A novel mutation in the albumin gene (c.1A>C) resulting in analbuminemia Gianluca Caridi * , Monica Dagnino * , Francesca Lugani * , Stavit A. Shalev † , Monica Campagnoli ‡ , Monica Galliano ‡ , Ronen Spiegel † and Lorenzo Minchiotti ‡ * Laboratory on Pathophysiology of Uremia, Istituto Giannina Gaslini IRCCS, Genoa, Italy, † Department of Pediatrics A’ and Genetic Institute, Ha’Emek Medical Center, Afula, Rappaport Faculty of Medicine, Technion, Haifa, Israel, ‡ Department of Molecular Medicine, University of Pavia, Pavia, Italy ABSTRACT Background Analbuminemia (OMIM # 103600) is a rare autosomal recessive disorder manifested by the absence or severe reduction of circulating serum albumin in homozygous or compound heterozygous subjects. The trait is caused by a variety of mutations within the albumin gene. Design We report here the clinical and molecular characterisation of two new cases of congenital analbumin- emia diagnosed in two members of the Druze population living in a Galilean village (Northern Israel) on the basis of their low level of circulating albumin. The albumin gene was screened by single-strand conformation poly- morphism and heteroduplex analysis, and the mutated region was submitted to DNA sequencing. Results Both the analbuminemic subjects resulted homozygous for a previously unreported c.1 A>C transver- sion, for which we suggest the name Afula from the hospital where the two cases were investigated. This muta- tion causes the loss of the primary start codon ATG for Met1, which is replaced by a – then untranslated – triplet CTG for Leu. (p.Met1Leu). The use of an alternative downstream ATG codon would probably give rise to a com- pletely aberrant polypeptide chain, leading to a misrouted intracellular transport and a premature degradation. Conclusions The discovery of this new ALB mutation, probably inherited from a common ancestor, sheds light on the molecular mechanism underlying the analbuminemic trait and may serve in the development of a rapid genetic test for the identification of a-symptomatic heterozygous carriers in the Druze population in the Galilee. Keywords Analbuminemia, DNA sequence, Druze community, human serum albumin, missense mutation, start codon. Eur J Clin Invest 2013; 43 (1): 72–78 Introduction Human serum albumin (ALB; UniProt ID: P02768) is encoded on chromosome 4q13.3 by an autosomal gene (ALB; GenBank accession no. NC_000004.11 74269972..74287129) composed of 15 exons, the last of which is untranslated [1]. The messenger RNA (GenBank coding reference sequence NM_000477.5) in liver cells encodes a precursor protein (preproalbumin) of 609 amino acid residues. Cleavage of the 18 residue signal peptide and of the 6 residue propeptide yields the mature ALB, which consists of a single unglycosylated chain of 585 amino acids. The protein is then secreted in the bloodstream, where it accounts for about 60% (reference range 35–45 g ⁄ L) of total serum proteins. [2]. Its main functions are to act as a transport and depot protein for a wide variety of endogenous and exogenous ligands, including fatty acids, hormones, steroids, bilirubin and heme, and to maintain the oncotic pressure and volume of blood [2]. ALB also binds heavy metal ions and many drugs, which is why a decrease in its serum level can have important pharmacokinetic consequences. In addition, the protein plays a role as a circulating antioxidant and is reported to possess some enzymatic properties. Analbuminemia (OMIM # 103600) is an autosomal recessive disorder manifested by the absence or severe reduction of cir- culating ALB. The condition should be suspected when more common causes of low ALB levels, such as renal or intestinal loss (glomerular nephritis, nephrotic syndrome and protein- losing gastroenteropathy), redistribution into extravascular compartments (septicaemia and other inflammatory states), and insufficient production rate (severe hepatic cirrhosis) can 72 European Journal of Clinical Investigation Vol 43 DOI: 10.1111/eci.12019 ORIGINAL ARTICLE