Identification, by Homozygosity Mapping, of a Novel Locus for Autosomal Recessive Congenital Ichthyosis on Chromosome 17p, and Evidence for Further Genetic Heterogeneity

Autosomal recessive congenital ichthyosis (ARCI) comprises a group of severe disorders of keratinization, characterized by variable erythema and skin scaling. It is known for its high degree of genetic and clinical heterogeneity. Mutations in the gene for keratinocyte transglutaminase (TGM1) on chromosome 14q11 were shown in patients with ARCI, and a second locus was described, on chromosome 2q, in families from northern Africa. Three other loci for ARCI, on chromosomes 3p and 19p, were identified recently. We have embarked on a whole-genome scan for further loci for ARCI in four families from Germany, Turkey, and the United Arab Emirates. A novel ARCI locus was identified on chromosome 17p, between the markers at D17S938 and D17S1856, with a maximum LOD score of 3.38, at maximum recombination fraction 0.00, at D17S945, under heterogeneity. This locus is linked to the disease in the Turkish family and in the German family. Extensive genealogical studies revealed that the parents of the German patients with ARCI were eighth cousins. By homozygosity mapping, the localization of the gene could then be refined to the 8.4-cM interval between D17S938 and D17S1879. It could be shown, however, that ARCI in the two Arab families is linked neither to the new locus on chromosome 17p nor to one of the five loci known previously. Our findings give evidence of further genetic heterogeneity that is not linked to distinctive phenotypes

Cord Blood Glutathione Depletion in Preterm Infants: Correlation with Maternal Cysteine Depletion

Background: Depletion of blood glutathione (GSH), a key antioxidant, is known to occur in preterm infants. Objective: Our aim was to determine: 1) whether GSH depletion is present at the time of birth; and 2) whether it is associated with insufficient availability of cysteine (cys), the limiting GSH precursor, or a decreased capacity to synthesize GSH. Methodology: Sixteen mothers delivering very low birth weight infants (VLBW), and 16 mothers delivering healthy, full term neonates were enrolled. Immediately after birth, erythrocytes from umbilical vein, umbilical artery, and maternal blood were obtained to assess GSH [GSH] and cysteine [cys] concentrations, and the GSH synthesis rate was determined from the incorporation of labeled cysteine into GSH in isolated erythrocytes ex vivo, measured using gas chromatography mass spectrometry. Principal Findings: Compared with mothers delivering at full term, mothers delivering prematurely had markedly lower erythrocyte [GSH] and [cys] and these were significantly depressed in VLBW infants, compared with term neonates. A strong correlation was found between maternal and fetal GSH and cysteine levels. The capacity to synthesize GSH was as high in VLBW as in term infants. Conclusion: The current data demonstrate that: 1) GSH depletion is present at the time of birth in VLBW infants; 2) As VLBW neonates possess a fully active capacity to synthesize glutathione, the depletion may arise from inadequate cysteine availability, potentially due to maternal depletion. Further studies would be needed to determine whether maternal-fetal cysteine transfer is decreased in preterm infants, and, if so, whether cysteine supplementation of mothers at risk of delivering prematurely would strengthen antioxidant defense in preterm neonates

1H-NMR-Based Metabolic Profiling of Maternal and Umbilical Cord Blood Indicates Altered Materno-Foetal Nutrient Exchange in Preterm Infants

Background: Adequate foetal growth is primarily determined by nutrient availability, which is dependent on placental nutrient transport and foetal metabolism. We have used 1H nuclear magnetic resonance (NMR) spectroscopy to probe the metabolic adaptations associated with premature birth. Methodology: The metabolic profile in 1H NMR spectra of plasma taken immediately after birth from umbilical vein, umbilical artery and maternal blood were recorded for mothers delivering very-low-birth-weight (VLBW) or normo-ponderal full-term (FT) neonates. Principal Findings: Clear distinctions between maternal and cord plasma of all samples were observed by principal component analysis (PCA). Levels of amino acids, glucose, and albumin-lysyl in cord plasma exceeded those in maternal plasma, whereas lipoproteins (notably low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) and lipid levels were lower in cord plasma from both VLBW and FT neonates. The metabolic signature of mothers delivering VLBW infants included decreased levels of acetate and increased levels of lipids, pyruvate, glutamine, valine and threonine. Decreased levels of lipoproteins glucose, pyruvate and albumin-lysyl and increased levels of glutamine were characteristic of cord blood (both arterial and venous) from VLBW infants, along with a decrease in levels of several amino acids in arterial cord blood. Conclusion: These results show that, because of its characteristics and simple non-invasive mode of collection, cord plasma is particularly suited for metabolomic analysis even in VLBW infants and provides new insights into the materno-foetal nutrient exchange in preterm infants

Plasma amino acid pools in the umbilical cord artery show lower 15 N natural isotope abundance relative to the maternal venous pools

International audienceN natural isotope abundance (NIA) is systematically higher in infants’ hair than in that of their mothers at birth. This study aimed to investigate this difference in plasma pools. We compared 15N NIA values for plasma amino acid (AA) pools (free + protein-bound) in the umbilical cord artery (UCA) and vein (UCV) and in the maternal vein (MV) at birth. This preliminary study included 7 mother–infant dyads. Whole plasma was treated (HCl) to hydrolyze protein. Following derivatization, AAs were separated using gas chromatography and compound-specific 15N NIA values were measured on-line using an isotope ratio monitoring mass spectrometer. 15N NIA plasma AA pools in the UCA and UCV were highly correlated to the MV, r2 > 0.89 and r2 > 0.88 (both P < 10−4) respectively. The full model found a significant effect of sampling compartment (P = 0.02) and AA type (P < 0.0001) on 15N NIA plasma AA values. 15N NIA plasma AA was 0.74 ‰ higher (P = 0.01) in the MV than in the UCA. This study indicates that a decrease in 15N NIA for plasma AA pools occurs in the fetal–placental unit

Maternal and cord blood plasma metabolite differences between full-term and VLBW subjects.

<p>Values are given as area normalized peak signals mean (n = 8 for each group).</p>§<p>designates spectral signals integrated from NOESY spectra, all other signals being integrated from CPMG spectra.</p>†<p>Significant differences at p<0.01 and p<0.05 are designated by # and *, respectively.</p

500 MHz 1H NMR CPMG spectra of blood plasma samples from VLBW deliveries.

<p>(A) Arterial cord blood, (B) Venous cord blood (C) Maternal blood. The same spectral profile was obtained for arterial and venous blood plasma, whereas the spectrum of maternal blood plasma was different. The differences are marked by +.</p

Multivariate analyses resulting from the standard 1D 500 MHz ¹H NMR spectra from FT and VLBW preterm deliveries.

<p>(A): PCA scores plot resulting from the analysis of maternal plasma. (B): PLS-DA scores plot resulting from the analysis of arterial umbilical cord plasma and validation by permutation test (C). (C): R²(X) = 0.366, R²(Y) = 0.695 and Q²(Cum) = 0.676. The model has been validated by a permutation test (n = 20). R² intercept is at 0.495 and Q² intercept is at −0.212.</p

500 MHz ¹H NMR spectra of arterial umbilical cord plasma from a VLBW delivery.

<p>(A) standard NOESYPR1D spectrum; (B) 1D relaxation–edited (CPMG) spectrum. Assignment: 1, HDL; 2, LDL; 3, VLDL; 4, valine; 5, leucine; 6, isoleucine; 7, lactate; 8, alanine; 9; lipid; 10, <i>N</i>-acetyl glycoprotein; 11, unsaturated lipid; 12, <i>β</i>-hydroxybutyrate; 13, lipid; 14, acetate; 15, glutamine; 16, acetone; 17, pyruvate; 18, succinate; 19, albumin-lysyl; 20, creatinine; 21, glucose; 22, threonine; 23, tyrosine; 24, methylhistidine; 25, phenylalanine; 26, formate.</p

Selected clinical characteristics of enrolled infants and their mothers.

<p>Data are reported as n (%) or median [interquartile 25–75].</p>†<p>Inter-group comparison by Mann-Whitney U test.</p

500 MHz ¹H NMR CPMG spectra of maternal, cord venous and cord arterial plasma.

<p>Note the presence of traces ethanol in most spectra and high ethanol and possibly propionate (1.05 ppm) in one unusual maternal profile (the top one). This figure also shows the differences in lipids between maternal and cord plasma (higher levels of lipid signals at 0.90, 1.23, 1.72 and 2.00 ppm) and in lysine levels (signals at 1.71 and 1.90 ppm higher in maternal plasma).</p