A novel splicing mutation causes analbuminemia in a Portuguese boy

• Published in: Molecular genetics and metabolism Vol. 105; no. 3; pp. 479 - 483
• Main Authors: Caridi, Gianluca, Dagnino, Monica, Di Duca, Marco, Pinto, Helena, Espinheira, Maria do Céu, Guerra, António, Fernandes, Susana, Campagnoli, Monica, Galliano, Monica, Minchiotti, Lorenzo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2012
• Subjects: Adolescent; Albumin gene; Analbuminemia; Base Sequence; boys; complementary DNA; consensus sequence; DNA and cDNA sequence analysis; exons; Frameshift Mutation; Genetic Predisposition to Disease; Heteroduplex analysis; heterozygosity; homozygosity; Human serum albumin; Humans; hypercholesterolemia; Hypoalbuminemia - genetics; introns; leukocytes; Male; messenger RNA; mutation; parents; Polymorphism, Single Nucleotide; Portugal; reverse transcriptase polymerase chain reaction; RNA Splicing; sequence analysis; Sequence Analysis, DNA; serum albumin; Serum Albumin - deficiency; Serum Albumin - genetics; Serum Albumin, Human; Splicing mutation; stop codon; Albumin gene; Human serum albumin; Heteroduplex analysis; ALB; HA; DNA and cDNA sequence analysis; SSCP; Splicing mutation; Analbuminemia
• ISSN: 1096-7192; 1096-7206; 1096-7206
• DOI: 10.1016/j.ymgme.2011.12.009

Analbuminemia is a rare autosomal recessive disorder manifested by the absence or severe reduction of circulating serum albumin in homozygous or compound heterozygous subjects. It is an allelic heterogeneous defect, caused by a variety of mutations within the albumin gene. The analbuminemic condition was suspected in a Portuguese boy who presented with low albumin level (about 3.8g/L) and a significant hypercholesterolemia, but with no clinical findings. The albumin gene was screened by single strand conformational polymorphism and heteroduplex analysis and submitted to direct DNA sequencing. The proband was found to be homozygous for a previously unreported G>A change at position c.1289+1, the first base of intron 10, which inactivates the strongly conserved GT dinucleotide at the 5′ splice site consensus sequence of the intron. The effect of this mutation was evaluated by examining the cDNA obtained by RT-PCR from the albumin mRNA extracted from proband's leukocytes. The splicing defect results in the skipping of the preceding exon. The subsequent reading frame-shift in exon 11 produces a premature stop codon located 33 codons downstream the 5′ end of the exon. This extensive cDNA alteration is responsible for the analbuminemic trait. Both parents were found to be heterozygous for the same mutation. DNA and cDNA sequence analysis established the diagnosis of congenital analbuminemia in the proband. The effects of the so far identified splice-site mutations in the albumin gene are discussed. ► We studied the mutation responsible for the analbuminemic trait in a Portuguese boy. ► The proband resulted homozygous for a G>A change at position c.1289+1. ► The mutation inactivated the conserved GT consensus sequence of intron 10. ► The splicing defect resulted in the skipping of the preceding exon. ► A premature stop codon was identified 33 codons downstream the 5′ end of exon 11.