Molecular Genetics of Analbuminaemia

Abstract

Congenital analbuminaemia (CAA) is a very rare condition manifested by the near complete absence of albumin, the major blood protein, because of defects in the albumin (ALB) gene. It is generally regarded as relatively benign in adults, but analbuminaemic individuals may be at risk during the perinatal and childhood period. Twenty‐one different molecular lesions in the ALB are now known as cause of the trait. These include one mutation in the start codon, one frameshift/insertion, five frameshift/deletions, seven nonsense mutations and seven mutations affecting splicing. Thus, nonsense mutations, mutations affecting splicing and frameshift/deletions seem to be the most common causes of CAA. These results indicate that the trait is an allelic heterogeneous disorder caused by homozygous or, in a single case, compound heterozygous inheritance of defects. Most mutations are unique, but one, named Kayseri, is responsible for about half of the known cases.

Key Concepts:

  • CAA is an autosomal recessive disorder.

  • Apart from the possibility of premature atherosclerotic complications, the phenotype seems to be benign in adults.

  • Analbuminaemic individuals may be at risk during the perinatal and the childhood period.

  • CAA is caused by homozygous or, in a single case, compound heterozygous inheritance of abnormal albumin alleles from both parents.

  • Twenty‐one different molecular defects in the ALB are known as cause of the trait.

  • Nonsense mutations, mutations affecting splicing and frameshift/deletions are the most common causes of CAA.

  • No evidence has so far been found for the presence in serum of the putative protein products produced as a consequence of the above 21 mutations.

  • The molecular defects are located in nine different exons and in four different introns.

  • This distribution seems to suggest that CAA is the result of widely scattered random sequence variations.

  • The increasing knowledge of the causative defects seems to reveal the presence of regions in the ALB that are prone to mutations.

Keywords: congenital analbuminaemia; clinical consequences; molecular diagnosis; albumin gene; mutations; DNA sequence

Figure 1.

The structure of ALB as revealed by X‐ray crystallography (He and Carter, ; Sugio et al., ). The subdivision of the protein into domains (I–III) and subdomains (A and B) is indicated. The figure was made with PyMol on the basis of the atomic coordinates (PDB ID: 1uor) available at the RCSB Protein Data Bank. We thank Dr. Konrad Bienk, University of Aarhus, for his valuable help with the preparation of Figure .

Figure 2.

Densitometric scanning of conventional cellulose acetate serum protein electrophoresis of an analbuminaemic individual (red) compared with a normal subject (blue). Inset: protein electrophoresis pattern of serum from a normal (lane 1) and from an analbuminaemic (lane 2) subject.

Figure 3.

Scheme of the mutations which, at the homozygous or compound heterozygous state, are known to cause CAA in humans. The molecular defects are named after the place from where the first detected carrier originates. Codon numbering is according to HGVS rules and is based on the cDNA sequence NM_000477.5.

Figure 4.

Distribution of mutations associated with CAA within the ALB. The linear map of the gene indicating the location of exons (orange) and introns (blue) is based on the data of Minghetti et al. (). The totally untranslated exon 15 as well as the untranslated regions of exon 1 and exon 14 are in yellow. The summary of the reported mutations is shown in exon or intron‐specific text ovals. All the mutations are at cDNA level (GenBank reference sequence: NM_000477.5). The 5′ and 3′ untranslated regions of the gene are in green.

Figure 5.

Regions in the ALB that seem to be prone to mutations. The linear map of the gene, the colours and the symbols are as in Figure . Codon numbering for bisalbumin Yanomama‐2 is according to HGVS rules and is based on the cDNA sequence NM_000477.5.

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Further Reading

Fanali G , di Masi A , Trezza V et al. (2012) Human serum albumin: from bench to bedside. Molecular Aspects of Medicine 33: 209–290.

Kragh‐Hansen U , Minchiotti L , Galliano M and Peters T Jr (2013) Human serum albumin isoforms: Genetic and molecular aspects and functional consequences. Biochimica et Biophysica Acta 1830: 5405–5417.

Minchiotti L , Galliano M , Caridi G , Kragh-Hansen U and Peters T Jr (2013) Congenital analbuminaemia: molecular defects and biochemical and clinical aspects. Biochimica et Biophysica Acta 1830: 5494–5502.

Web Links

The Albumin Website, available at www.albumin.org.

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Minchiotti, Lorenzo, Caridi, Gianluca, Campagnoli, Monica, Galliano, Monica, Kragh‐Hansen, Ulrich, and Peters, Theodore(Jan 2014) Molecular Genetics of Analbuminaemia. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025443]