Diagnosis, Phenotype, and Molecular Genetics of Congenital Analbuminemia

Abstract

Congenital analbuminemia (CAA) is an inherited, autosomal recessive disorder with an incidence of 1:1,000,000 live birth. Affected individuals have a strongly decreased concentration, or complete absence, of serum albumin. The trait is usually detected by serum protein electrophoresis and immunochemistry techniques. However, due to the existence of other conditions in which the albumin concentrations are very low or null, analysis of the albumin (ALB) gene is necessary for the molecular diagnosis. CAA can lead to serious consequences in the prenatal period, because it can cause miscarriages and preterm birth, which often is due to oligohydramnios and placental abnormalities. Neonatally and in early childhood the trait is a risk factor that can lead to death, mainly from fluid retention and infections in the lower respiratory tract. By contrast, CAA is better tolerated in adulthood. Clinically, in addition to the low level of albumin, the patients almost always have hyperlipidemia, but they usually also have mild oedema, reduced blood pressure and fatigue. The fairly mild symptoms in adulthood are due to compensatory increment of other plasma proteins. The condition is rare; clinically, only about 90 cases have been detected worldwide. Among these, 53 have been studied by sequence analysis of the ALB gene, allowing the identification of 27 different loss of function (LoF) pathogenic variants. These include a variant in the start codon, frame-shift/insertions, frame-shift/deletions, nonsense variants, and variants affecting splicing. Most are unique, peculiar for each affected family, but one, a frame-shift deletion called Kayseri, has been found to cause about one third of the known cases allowing to presume a founder effect. This review provides an overview of the literature about CAA, about supportive and additional physiological and pharmacological information obtained from albumin-deficient mouse and rat models and a complete and up-to-date dataset of the pathogenic variants identified in the ALB gene.

Keywords: DNA-sequencing; analbuminemia; autosomal recessive; compensatory mechanisms; frequency; hyperlipidemia; pathogenic variations; preterm birth.

FIGURE 1

The chromosomal localization (A) and genomic organization (B) of five of the six albumin superfamily genes. The gene for ECM1 is located at 1q21.3. The arrows represent the start of transcription. The figure is constructed using information published by Speeckaert et al. (2006) and Naidu et al. (2010) and found in the GenBank (http://www.ncbi.nlm.nih.gov/pubmed). GC, vitamin D-binding protein (GenBank Gene ID: 2638); ALB, albumin (GenBank Gene ID: 213); AFP, α-fetoprotein (GenBank Gene ID: 174); AFM, afamin (GenBank Gene ID: 1731); ARG, α-fetoprotein related gene, which is inactive in primates. As shown, the genes for ALB, AFP, and AFM are tandemly arranged in the same transcriptional orientation; ARG is also oriented in the same way but it is in parenthesis, because in humans it is an inactive pseudogene (Naidu et al., 2010). Whether the reverted orientation of DBP has a regulatory or other function has not yet been clarified. (C) Genomic structure of the human albumin gene. The linear map of the gene indicating the location of exons (red) and introns (blue) is constructed on the basis of information found in GenBank. The partially untranslated regions of exons 1 and 14, and the completely untranslated exon 15, are in yellow, and the 5′ and 3′ untranslated region UTR are in green. The numbers below the exons indicate the exon size (in bp); numbers in parentheses for exons 1 and 14 represent the number of coding nucleotides. The number between exons represent intron length (in bp).

FIGURE 2

Capillary electrophoresis of serum proteins. The profiles were obtained via the fully automated Helena V8 Capillary Electrophoresis System. (A) Normal; (B) patient having the Erzurum trait (Caridi et al., 2016a). Inset: conventional serum protein electrophoresis (A, normal; B, analbuminemic subject). Both types of electrophoresis allow to detect that in the patient ALB is near absent, whereas all the globulin fractions are increased.

FIGURE 3

Scheme of the type of variants, which 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 based on the cDNA sequence NM_000477.6.

FIGURE 4

Genomic structure and distribution of variants resulting in CAA within the ALB gene. The linear map of the gene, the colors, and the symbols are as in Figure 1C. The map indicates the locations of 14 coding exons (red), the non-coding regions (yellow), the introns (blue) and the 5′ and 3′ untranslated region UTR (green). A summary of the reported variants is given in exon and intron-specific boxes. The variants are at the cDNA level (GenBank reference sequence: NM_000477.6).

FIGURE 5

Regions in the ALB that seem to be more prone to variants resulting in CAA. The linear map of the gene, the colors, and the symbols are as in Figure 1C, 4. Variants at position c.412 in exon 4 may result in analbuminemia Bethesda (c.412C > T) or in bisalbumin Yanomama-2 (p.Arg138Gly; c.412C > G). These two variants are in a CpG sequence (c.412–413). LoF variants present in public database, but not yet identified as cause of CAA, are in parenthesis.