A novel mutation in the albumin gene (c.1A&gt;C) resulting in analbuminemia

Caridi, Gianluca; Dagnino, Monica; Lugani, Francesca; Shalev, Stavit A.; Campagnoli, Monica; Galliano, Monica; Spiegel, Ronen; Minchiotti, Lorenzo

doi:10.1111/eci.12019

Cited by 18 publications

(19 citation statements)

References 26 publications

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“…Although we have not yet confirmed the phenotype of this variant, M1L is predicted to disrupt mRNA translation, by alteration of the first codon. Similar disruption of codon 1 ( M1V or M1L ) in other genes is associated with a highly penetrant, loss of function phenotype [46-49]. Indeed, the extremely rare M1V variant of CYP2C9 ( CYP2C9*36 ) was recently described in a Chinese population, and its recombinant expression was found to result in low accumulation of the variant enzyme relative to wild-type in COS cells [50].…”

Section: Discussionmentioning

confidence: 99%

Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people

Fohner

Robinson

Yracheta

et al. 2015

Pharmacogenetics and Genomics

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Objectives Pharmacogenetic testing is projected to improve health outcomes and reduce the cost of care by increasing therapeutic efficacy and minimizing drug toxicity. American Indian and Alaska Native (AI/AN) people historically have been excluded from pharmacogenetic research and its potential benefits, a deficiency we sought to address. The vitamin K antagonist warfarin is prescribed for prevention of thromboembolic events, although its narrow therapeutic index and wide inter-individual variability necessitate close monitoring of drug response. Therefore, we were interested in variation in CYP2C9, VKORC1, CYP4F2, CYP4F11, and GGCX, which encode enzymes important for the activity of warfarin and synthesis of vitamin K dependent blood clotting factors. Methods We resequenced these genes in 188 AI/AN people in partnership with Southcentral Foundation (SCF) in Anchorage, AK and 94 Yup'ik people living in the Yukon-Kuskokwim Delta of southwest Alaska to identify known or novel function-disrupting variation. We conducted genotyping for specific SNPs in larger cohorts of each study population (380 and 350, respectively). Results We identified high frequencies of the lower-warfarin dose VKORC1 haplotype (−1639G>A and 1173C>T) and the higher-warfarin dose CYP4F2*3 variant. We also identified two relatively common, novel, and potentially function-disrupting variants in CYP2C9 (M1L and N218I), which, along with CYP2C9*3, CYP2C9*2 and CYP2C9*29, predict that a significant proportion of AI/AN people will have decreased CYP2C9 activity. Conclusions Overall, we predict a lower average warfarin dose requirement in AI/AN populations in Alaska than that seen in non-AI/AN populations of the US, a finding consistent with clinical experience in Alaska.

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Section: Discussionmentioning

confidence: 99%

Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people

Fohner

Robinson

Yracheta

et al. 2015

Pharmacogenetics and Genomics

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“…For these reasons, the clinical diagnosis needs always to be confirmed by a molecular diagnosis, based on the identification of the causative mutation within the ALB . The Ankara mutation is the twenty-second different molecular defect identified as a cause of the analbuminemic trait (2,11). Twenty among them cause CAA at the homozygous state: six nonsense mutations, seven mutations affecting splicing, five frame-shift/deletions, one frame-shift/ insertion and one mutation in the start codon (2,11).…”

Section: Discussionmentioning

confidence: 99%

“…The Ankara mutation is the twenty-second different molecular defect identified as a cause of the analbuminemic trait (2,11). Twenty among them cause CAA at the homozygous state: six nonsense mutations, seven mutations affecting splicing, five frame-shift/deletions, one frame-shift/ insertion and one mutation in the start codon (2,11). Compound heterozygosity for the remaining two molecular defects, a nonsense mutation and a splice site mutation with subsequent reading frame-shift, caused CAA in an Italian man (2,11).…”

Section: Discussionmentioning

confidence: 99%

“…However, as the number of the known molecular defects is increasing, the data seem to point out to the presence of regions in the ALB that are prone to mutations resulting in CAA. Two of them appear to be localised in the intron 6-exon 7 and exon 11-intron 11 junctions (2, 11). Other hypermutable regions seem to be the sequence c.228 – c.230 of exon 3, the CpG sequence at position c.412 – 413 in the codon CGA for Arg138 in exon 4, and the sequence c.1610 – 1615 near the 3′ end of exon 12 (2,11).…”

Section: Discussionmentioning

confidence: 99%

“…Genomic DNA from two unrelated volunteers was available as a control. Heteroduplex and single strand conformational polymorphism analysis and DNA sequencing were performed as previously reported (11,12). …”

Section: Methodsmentioning

confidence: 99%

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Congenital analbuminemia caused by a novel aberrant splicing in the albumin gene

et al. 2014

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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.

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Molecular Genetics of Analbuminaemia

Minchiotti

Caridi

Campagnoli

et al. 2014

Encyclopedia of Life Sciences

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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.

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A novel mutation in the albumin gene (c.1A>C) resulting in analbuminemia

Cited by 18 publications

References 26 publications

Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people

Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people

Congenital analbuminemia caused by a novel aberrant splicing in the albumin gene

Molecular Genetics of Analbuminaemia

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