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

Abstract

In analbuminemia, a very rare inherited syndrome, subjects produce little or no albumin (1/100th to 1/1000th normal), presumably because of a mutation in the albumin gene; yet, they have only moderate edema and few related symptoms owing to a compensatory increase in other plasma proteins. Because of the virtual absence of albumin the defect must be identified at the DNA level. In this study the mutation causing analbuminemia in an Italian family was investigated by analysis of DNA from a mother and her daughter. The mother was homozygous for the trait and had a serum albumin value of <0.01 g/dl (about 1/500th normal); the daughter was heterozygous for the trait and had a nearly normal albumin value. Molecular cloning and sequence analysis of DNA from both mother and daughter showed that the mutation is caused by a nucleotide insertion in exon 8; this produces a frameshift leading to a premature stop, seven codons downstream. The methods of heteroduplex hybridization and single-strand conformation polymorphism were used to compare the DNA of the mother and daughter to the DNA of two unrelated analbuminemic individuals (one Italian and one American). This showed that all three analbuminemic individuals had different mutations; these also differed from the mutation in the only human case previously studied at the DNA level, which was a splicing defect affecting the ligation of the exon 6-exon 7 sequences. Thus, analbuminemia may result from a variety of mutations and is genetically heterogeneous.Serum albumin is the most abundant secreted protein in the body; it comprises about 50%o of the total protein in serum where it has a normal concentration of 3.5-4.5 g/dl (1

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.…”

A nucleotide insertion and frameshift cause albumin Kenitra, an extended and O-glycosylated mutant of human serum albumin with two additional disulfide bridges

“…A 339-bp fragment containing exon 14 of the albumin gene was amplified by PCR using primers A27A and A28A [23]. PCR was performed in a 25-mL reaction volume using Ready to Go Beads (Amersham Pharmacia Biotech) with a final MgCl 2 concentration of 1.5 mm.…”

“…Genomic DNA was extracted from whole blood by using the lysis buffer and proteinase K digestion protocol [23]. A 339-bp fragment containing exon 14 of the albumin gene was amplified by PCR using primers A27A and A28A [23].…”

Analbuminemia Produced by a Novel Splicing Mutation

“…Compound heterozygosity for 2 different mutations, a nonsense and a splice-site mutation, was found in an Italian man (11 ). In all reported mutations, the protein product was predicted to range in length from 19 to 463 residues, although no data are available regarding the presence of the abnormal protein products (4,8,11 ).…”

“…The frequency of this disorder is estimated to be Ͻ1 ϫ 10 6 and is apparently unaffected by sex or ethnic predilection (2,4 ). The 42 cases described to date are listed in the "analbuminemia register" (2 ).…”