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To investigate albumin (ALB) gene variations in patients suspected from familial dysalbuminemic hyperthyroxinemia (FDH). Eight Turkish patients were included into the study. Clinical and laboratory characteristics of the subjects and their parents were evaluated and genetic analysis were performed. In genetic analysis, a previously reported heterozygous, c.725G>A variant was detected in exon seven of the ALB gene. FDH is an asymptomatic condition however there is still a risk of misdiagnosis and unnecessary treatment. Therefore, if FDH is considered, initial ALB hotspot sequencing as a rapid and simple method is recommended instead of complex and expensive laboratory and imaging techniques. [ABSTRACT FROM AUTHOR]

Abstract Congenital analbuminemia (OMIM # 616000) is an extremely rare autosomal recessive disorder, caused by variations in the albumin gene (ALB), which is generally thought to be a relatively benign condition in adulthood, but seems to be potentially life threatening in the pre- and peri-natal period. The subject of our study was a consanguineous family, in which we identified two analbuminemic individuals. Mutation analysis of ALB revealed that both are homozygous for a previously unreported insertion in exon 9 (c.1098dupT), causing a subsequent frame-shift with the generation of a premature stop codon, and an aberrant truncated putative protein product, p.Val367fsTer12. This variation is present in heterozygous condition in several other members of the family. The phenotype and the molecular genetics of CAA are discussed. [ABSTRACT FROM AUTHOR]

Congenital analbuminaemia is a rare autosomal recessive disorder manifested by the presence of a very low amount of circulating serum albumin. The clinical diagnosis may be challenging because of the absence of unambiguous symptoms and because hypoalbuminemia may have many causes different from a genetic lack of the protein. We describe the clinical and molecular characterization of a new case of congenital analbuminaemia in an infant of apparently non-consanguineous parents from Treves, Germany. For molecular diagnosis, we used our strategy, based on the screening of the albumin gene by single-strand conformation polymorphism, heteroduplex analysis and direct DNA sequencing, which revealed that the proband is homozygous and both parents are heterozygous, for a novel G > T transversion at nucleotide c.270+ 1, the first base of intron 3. The mutation inactivates the strongly conserved GT dinucleotide at the 5' splice site consensus sequence of this intron. In conclusion, we report the clinical findings and the molecular defect of this case, which contributes to a better understanding of the biological mechanism of congenital analbuminaemia. [ABSTRACT FROM AUTHOR]

Familial dysalbuminemic hyperthyroxinemia (FDH) is an inherited disease characterized by increased circulating total thyroxine (T4) levels and normal physiological thyroid function. Heterozygous albumin gene (ALB) variants have been reported to be the underlying cause of FDH. To our knowledge, there have been no confirmed FDH cases in Korea. We recently observed a female patient with mild T4 elevation (1.2 to 1.4-fold) and variable levels of free T4 according to different assay methods. Upon Sanger sequencing of her ALB, a heterozygous c.725G>A (p.Arg242His) variant was identified. The patient's father and eldest son had similar thyroid function test results and were confirmed to have the same variant. Although the prevalence of FDH might be very low in the Korean population, clinical suspicion is important to avoid unnecessary evaluation and treatment. [ABSTRACT FROM AUTHOR]

Introduction: Congenital analbuminemia is a rare autosomal recessive disorder manifested by the presence of a very low amount of circulating serum albumin. It is an allelic heterogeneous defect, caused by variety of mutations within the albumin gene in homozygous or compound heterozygous state. Herein we report the clinical and molecular characterization of a new case of congenital analbuminemia diagnosed in a female newborn of consanguineous (first degree cousins) parents from Ankara, Turkey, who presented with a low albumin concentration (< 8 g/L) and severe clinical symptoms. Materials and methods: The albumin gene of the index case was screened by single-strand conformation polymorphism, heteroduplex analysis, and direct DNA sequencing. The effect of the splicing mutation was evaluated by examining the cDNA obtained by reverse transcriptase - polymerase chain reaction (RT-PCR) from the albumin mRNA extracted from proband's leukocytes. Results: DNA sequencing revealed that the proband is homozygous, and both parents are heterozygous, for a novel G>A transition at position c.1652+1, the first base of intron 12, which inactivates the strongly conserved GT dinucleotide at the 5' splice site consensus sequence of this intron. The splicing defect results in the complete skipping of the preceding exon (exon 12) and in a frame-shift within exon 13 with a premature stop codon after the translation of three mutant amino acid residues. Conclusions: Our results confirm the clinical diagnosis of congenital analbuminemia in the proband and the inheritance of the trait and contribute to shed light on the molecular genetics of analbuminemia. [ABSTRACT FROM AUTHOR]

Abstract: Background: DNA and mRNA sequencing of the coding regions of the human albumin gene (ALB) and of its intron/exon junctions has revealed twenty-one different molecular defects causing congenital analbuminaemia (CAA). Scope of review: To describe the mutations in molecular terms and to present the current knowledge about the most important biochemical and clinical effects of CAA. Major conclusions: CAA is rare, but its frequency seems to be significantly higher in restricted and minimally admixed populations. The condition affects especially the lipid metabolism but apart from a possible increased risk for atherosclerotic complications, it is generally associated with mild clinical symptoms in adults. By contrast, several reports indicate that analbuminaemic individuals may be at risk during the perinatal and childhood periods, in which they seem to show increased morbidity and mortality. The twenty-one causative defects include seven nonsense mutations, seven changes affecting splicing, five frame-shift/deletions, one frame-shift/insertion and one mutation in the start codon. These results indicate that the trait is an allelic heterogeneous disorder caused by homozygous (nineteen cases) or compound heterozygous (single case) inheritance of defects. Most mutations are unique, but one, named Kayseri, is responsible for about half of the known cases. General significance: Study of the defects in the ALB resulting in CAA allows the identification of “hot spot” regions and contributes to understanding the molecular mechanism underlying the trait. Such studies could also give molecular information about different aspects of ALB regulation and shed light on the regulatory mechanisms involved in the synthesis of the protein. This article is part of a Special Issue entitled Serum Albumin. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

The adult liver contains hematopoietic stem cells that can reconstitute the bone marrow. We tested whether bone marrow cells (BMCs) derived from liver nonparenchymal cells (LNPCs) can increase the number of hepatocytes within livers. LNPCs from Fischer 344 rats (F344) were infused into the penile veins of F344 congenic Nagase’s analbuminenic rats (F344alb) immediately after whole-body irradiation, and the recipients were sacrificed 8 weeks later. Eleven of 15 (73.3%) F344alb that received the LNPC transplantation after irradiation survived, while only 1 of 8 (12.5%) F344alb that received irradiation alone was alive after 8 weeks. Normal albumin gene sequences were detected by PCR in BMCs of the recipient F344alb that received LNPC transplantation after irradiation, indicating that F344alb bone marrow was reconstituted by F344 LNPCs. Although single or pairs of albumin-positive (Alb+) hepatocytes were seen in the liver of untreated F344alb and those with irradiation or LNPC transplantation alone, clusters consisting of >3 Alb+ hepatocytes were detected in the livers of F344alb with the LNPC or BMC transplantation after irradiation together with single or double Alb+ cells. Normal albumin gene sequences were detected by PCR in the DNA isolated from such Alb+ hepatocyte clusters microdissected from the immunostained sections. The data indicate that BMCs derived from F344 LNPCs could increase the number Alb+ hepatocytes within the F344alb liver. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

hematopoietic stem cells (SCs) mobilized from the bone marrow (BM) into peripheral blood (PB) are reported to have ability to differentiate into various cell types. We investigated whether PB-SCs mobilized by treatment with granulocyte-colony stimulating factor (G-CSF) in normal rats can raise albumin-producing hepatocytes after transplantation within the liver of analbuminemic rats.Fischer 344 rats (F344) were used as donors, and F344 congenic Nagase’s analbuminemic rats (F344alb) as recipients. The donors were repeatedly treated with human recombinant G-CSF, and their PB mononuclear cells (MNCs) were infused into the portal veins of recipients immediately after 70% hepatectomy (PH).Although a few single and small clusters (less than five cells) of albumin positive (alb+) hepatocytes were seen in the livers of untreated F344alb and of the animals undergoing PH alone or transplantation of PB-MNCs with or without the prior G-CSF treatment, clusters consisting of more than 6 alb+ hepatocytes were only detected in the livers of recipients that received transplantation of mobilized PB-MNCs or BM-MNCs under the regenerating condition induced by PH. Sry3, a Y chromosome marker, could be detected corresponding to the alb+ clusters by in situ hybridization when male donors and female recipients were used. Moreover, normal albumin gene sequences were demonstrated in the microdissected alb+ clusters by polymerase chain reaction, and the serum albumin levels were elevated in the recipients.Hematopoietic SCs mobilized from BM into PB by the G-CSF treatment may raise hepatocyte colonies, when transplanted into regenerating livers. [Copyright &y& Elsevier]

A letter to the editor is presented in response to the article on how a two-base-pairs deletion in the albumin gene causes a new case of analbuminemia.

Familial dysalbuminemic hyperthyroxinemia (FDH) is an inherited disease characterized by increased circulating total thyroxine (T4) levels and normal physiological thyroid function. Heterozygous albumin gene (ALB) variants have been reported to be the underlying cause of FDH. To our knowledge, there have been no confirmed FDH cases in Korea. We recently observed a female patient with mild T4 elevation (1.2 to 1.4-fold) and variable levels of free T4 according to different assay methods. Upon Sanger sequencing of her ALB, a heterozygous c.725G>A (p.Arg242His) variant was identified. The patient's father and eldest son had similar thyroid function test results and were confirmed to have the same variant. Although the prevalence of FDH might be very low in the Korean population, clinical suspicion is important to avoid unnecessary evaluation and treatment., Competing Interests: Authors' Disclosures of Potential Conflicts of Interest: No potential conflicts of interest relevant to this article were reported.

Serum albumin is regarded as an important and indispensable protein, but analbuminemic rats established by Sumi Nagase in 1977 seems to exhibit few symptoms in spite of an almost total lack of albumin in the serum. The albumin gene of analbuminemic rats was found to have a seven-base-pair deletion in an intron, close to exon-intron junction, resulting in the formation of non-functional mRNA in hepatocytes. Immunostaining for albumin was negative in young analbuminemic rat hepatocytes, but a significant number of immunoreactive hepatocytes were observed in aged rats. The incidence of immunoreactive hepatocytes increased with aging. Surprisingly, many immunoreactive hepatocytes were observed after hepatocarcinogen treatment sometimes in large clusters. Albumin transcripts in analbuminemic rat liver after treatment with carcinogen, showed an altered pattern of exon-skipping. The altered albumin molecules thus synthesized accumulated in cellular organelles. Analbuminemic rats exhibited a high sensitivity in various organs to different types of carcinogens. Further challenges remain regarding the biology of analbuminemic rats.