower than normal and comprised only about 18% of the total albumin. In SDS/PAGE, the molecular weight of the variant appeared slightly lower than normal. Sequence analysis revealed deletion of the thymine nucleotide at position 15332 in the genomic sequence. This led to a frameshift and a divergent amino acid sequence of 16 residues beginning at position 567, with early termination after 582. The extensive modification caused an increase in positive charge, which explained the unusually slow mobility of the alloalbumin. The normal termination codon in albumin is 586. Other carboxy-terminal variants are albumin Venezia (103600.0028), albumin Rugby Park (103600.0038), and albumin Catania (103600.0032).
In 2 members of a family living in Asola in Lombardia, Italy, Minchiotti et al. (1995) detected a slow migrating variant of human serum albumin present in lower amounts than the normal protein by routine clinical electrophoresis at pH 8.6. Isoelectric focusing analysis of CNBr fragments localized the mutation to fragment CNBr3 (amino acid residues 124-298). Amino acid sequence analysis showed a tyr140-to-cys substitution, confirmed by DNA sequence analysis, which resulted from a single transition of TAT to TGT at nucleotide 5074. Despite the presence of an additional cysteine residue, several lines of evidence indicated that albumin Asola had no free sulfhydryl group; therefore, Minchiotti et al. (1995) proposed that the mutant amino acid, cysteine, was involved in the formation of a new disulfide bond with cys34, the only free sulfydryl group present in the normal protein.
This variant has also been called albumin Dalakarlia-1.
Carlson et al. (1992) demonstrated that albumin Malmo-95 has a substitution of asparagine for aspartic acid-63. A GAC-to-AAC change is responsible for the substitution.
Brennan and Fellowes (1993) demonstrated that albumin Hawkes Bay has a substitution of phenylalanine for cysteine-177. A TGC-to-TTC change is responsible for the substitution.
This variant has also been called albumin Skaane SA.
Carlson et al. (1992) demonstrated that albumin Malmo-10 has a substitution of arginine for glutamine-268. A CAA-to-CGA change is responsible for the substitution.
This variant has also been called albumin Orebro SW.
Carlson et al. (1992) demonstrated that albumin Malmo-47 has a substitution of lysine for asparagine-318. A change from AAC to AAA or AAG is responsible for the substitution.
Minchiotti et al. (1992) demonstrated that albumin Sondria has a substitution of lysine for glutamic acid-333. A GAA-to-AAA change is responsible for the substitution.
Carlson et al. (1992) demonstrated that albumin Malmo-5 has a substitution of glutamine for glutamic acid-376. A GAA-to-CAA change is responsible for the substitution.
Sakamoto et al. (1991) demonstrated that albumin Dublin has a substitution of lysine for glutamic acid-479. A GAA-to-AAA change is responsible for the substitution.
Galliano et al. (1993) demonstrated that albumin Ortonovo has a substitution of lysine for glutamic acid-505. A GAA-to-AAA change is responsible for the substitution.
Of 8 members of a 3-generation Japanese family, Wada et al. (1997) documented 6 who had dysalbuminemic hyperthyroxinemia (FDAH; 615999). Serum total T4 levels ranged from 1763 to 2741 nmol/L (normal range, 66-165), serum total T3 levels ranged from 2.73-5.62 nmol/L (normal range, 1.47-2.95), and rT3 levels ranged from 1.08 to 2.52 nmol/L (normal range, 0.22-0.60). All affected family members were heterozygous for a G-to-C transition in the second nucleotide of codon 218 of the albumin gene, resulting in an arg218-to-pro substitution.
Sunthornthepvarakul et al. (1998) reported an abnormal albumin in members of a Thai family that presented with high serum total T3 but not T4 when measured by radioimmunoassay. In contrast, total T3 values were very low when measured by ELISA and chemiluminescence. The subjects did not have a goiter and were clinically euthyroid. Their serum free T4, free T3, and TSH levels were normal (see 615999). Spiking of T3 to affected serum showed good recovery by radioimmunoassay but very poor recovery by ELISA and by chemiluminescence. Immunoprecipitation with labeled T3 bound to albumin showed a high percent of precipitation in affected serum. T3-binding studies showed that the association constant of serum albumin in affected subjects, 1.5 x 10(6)M(-1), was 40-fold that of unaffected relatives, 3.9 x 10(4)M(-1). The authors found a T-to-C (CTT-to-CCT) transition in the second nucleotide of codon 66, resulting in replacement of the normal leucine by proline.
In a male newborn of Iraqi extraction with analbuminemia (ANALBA; 616000), Campagnoli et al. (2002) found a G-to-A substitution at nucleotide 118 in the ALB gene. The mutation, involving the first base of intron 1, destroyed the GT dinucleotide consensus sequence found at the 5-prime end of most intervening sequences and caused defective pre-mRNA splicing. The child was homozygous; both parents were heterozygous. The infant presented with low birthweight due to placental infarctions, and mild edema was noted after 1 week. There was no jaundice and the bilirubin level was normal. Only minute amounts of albumin were detected. Hypercholesterolemia developed in spite of total lipid values within the normal range. At 18 months he was in good general condition, without edema, and had normal weight and length for his age. The parents, who were first cousins, had low albumin concentration values: the father 33 g/l and the mother 27 g/l.
In 2 sibs, born to consanguineous Algerian parents, with analbuminemia (ANALBA; 616000), Caridi et al. (2019) identified a homozygous 1-bp duplication (c.1098dupT) in exon 9 of the ALB gene, resulting in a frameshift and generation of a premature stop codon (Val367fsTer12). The mother was heterozygous for the mutation; DNA from the father was not available for testing. The variant was not found in the ExAC or gnomAD databases.
In an Italian man with analbuminemia (ANALBA; 616000) reported by Di Guardo et al. (1977), Watkins et al. (1994) identified a c.2368C-T transition in exon 3 of the ALB gene, resulting in a gln32-to-ter (Q32X) substitution.
In an American woman (patient G.M.) with analbuminemia (ANALBA; 616000) reported by Gordon et al. (1959), Watkins et al. (1994) identified a c.4446C-T transition in the ALB gene, resulting in an arg114-to-ter (R114X) substitution.
In a Canadian male neonate with analbuminemia (ANALBA; 616000), Watkins et al. (1994) identified a c.7708G-A transition in the ALB gene, resulting in a trp214-to-ter (W214X) substitution.
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