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T Costa

Publications and source records attributed to T Costa.

At least 37 records · Page 2Linked to original sources
PubMed1998

Grebe syndrome: clinical and radiographic findings in affected individuals and heterozygous carriers.

Grebe syndrome is a recessively inherited acromesomelic dysplasia. We studied, clinically and radiographically, 10 affected individuals, originating from Bahia, Brazil. The phenotype is characterized by a normal axial skeleton and severely shortened and deformed limbs, with a proximo-distal gradient of severity. The humeri and femora were relatively normal, the radii/ulnae and tibiae/fibulae were short and deformed, carpal and tarsal bones were fused, and several metacarpal and metatarsal bones were absent. The proximal and middle phalanges of the fingers and toes were invariably absent, while the distal phalanges were present. Postaxial polydactyly was found in several affected individuals. Several joints of the carpus, tarsus, hand, and foot were absent. Heterozygotes presented with a variety of skeletal manifestations including polydactyly, brachydactyly, hallux valgus, and metatarsus adductus. Grebe syndrome is caused by a missense mutation in the gene encoding cartilage-derived morphogenetic protein-1.

Abnormalities, Multiple↗
PubMed1998

Monozygotic twins with 45,X/46,XY mosaicism discordant for phenotypic sex.

We report on two sets of monozygotic twins (MZTs) discordant for phenotypic sex ascertained at birth when the female twin was noted to have signs of the Ullrich-Turner syndrome. Cytogenetic investigations on the female of the first pair showed 45,X/46,XY mosaicism in lymphocytes but fibroblasts grown from two skin biopsies at separate sites and from gonadal tissue showed only 45,X cells. The male showed mosaicism in both blood lymphocytes and skin fibroblasts. In the second family, both twins also showed mosaicism in lymphocytes. The female had a 45,X karyotype in fibroblasts from skin and gonadal tissue, but in contrast to the first family, the male twin had a normal male karyotype in fibroblasts from skin biopsy and from connective tissue adjacent to the vas deferens. Discordant phenotypic sex in monozygotic twins is rare. As in our cases, the nine previously reported sets of MZTs all had mosaicism for sex chromosome abnormalities. A mitotic error leading to the loss of a Y chromosome prior to, accompanying, or following the twinning process would account for the reported combinations of karyotypes.

Female↗
PubMed1998

Interaction mode of the phe-phenyl group of thrombin receptor-tethered ligand SFLLRNP in receptor activation.

Phenylalanine at position 2 of thrombin receptor-tethered ligand peptide (SFLLRNP) is crucially important for the activation of thrombin receptor. Its substitution by para-fluorophenylalanine [(p-F)Phe] enhanced several times the activity in human epithelial-like SH-EP cells [Nose et al. (1993) Biochem. Biophys. Res. Commun. 193, 694-699]. To clarify the interaction mode of Phe-2-phenyl in receptor activation, a series of analogs having chemical modifications on the benzene ring of Phe-2 were synthesized and examined for their ability to induce the aggregation of human platelets. When the fluorine atom was placed at the meta or ortho position, the resulting analogs exhibited considerably diminished activity (about 10-20% of para-derivative), indicating that the substitution is allowed only at the para position. The derivative with pentafluorophenylalanine was totally devoid of activity. These results suggested that Phe-2 requires hydrogen atom(s) on the benzene ring presumably for interaction with the receptor. No activity enhancement was observed for analogs with para-chloro-, bromo-, or iodophenylalanine, indicating the importance of the high electronegativity of fluorine to intensify the dipole of CH(s) remaining in the Phe-2-benzene ring. Inactivity of analogs having para-iodophenylalanine and homophenylalanine indicated the importance of the size of para substituents, and the placement of hydroxyl, nitro, and trifluoromethyl groups at the para position led to no activity. The interaction of Phe-2 of SFLLRNP appeared to be structurally restricted to a limited space in the receptor. The results suggested the presence of face-to-edge pi-pi interaction based upon the CH/pi interaction between the ligand Phe-2-phenyl group and the receptor aromatic group.

Amino Acid Sequence↗
PubMed1998

Severe prenatal growth retardation, dysmorphic features, pigmentary retinopathy, and generalized absence of subcutaneous tissues: a new entity?

We report a girl with severe prenatal and postnatal growth retardation, congenital generalized absence of subcutaneous tissue, and facial and somatic changes with some similarities to Wiedemann-Rautenstrauch syndrome (WRS). However, the patient's condition is sufficiently different from those reported previously to suggest that this patient represents a new syndrome. The abnormalities observed in this patient overlap with those of WRS, Cockayne syndrome, type A (CSA), and osteodysplastic primordial dwarfism type III (OPD III), but also include choanal atresia and pigmentary retinopathy.

Abnormalities, Multiple↗
PubMed1997

A mutation changes ligand selectivity and transmembrane signaling preference of the neurokinin-1 receptor.

We studied the biochemical properties of a genetically engineered neurokinin-1 receptor (NK1R) in which two residues lying on the extracellular edge of the fourth transmembrane domain were replaced by equivalently located elements of the neurokinin-2 receptor (G166C, Y167F NK1R mutant). The mutation produced two effects. The first is enhancement of the apparent binding affinity for heterologous tachykinins (substance K and neurokinin B) and for N- or C-terminal modified analogues of substance P, but not for substance P itself, its full-length analogues, and several peptide and nonpeptide antagonists. Only two antagonists, as exceptions, were found to exhibit a diminished affinity for the mutant receptor. The second effect is a shift in NK1R preference for distinct G protein-mediated signaling pathways. NK1R-mediated phosphoinositide hydrolysis was enhanced both in transiently and permanently transfected cells, while stimulation of cAMP accumulation did not change in transient expression experiments and was reduced in permanently expressing cells. The effect of the mutation on ligand affinity was not related to any obvious structural commonality, nor to the selectivity for different neurokinin receptors or the agonistic/antagonistic nature of the ligand. However, all ligands responding to the mutation appear to share the ability to induce phosphoinositide signaling more efficiently than cAMP responses when binding to NK1R. We suggest that the mutation shifts the internal equilibria of different functional forms of NK1R. A theoretical analysis according to a multistate allosteric model suggests that the link between binding and biological changes can result from altered stability constants of substates in the conformational space of the receptor.

Allosteric Site↗
PubMed1997

The activation process of the alpha1B-adrenergic receptor: potential role of protonation and hydrophobicity of a highly conserved aspartate.

In this study, a quantitative approach was used to investigate the role of D142, which belongs to the highly conserved E/DRY sequence, in the activation process of the alpha1B-adrenergic receptor (alpha1B-AR). Experimental and computer-simulated mutagenesis were performed by substituting all possible natural amino acids at the D142 site. The resulting congeneric set of proteins together with the finding that all the receptor mutants show various levels of constitutive (agonist-independent) activity enabled us to quantitatively analyze the relationships between structural/dynamic features and the extent of constitutive activity. Our results suggest that the hydrophobic/hydrophilic character of D142, which could be regulated by protonation/deprotonation of this residue, is an important modulator of the transition between the inactive (R) and active (R*) state of the alpha1B-AR. Our study represents an example of quantitative structure-activity relationship analysis of the activation process of a G protein-coupled receptor.

Adrenergic alpha-Agonists↗
PubMed1997

Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1.

Alagille syndrome is an autosomal dominant disorder characterized by abnormal development of liver, heart, skeleton, eye, face and, less frequently, kidney. Analyses of many patients with cytogenetic deletions or rearrangements have mapped the gene to chromosome 20p12, although deletions are found in a relatively small proportion of patients (< 7%). We have mapped the human Jagged1 gene (JAG1), encoding a ligand for the developmentally important Notch transmembrane receptor, to the Alagille syndrome critical region within 20p12. The Notch intercellular signalling pathway has been shown to mediate cell fate decisions during development in invertebrates and vertebrates. We demonstrate four distinct coding mutations in JAG1 from four Alagille syndrome families, providing evidence that it is the causal gene for Alagille syndrome. All four mutations lie within conserved regions of the gene and cause translational frameshifts, resulting in gross alterations of the protein product Patients with cytogenetically detectable deletions including JAG1 have Alagille syndrome, supporting the hypothesis that haploinsufficiency for this gene is one of the mechanisms causing the Alagille syndrome phenotype.

Alagille Syndrome↗
PubMed1997

Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1.

Chondrodysplasia Grebe type (CGT) is an autosomal recessive disorder characterized by severe limb shortening and dysmorphogenesis. We have identified a causative point mutation in the gene encoding the bone morphogenetic protein (BMP)-like molecule, cartilage-derived morphogenetic protein-1 (CDMP-1). The mutation substitutes a tyrosine for the first of seven highly conserved cysteine residues in the mature active domain of the protein. We demonstrate that the mutation results in a protein that is not secreted and is inactive in vitro. It produces a dominant negative effect by preventing the secretion of other, related BMP family members. We present evidence that this may occur through the formation of heterodimers. The mutation and its proposed mechanism of action provide the first human genetic indication that composite expression patterns of different BMPs dictate limb and digit morphogenesis.

Amino Acid Sequence↗
PubMed1997

Discrimination of a novel type of rat brain delta opioid receptors by enkephalin analog containing structurally constrained cyclopropylphenylalanine (inverted delta Phe).

Four different stereoisomers of cyclopropylphenylalanine (inverted delta Phe) were incorporated into [D-Ala2,Leu5]enkephalin at the position 4. These conformationally restricted enkephalin analogs were evaluated for their binding characteristics to mu and delta opioid receptors in rat brain. A striking finding is that the E-(2R,3S)-isomer binds to a novel class of delta receptors and discriminates this receptor from the ordinary delta receptor. This new type of delta receptor suspected to be a receptor which suppresses the thermal analgesia mediated through mu receptor. The Z-(2R,3R)-isomer was very potent with several times more enhanced affinity to delta receptors than to mu receptors, but could not differentiate the delta receptors. The Z-(2S,3S)-isomer was weak, and E-(2S,3R)-isomer was almost inactive.

Animals↗
PubMed1997

Monozygotic twins discordant for Aicardi syndrome.

Aicardi syndrome is a developmental disorder characterised by agenesis of the corpus callosum, retinal lacunae, seizures, and developmental delay. It is believed to be X linked with lethality in males. We report a set of monozygotic female twins one of whom is healthy and intellectually normal while the other has the classical Aicardi phenotype with profound retardation. Family history is negative. Both had normal karyotypes. Monozygosity was established by blood grouping, chromosomal heteromorphisms, and DNA analysis using six hypervariable probes (five autosomal and one X linked) and three X linked RFLP probes. We tested the hypothesis that preferential inactivation of a different X chromosome had occurred in each girl. Methylation sensitive RFLP analysis of DNA from EBV transformed B lymphocytes and cultured skin fibroblasts using MspI/HpaII digestion and probing with M27 beta showed a very similar pattern of X inactivation in both twins with no evidence of preferential expression of one particular X chromosome. We conclude that the abnormalities in the affected twin are probably the consequence of a postzygotic mutation in early embryonic development.

Abnormalities, Multiple↗
PubMed1996

Identification of genes from a 500-kb region at 7q11.23 that is commonly deleted in Williams syndrome patients.

Williams syndrome (WS) is a multisystem developmental disorder caused by the deletion of contiguous genes at 7q11.23. Hemizygosity of the elastin (ELN) gene can account for the vascular and connective tissue abnormalities observed in WS patients, but the genes that contribute to features such as infantile hypercalcemia, dysmorphic facies, and mental retardation remain to be identified. In addition, the size of the genomic interval commonly deleted in WS patients has not been established. In this study we report the characterization of a 500-kb region that was determined to be deleted in our collection of WS patients. A detailed physical map consisting of cosmid, P1 artificial chromosomes, and yeast artificial chromosomes was constructed and used for gene isolation experiments. Using the techniques of direct cDNA selection and genomic DNA sequencing, three known genes (ELN, LIMK1, and RFC2), a novel gene (WSCR1) with homology to RNA-binding proteins, a gene with homology to restin, and four other putative transcription units were identified. LIMK1 is a protein kinase with two repeats of the LIM/double zinc finger motif, and it is highly expressed in brain. RFC2 is the 40-kDa ATP-binding subunit of replication factor C, which is known to play a role in the elongation of DNA catalyzed by DNA polymerase delta and epsilon. LIMK1 and WSCR1 may be particularly relevant when explaining cognitive defects observed in WS patients.

Amino Acid Sequence↗
PubMed1996

Constitutively active mutants of the alpha 1B-adrenergic receptor: role of highly conserved polar amino acids in receptor activation.

Site-directed mutagenesis and molecular dynamics simulations of the alpha 1B-adrenergic receptor (AR) were combined to explore the potential molecular changes correlated with the transition from R (inactive state) to R (active state). Using molecular dynamics analysis we compared the structural/dynamic features of constitutively active mutants with those of the wild type and of an inactive alpha 1B-AR to build a theoretical model which defines the essential features of R and R. The results of site-directed mutagenesis were in striking agreement with the predictions of the model supporting the following hypothesis. (i) The equilibrium between R and R depends on the equilibrium between the deprotonated and protonated forms, respectively, of D142 of the DRY motif. In fact, replacement of D142 with alanine confers high constitutive activity to the alpha 1B-AR. (ii) The shift of R143 of the DRY sequence out of a conserved 'polar pocket' formed by N63, D91, N344 and Y348 is a feature common to all the active structures, suggesting that the role of R143 is fundamental for mediating receptor activation. Disruption of these intramolecular interactions by replacing N63 with alanine constitutively activates the alpha 1B-AR. Our findings might provide interesting generalities about the activation process of G protein-coupled receptors.

Adrenergic beta-Agonists↗
PubMed1996

Selective enhancement by serum factors of cyclic AMP accumulation in rat microglial cultures.

Using purified microglial cultures obtained from the neonatal rat brain we found that media containing fetal calf serum (as well as human, horse and goat sera) enhanced by about 3-fold the accumulation of cyclic AMP induced by the beta-adrenergic agonist isoproterenol and did not affect in a significant way that induced by the direct adenylyl cyclase stimulator forskolin. The effect of fetal calf serum was (i) dose dependent, and statistically significant also at serum concentrations below 1%; (ii) rapidly lost (half life of about 15 min) when the serum-containing medium was exposed to microglia, astrocytes or neuroblastoma cells; (iii) present also when cyclic AMP accumulation was enhanced by prostaglandin E2 or by cholera toxin; (iv) absent on basal cyclic AMP levels. When media containing fetal calf serum or the other mammalian sera mentioned above were tested on astrocyte cultures, an inhibitory, rather than enhancing activity on cyclic AMP levels was observed, indicating that the facilitatory factor(s) present in serum acts specifically on microglial cells. Moreover, in astrocytes the effect of serum was identical when tested on basal and on isoproterenol or forskolin-stimulated cyclic AMP levels. Thus, the mechanism of cyclic AMP inhibition in astrocytes is unrelated to the mechanism of activation in microglia. Our observations suggest that serum contains factor(s), promptly cleared by different cell types. Such factors may interact with so far unidentified microglial receptors responsible for a facilitation of G protein-mediated activation of adenylyl cyclase. Regulation of the cyclic AMP cascade at this step has not been described previously, and may be important for the modulation of microglial functions controlled by the cyclic nucleotide.

Adrenergic beta-Agonists↗