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Molecular Genetics of Analbuminemia
No full textCongenitalanalbuminaemia (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
A novel splicing mutation causes an undescribed type of analbuminemia.
No full textAnalbuminemia is a rare autosomal recessive disorder manifested by the absence or severe reduction of circulating serum albumin in homozygous subjects. In this report we describe a new molecular defect that caused the analbuminemic trait in a newborn of Iraqi origin. When the parents' DNA was analyzed, both subjects were found to be heterozygous for the same mutation found in the infant. All the 14 exon and flanking intron sequences of the albumin gene were amplified via PCR and screened for mutations by SSCP and heteroduplex analysis. A mutation in the DNA region encoding exon 1 and its flanking intron was revealed by the presence of a heteroduplex. The fragment, which was directly DNA sequenced, contains a previously unreported single nucleotide change, consisting in a G to A substitution at nucleotide 118 in the structural gene of the human protein. This mutation, involving the first base of intron 1, destroys the GT dinucleotide consensus sequence found at the 5' end of most intervening sequences and causes the defective pre-mRNA splicing responsible for the analbuminemic trait
Albumin Benkovac (c.1175 A > G; p.Glu392Gly): a novel genetic variant of human serum albumin.
No full textHuman alpha-1-Microglobulin is Covalently Bound to Kynurenine Derived Chromophores
No full textAlpha-1-Microglobulin carries a set of covalently linked
chromophores that give it a peculiar yellow-brown
color, fluorescence properties, and both charge and size
heterogeneity. In this report it is shown that these features
are due to the adducts with the tryptophan metabolite,
3-hydroxykynurenine, and its autoxidation products
and that the modification is more pronounced in
the protein isolated from urine of hemodialyzed patients.
The light yellow amniotic fluid alpha -1-microglobulin
acquires the optical properties and charge heterogeneity
of the urinary counterpart following incubation with
kynurenines. The colored amino acid adducts of urinary
and amniotic fluid alpha -1-microglobulins were separated
by chromatography after acid hydrolysis and analyzed
by mass spectrometry. Human serum albumin samples,
native and treated with 3-hydroxykynurenine in the
presence of oxygen, were used as a control. The retention
times and mass fragmentation products were compared,
and a lysyl adduct with hydroxantommathin was
identified in the urinary alpha -1-microglobulin and in the
modified albumin samples. The more extensive modification
of the urinary protein appears to be correlated
with uremia, a condition in which the catabolism of
tryptophan via the kynurenine pathway is increased, and
the consequent rise in the concentration of its derivatives is
accompanied by the oxidative processes due to the hemodialysis
treatment. The oxidative derivatives of 3-hydroxykynurenine,
which are known to act as protein crosslinking
agents, are the likely cause of the propensity of
urinary alpha -1-microglobulin to form dimers and oligomers.
This process, as well as the redox properties of these metabolites,
may contribute to the toxic effects of the kynurenine
species
A novel splicing mutation in the albumin gene (c.270+1G>T) causes analbuminaemia in a German infant
No full textA novel mutation in the albumin gene (c.1A>C) resulting in analbuminemia.
No full textBACKGROUND:
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 analbuminemia 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 polymorphism 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 transversion, for which we suggest the name Afula from the hospital where the two cases were investigated. This mutation 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 completely 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
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