Biomedical subjects
Publications and source records attributed to C Vulpe.
In nine population samples from Bulgaria, Croatia, Greece, Hungary, Republic of Macedonia (Skopje and Aromuns from Stip region), Romania, Serbia and Slovakia 12 dermatoglyphic variables have been studied. There are distinct differences between the populations and between males and females. The Macedonian Aromuns are clearly separated from the other populations.
Copper chaperones, soluble copper-binding proteins, are essential for ensuring proper distribution of copper to cellular compartments and to proteins requiring copper prosthetic groups. They are found in all eukaryotic organisms. Orthologues of the three copper chaperones characterized in yeast, ATX1, CCS and COX17, are present in Arabidopsis thaliana. Plants are faced with unique challenges to maintain metal homoeostasis, and thus their copper chaperones have evolved by diversifying and gaining additional functions. In this paper we present our current knowledge of copper chaperones in A. thaliana based on the information available from the complete sequence of its genome.
Iron, copper and zinc are essential metals for cell metabolism. Plants have evolved different schemes to efficiently mobilize low-solubility nutrients such as metals from their environment and to transport them between organs. In this review we highlight the divergences and convergences of the iron, copper and zinc uptake, transport and homoeostatic pathways.
ATP-driven heavy metal pumps represent a newly defined class of proteins that translocate toxic and essential metals across biological membranes. These transporters form a separate evolutionary branch of the ion-transporting P-type ATPases. We propose to call these enzymes CPx-type ATPases, based on the common novel feature of a conserved intramembranous cysteine-proline-cysteine or cysteine-proline-histidine motif.
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The connective-tissue disorder occipital horn syndrome (OHS) is hypothesized to be allelic to Menkes disease. The two diseases have different clinical presentations but have a similar abnormality of copper transport. Mice hemizygous for the blotchy allele of the X-linked mottled locus have similar connective-tissue defects as OHS and may represent a mouse model of this disease. We have analyzed the Menkes/mottled copper-transporting ATPase in these two potentially homologous disorders and have identified similar splicing mutations in both. Some expression of normal mRNA was detectable by reverse transcription-PCR in the mutant tissues. These findings contrast with the more debilitating mutations observed in Menkes disease and suggest that low amounts of an otherwise normal protein product could result in the relatively mild phenotype of OHS and of the blotchy mouse.
The mottled mouse has been proposed as an animal model for Menkes disease, an X-linked disorder of copper transport. The recent isolation of a copper-transporting ATPase gene responsible for Menkes disease has allowed us to test this hypothesis. Here we report the isolation and sequence of the mouse homologue of this gene. We show that two mottled (Mo) alleles, dappled (Modp) and blotchy (Moblo), have abnormalities in the murine mRNA and that Modp has a partial gene deletion. These studies prove that the mottled mouse is the murine model for Menkes disease, providing the basis for future biochemical and therapeutic studies.
Fibroblast cultures from 12 unrelated patients with classical Menkes disease were analyzed for mutations in the MNK gene, by reverse transcription-PCR (RT-PCR) and chemical cleavage mismatch detection. Mutations were observed in 10 patients, and in each case a different mutation was present. All of the mutations would be predicted to have adverse effects on protein expression. Mutations that resulted in splicing abnormalities, detected by RT-PCR alone, were observed in six patients and included two splice-site changes, a nonsense mutation, a missense mutation, a small duplication, and a small deletion. Chemical cleavage analysis of the remaining six patients revealed the presence of one nonsense mutation, two adjacent 5-bp deletions, and one missense mutation. A valine/leucine polymorphism was also observed. These findings, combined with the prior observation of deletions in 15%-20% of Menkes patients, suggest that Southern blot hybridization and RT-PCR will identify mutations in the majority of patients.
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Menkes disease is an X-linked disorder of copper transport characterized by progressive neurological degeneration and death in early childhood. We have isolated a candidate gene (Mc1) for Menkes disease and find qualitative or quantitative abnormalities in the mRNA in sixteen of twenty-one Menkes patients. Four patients lacking Mc1RNA showed rearrangements of the Menkes gene. The gene codes for a 1,500 amino acid protein, predicted to be a P-type cation-transporting ATPase. The gene product is most similar to a bacterial copper-transporting ATPase and additionally contains six putative metal-binding motifs at the N-terminus. The gene is transcribed in all cell types tested except liver, consistent with the expression of the Menkes defect.
Cytogenetic and dermatoglyphic studies were carried out in Down's Syndrome (DS) malformed girl aged 2 years, suffering with Acute Lymphoblastic Leukemia (ALL) as well as in her healthy parents. The malformed leukemic girl has about 90 percent of the analysed metaphases with the modal number 47 XX + 21, but in 15 percent of the same metaphases one notices t (9;22)(q34;q11) coexisting with trisomy 21. The mother has an inconsistent chromosomal change and the father is cytogenetically normal. The proband child's fingerprints distribution is partly similar to the mother's, but while the diseased girl has a simian line (SL) in her left hand, the healthy Father has a F1 transition form of palmar flexion creases in the left hand too. We have analysed two coexistent types of chromosomal aberrations in some metaphases of the proband girl who combines only some dermatoglyphic characteristics which are similar to each of the parents. Although the molecular basis is not known but partly in restructuring and/or repositioning of the genes in coexistent chromosomal changes we have suggested a possible way of expressing predispositional potential in leukemogenesis in which the chromosomes 21 and the genes located in them are implied.
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The incidence of spontaneous electrical activity during ischemia was studied in normal and spasmophilic subjects with a Bronk electrode inserted in the first dorsal interosseous muscle. Subjects were of both sexes, aged 16 to 65 years. The diagnosis of spasmophilia was established electromyographically by a variant of the Alajouanine test. Ischemia induced in many cases an electrical activity consisting of discharge potentials that have the amplitude, duration and morphology of motor unit potentials. The number of discharging motor units varied, sometimes leading to an electrical Trousseau associated to a carpal spasm. The discharge of individual motor units was irregular and practically uninfluenced by passive manipulations on the muscle or voluntary contraction. The activity started usually 30 sec to 1 min after the onset of ischemia, reached a maximal intensity (as to the number of motor units and frequency of discharge) in about 1 min and declined gradually in the following minutes. This activity was encountered in 55.06% of 770 cases of spasmophilia and only in 11.66% of 283 normal subjects, with a tendency to more intense discharge in spasmophilia. Its incidence in the spasmophilic group was closely related to the intensity of spontaneous repetitive discharges appearing electromyographically after the activation test, reaching 78.63% in most severe cases. The behaviour was interpreted as indicating a higher susceptibility in spasmophilia of axons to depolarization induced by hypoxia. This higher susceptibility appears as an important component of the excitability alterations leading to the complex neuromuscular disorders occurring in spasmophilia.
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