Secretion of the vasoactive peptides, endothelin, and parathyroid hormone-related peptide, by decidual explants from pregnancies complicated by intrauterine growth restriction.

OBJECTIVE: To determine whether in vitro secretion of two vasoactive peptides, endothelin and parathyroid hormone-related peptide (PTHrP), is different in decidua from pregnancies complicated by intrauterine growth restriction (IUGR) than in normal pregnancies. METHODS: In ten IUGR and nine gestational age-matched control pregnancies, decidua was collected at delivery and explants cultured for 24 hours. Endothelin and PTHrP concentrations in the conditioned medium were determined. Lactate dehydrogenase release into the medium was measured at 4 and 24 hours in a separate group of four IUGR and three control decidua. RESULTS: Endothelin and PTHrP secretion by the decidua of the IUGR pregnancies were markedly lower than those in controls (endothelin 51 +/- 11 versus 105 +/- 16 pg/100 mg tissue/24 hours, P = .01; PTHrP 164 +/- 17 versus 641 +/- 209 ng/100 mg tissue/24 hours, P = .02). Lactate dehydrogenase release into the medium was not different between the IUGR and control decidua. CONCLUSIONS: Based on the known effects of endothelin and PTHrP on vascular smooth muscle, it was originally anticipated that more endothelin and less PTHrP would be secreted by the IUGR decidua than the control. The finding that both peptides decreased could not be explained by route of delivery or global tissue dysfunction. Investigation of potential mediators of decidual ET and PTHrP will be necessary to determine why these hormones are both decreased in pregnancies complicated by IUGR.

The secretion of insulin-like growth factor I, prolactin and insulin-like growth factor binding protein 1 by the decidua as predictors of human fetal growth.

To determine if in vitro secretion of the decidual peptides insulin-like growth factor I (IGF-I), prolactin or insulin-like growth factor binding protein 1 (IGFBP-1) correlates with infant birthweight in uncomplicated, term human pregnancies, decidua from 45 pregnancies with normally distributed birthweights was cultured in defined medium for 24 h. IGF-I, prolactin and IGFBP-1 concentrations in the culture medium were measured by radioimmunoassay. Neither infant birthweight nor a normalized measure of infant birthweight (birthweight z-score) correlated with the quantity of IGF-I, prolactin or IGFBP-1 secreted by the decidua from that pregnancy. There were no differences in any of the peptide hormones assayed when the pregnancies were grouped by infant sex. IGF-I and prolactin secretion by individual decidual samples correlated positively. IGF-I and IGFBP-1 secretion also correlated positively in individual samples. A previously identified correlation between decidual IGF-I secretion and infant birthweight among a group of normal and growth restricted (IUGR) pregnancies was not confirmed in the current study. These data indicate that the decrease in decidual IGF-I and prolactin secretion seen in IUGR pregnancies is not the hormone profile of the low birthweight end of a normal population, but a distinct endocrine profile.

Molecular basis of ornithine aminotransferase deficiency in B-6-responsive and -nonresponsive forms of gyrate atrophy.

Gyrate atrophy (GA), a recessive eye disease involving progressive loss of vision due to chorioretinal degeneration, is associated with a deficiency of the mitochondrial enzyme ornithine aminotransferase (OATase; ornithine-oxo-acid aminotransferase; L-ornithine:2-oxo-acid aminotransferase, EC 2.6.1.13) with consequent hyperornithinemia. Genetic heterogeneity of GA has been suggested by the demonstration that administration of pyridoxine to increase the level of pyridoxal phosphate, a cofactor of OATase, reduces hyperornithinemia in a subset of patients. We have cloned and sequenced cDNAs for OATase from two GA patients, one responsive and one nonresponsive to pyridoxine treatment. The respective cDNAs contained different single missense mutations, which were sufficient to eliminate OATase activity when each cDNA was tested in a eukaryotic expression system. However, like the enzyme in fibroblasts from the pyridoxine-responsive patient, OATase encoded by the corresponding cDNA from this individual showed a significant increase in activity when assayed in the presence of an increased pyridoxal phosphate concentration. These data firmly establish that both pyridoxine responsive and nonresponsive forms of GA result from mutations in the OATase structural gene. Moreover, they provide a molecular characterization of the primary lesion in a pyridoxine-responsive genetic disorder.

The ornithine aminotransferase (OAT) locus: analysis of RFLPs in gyrate atrophy.

A cDNA probe (HOAT1) for ornithine aminotransferase (OAT) has recently been used to map (1) the structural gene for this enzyme to chromosome 10 and (2) several related DNA sequences to the X chromosome. We have defined six RFLPs for OAT, to explore its possible role in gyrate atrophy (GA) of the choroid and retina, an autosomal recessive genetic disorder associated with a deficiency of OAT activity. The RFLPs, which are detected by noncoding single-copy probes from the OAT gene and by subclones of the HOAT1 cDNA, all map on human chromosome 10, producing an overall level of heterozygosity for the OAT locus of 83%. Using the RFLPs, we have determined that the OAT locus segregates concordantly with GA in one available pedigree. Furthermore, the RFLPs display significant disequilibrium with GA, providing genetic evidence implicating a defect in the OAT structural gene as the cause of this disorder. The RFLPs for OAT are potentially applicable to prenatal diagnosis and carrier detection in families with a previous history of GA. They will also allow identification of specific haplotypes associated with GA chromosomes, as a guide for more detailed molecular-genetic investigations of the mutations underlying the disorder.