Noonan-like phenotype in monozygotic twins with a duplication-deficiency of the long arm of chromosome 18 resulting from a maternal paracentric inversion.

We report on newborn monozygotic twins with a Noonan-like phenotype, and multiple congenital anomalies due to a monocentric recombinant chromosome 18. The mother carried a paracentric inversion of the long arm of chromosome 18, inv(18)(q21.1q22.3). Cytogenetic, fluorescent in situ hybridization, comparative genomic hybridization and DNA marker analyses allowed the delineation of the deleted (18q22.3-qter) and duplicated (18q12.1-q21.1) chromosomal regions in the recombinant chromosome 18, and suggest that this duplication-deletion chromosome 18 resulted from breakage of a dicentric recombinant chromosome 18 with subsequent reconstitution of telomeric sequences on the long arm. Marked variability is observed in the phenotypic expression of the same chromosomal anomaly in these monozygotic twins. The clinical findings of these patients are compared with those reported in proximal 18q-duplication and distal 18q-deletion patients. The clinical features of both infants are compatible with Noonan syndrome, suggesting that a locus for this syndrome may be located on the long arm of chromosome 18.

Structure, evolution and chromosomal localization of the human pregnancy-specific beta 1 glycoprotein gene family.

Cloning and sequencing of the cDNA of a new member of the PS beta G gene family is reported. Comparison of the sequence with those of other PS beta G cDNAs reveals a remarkable conservation of their sequence (greater than 90%) and of their general structural organization: an NH2 domain is followed by 93- and 85-residue Ig-like domains termed A and B, respectively. Most PS beta G contain two domains A in tandem followed by a single domain B. In some PS beta G members described here, alternative splicing skips the AI domain in some transcripts, yielding two- and three-domain variants, respectively. Individual PS beta G members have specific short carboxyl domains displaying little sequence conservation. The PS beta G family is closely related to the CEA gene family. A detailed comparison of the sequence of both families is given and used to construct an evolutionary tree, using the method of Li, Wu, and Luo (1985, Mol. Biol. Evol. 2: 150-174). Computation of the number of substitutions of synonymous (Ks) and nonsynonymous (Ka) sites and of the Ks/Ka ratio suggests that the PS beta G gene family appeared concomitantly with the expansion of the placental mammals and belongs to the class of rapidly evolving genes. Very little selective pressure has been exerted on the body of the molecules, especially on domain A. The analysis also suggests that PS beta G genes encoding different carboxyl domains would have been positively selected and fixed during the evolution. The PS beta G gene family was assigned to chromosome 19, which also carries the CEA genes.

Expression of human pregnancy specific beta 1 glycoprotein (PSG) genes during placental development.

Using gene-specific oligonucleotide probes, the expression of four pregnancy specific beta 1 glycoprotein (PSG) genes termed A, B, C-D and E (Streydio et al., 1988 and in press) and of some of their splice variants Ci, C and D were analysed during human placental development. Except for a stronger hybridization signal obtained at 9 weeks of gestation, which might be correlated to the development of the placenta, the relative amounts of the different PSG mRNAs showed little variation throughout pregnancy as revealed by Northern blots performed at 6, 13, 18 and 40 weeks of gestation. The expression of the different PSG genes does not seem to be developmentally regulated, in contrast to placental lactogen, used as a control, the expression of which is clearly correlated with the age of gestation. PSG D, A, E transcripts seem equally abundant, while PSG B expression was much lower. Moreover, the proportion of the PSG C-D variants resulting from alternative splicing remained constant during gestation.

The human pregnancy-specific beta 1-glycoprotein (PS beta G) and the carcinoembryonic antigen (CEA)-related proteins are members of the same multigene family.

Pregnancy-specific beta 1-glycoprotein (PS beta G), a major product of the placenta with unknown function, consists of a set of glycoproteins synthesized by the syncytiotrophoblast. We report here the molecular cloning of 3 cDNA encoding different members of the PS beta G family. Two clones (C, D) correspond to a single transcript undergoing differential splicing. The third one (E) originates from a different gene. All three clones have identical (C, D) or similar (E) coding sequences except for the last residues at their carboxyl end. They contain 93 residue motifs related to the ancestral Ig-like domain which makes them new members of this gene superfamily. A striking sequence similarity (50 to 60%) is observed between PS beta G and carcinoembryonic antigen (CEA)-related proteins. The evolutionary relationship between CEA and PS beta G points to a possible common function in the control of cell invasion and/or metastasis.

Thyrotropin controls transcription of the thyroglobulin gene.

The availability of rat thyroglobulin cDNA clones was exploited to study the regulation of thyroglobulin gene transcription by thyrotropin (TSH). Groups of rats were subjected to treatments leading to reduction or increase in the rat serum TSH (rTSH) levels. Thyroid gland nuclei were isolated, incubated in vitro in the presence of 32P-labeled uridine triphosphate, and thyroglobulin transcripts were quantitated by hybridization to immobilized rat thyroglobulin cDNA clones. Transcription of the thyroglobulin gene was found to be very active in thyroid nuclei from control animals. It represented about 10% of total RNA polymerase II activity. Chronic hyperstimulation of the thyroid glands with endogenous rTSH was achieved in rats treated with the goitrogen propylthiouracil. No significant increase of thyroglobulin gene transcription could be measured in thyroid nuclei from these animals. On the contrary, a dramatic decrease in thyroglobulin gene transcription was observed in those animals in which endogenous rTSH levels had been suppressed by hypophysectomy or by the administration of triiodothyronine. Injection of exogenous bovine TSH in such animals readily restored transcriptional activity of the gene. Our results identify transcription as an important regulatory step involved in TSH action. They suggest that normal TSH levels induce close to maximal expression of the thyroglobulin gene but that continuous presence of TSH is required in order to maintain the gene in an activated state.