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Biomedical subjects

Antonio Cao

Publications and source records attributed to Antonio Cao.

36 records · Page 2Linked to original sources
PubMed2003

Fetal HLA typing in beta thalassaemia: implications for haemopoietic stem-cell transplantation.

Stem-cell transplantation can cure beta thalassaemia. We aimed to assess whether fetal HLA typing done early in the pregnancy of couples who were at risk of beta thalassaemia could provide an alternative to pregnancy termination if the prospect of a bone-marrow transplantation from a family member was available. In our clinic in Sardinia, we did fetal HLA typing for 49 couples at risk of having a baby with beta thalassaemia. Two affected children were born and successfully received a transplantation from a family donor. Five non-affected fetuses were HLA compatible with an affected sibling and their cord blood was harvested for a future transplantation.

Fetal Diseases↗
PubMed2003

Characterization of the molecular defect in the ATP7B gene in Wilson disease patients from Yugoslavia.

Wilson disease (WD) is an autosomal recessive disorder of copper metabolism resulting from the absence or dysfunction of a copper transporting P-type ATPase (ATP7B). Approximately 150 mutations of the ATP7B have been identified to date. In this paper, we report the results of molecular characterization and genotype-phenotype analysis, which we have carried out on 35 patients from Yugoslavia affected by WD. Using single-strand conformational polymorphism (SSCP) followed by direct sequencing, we characterized the molecular defect in 80% of WD chromosomes and found 11 different mutations, three of which are novel. The most common mutations that accounted for the molecular defect in 71.3% of WD chromosomes were H1069Q (48.9%), 2304-2305insC (11.4%), R616Q (5.7%), and A1003T (5.7%). The results produced in this paper indicate that the best strategy for mutation detection in Yugoslavian patients with WD is an SSCP analysis of exons 14, 8, 5, and 13, where most of the defects (73.1%) lie, followed by mutation analysis of the remaining exons in ATP7B in patients in whom the mutation was not detected by the finitial screening. These data can be used to develop straightforward genetic testing in this population or in other countries composed of a genetically mixed population like the United States, where a significant number of immigrants came from Central and Eastern Europe.

Adenosine Triphosphatases↗
PubMed2002

Homozygosity for nondeletion delta-beta(0) thalassemia resulting in a silent clinical phenotype.

The clinical phenotype of homozygous beta thalassemia varies in severity from the mild thalassemia intermedia to the severe thalassemia major. This variability depends largely on the molecular heterogeneity of beta thalassemia defects. We report the first case of a homozygous state for nondeletion Sardinian delta-beta(0) thalassemia, which resulted in a symptomless clinical phenotype with a peculiar hemoglobin (Hb) pattern (99.8% Hb F and 0.2% Hb A(2)). The molecular defect was characterized by the presence of 2 nucleotide substitutions: -196C>T in the promoter of the Agamma-globin gene and beta 39C>T nonsense mutation. The absence of typical beta thalassemia clinical findings was due to the high Hb F output, which compensated for the absence of beta chains. The near absence of Hb A(2) may have resulted from either alterations in the globin gene transcriptional complex with preferential activation of gamma-globin genes and suppression of delta-globin genes or preferential survival of red blood cells with the highest Hb F content and low Hb A(2) level.

Female↗
PubMed2002

Carrier screening and genetic counselling in beta-thalassemia.

This paper review the most important aspects of carrier detection procedures, genetic counselling, population screening and prenatal diagnosis of beta-thalassemias. Carrier detection can be made retrospectively, following the birth of an affected child or prospectively. Several programmes, with the aim of preventing homozygous beta-thalassemia, based on carrier screening and counselling of couples at marriage; preconception or early pregnancy, are operating in several Mediterranean at-risk populations. These programmes have been very effective, as indicated by increasing knowledge on thalassemia and its prevention by the target population and by the marked decline of the incidence of thalassemia major. Carrier detection is carried out by haematological methods followed by mutation detection by DNA analysis. Prenatal diagnosis is accomplished by mutation analysis on PCR-amplified DNA from chorionic villi. Future prospects include automation of the process of mutation-detection, simplification of preconception and preimplantation diagnosis and fetal diagnosis by analysis of fetal cells in maternal circulation.

Female↗
PubMed2002

Screening for thalassemia: a model of success.

Programs of prospective carrier screening and genetic counseling for beta-thalassemia among couples planning marriage, preconception, or during early pregnancy are ongoing in several at-risk populations in the Mediterranean area, including Greeks, Greek Cypriots and Continental Italians. Carrier detection is carried out by haematological analysis followed by mutation detection by DNA analysis. Once carrier couples are identified, prenatal diagnosis is accomplished by mutation analysis on PCR amplified DNA from chorionic villi. These programs have been very effective, due to education programs and subsequent acceptance of screening. Future prospects include automation of the process of mutation detection by microchips analysis, introduction of preconception and preimplantation diagnosis and hopefully fetal diagnosis by analysis of fetal cells in maternal circulation.

DNA Mutational Analysis↗
PubMed2002

A novel DKC1 mutation, severe combined immunodeficiency (T+B-NK- SCID) and bone marrow transplantation in an infant with Hoyeraal-Hreidarsson syndrome.

X-linked Hoyeraal-Hreidarsson syndrome (XL-HHS) is the severe infantile variant of X-linked dyskeratosis congenita (XL-DC) and both are due to mutations in the DKC1 gene within Xq28. We report a novel missense mutation in DKC1 exon 3 (T113-->C, Ile38Thr) in a Sardinian infant with XL-HHS in whom the disease was characterized by 'T+B-NK-' severe combined immunodeficiency and bone marrow failure. He underwent sibling bone marrow transplantation using a conditioning regimen (fludarabine, rabbit antithymocyte globulin, low-dose melphalan) selected according to the HHS/DC phenotype. This was associated with low toxicity, prompt engraftment with adequate immune reconstitution and full donor haemopoiesis.

Bone Marrow Diseases↗
PubMed2002

Frequency of hemochromatosis C282Y and H63D mutations in Sardinia.

Hereditary hemochromatosis (HH) is one of the most common autosomal recessive disorders of iron metabolism among Caucasians, and it is associated with C282Y mutation of the HFE gene in populations of Celtic origins. A second mutation, H63D, shows a very high widespread frequency, although its role in iron metabolism is still inconclusive. There are no data on the frequencies of these two mutations in Sardinia, an island in the Mediterranean sea that has not been invaded by Celtic peoples. We examined 836 chromosomes from Sardinian subjects and tested for the mutation by restriction enzyme digestion of PCR products. Among the 836 analyzed chromosomes, we found a C282Y allele frequency of 0.0036 and an H63D allele frequency of 0.173. These data could explain the observed rarity of HH in Sardinia. The high allele frequency of H63D and the rarity of HH in Sardinia is suggestive that this mutation is not a major contributor to this disease.

Gene Frequency↗
PubMed2002

Regulation of the globin genes.

The a- and b-globin gene clusters are subject to several levels of regulation. They are expressed exclusively in the erythroid cells, only during defined periods of development and in a perfectly tuned way, assuring, at any stage of ontogeny, a correct balance in the availability of a- and b-globin chains for hemoglobin assembling. Such a tight control is dependent on regulatory regions of DNA located either in proximity or at great distances from the globin genes in a region characterized by the presence of several DNAse I hypersensitive sites and known as the Locus Control Region. All these sequences exert stimulatory, inhibitory or more complex activities by interacting with transcription factors that bridge these regions of DNA to the RNA polymerase machinery. Many of these factors have now been cloned and the corresponding mouse genes inactivated, shading new light on the metabolic pathways they control. It is increasingly recognized that such factors are organized into hierarchies according to the number of genes and circuits they regulate. Some genes such as GATA-1 and 2 are master regulators that act on large numbers of genes at early stage of differentiation whereas others, like EKLF, stand on the lowest step and control only single or limited number of genes at late stages of differentiation. We will review recent data gathered from expression studies in cell cultures, in transgenic or K.O. murine models as well as from a clinical settings. We will also discuss the development of novel theories on the regulation of the a- and b-globin genes and clusters.

Animals↗
PubMed2002

Delineation of the molecular defects in the AIRE gene in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients from Southern Italy.

In this study, we have carried out molecular analysis of the AIRE (autoimmune regulator) gene in 11 patients (from 8 families) affected by autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, originating from a restricted area of Southern Italy (the Salento peninsula in Puglia). Of the 16 mutant AIRE alleles from the 8 probands studied, 12 carried a missense mutation (W78R in 9, P539L in 2, and P252L in 1), 2 carried the Q358X nonsense mutation, and 2 carried the 1058delT frameshift mutation. All these mutations except the 1058delT are novel. Each of the detected mutations either predicts a premature termination of the protein or results in a nonconservative amino acid change, most likely adversely affecting the function of the protein. The W78R missense mutation is relatively common in these patients, having been detected (in homozygosity or compound heterozygosity) in 6 of the 8 probands tested, indicating the presence of a founder effect. The results of this study contribute to the delineation of the molecular pathology of the AIRE gene and enhance our ability to perform a molecular diagnosis in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients from Southern Italy.

Adolescent↗
PubMed2002

H63D mutation in the HFE gene increases iron overload in beta-thalassemia carriers.

BACKGROUND AND OBJECTIVES: Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism. The HFE gene implicated in this disorder has been identified on chromosome 6 (6p21.3). The most prevalent mutation in HH patients changes the 282 cysteine residue to tyrosine (C282Y). The role of a second mutation which changes the 63 histidine to aspartic acid (H63D) in iron overload has been controversial. The aim of this study was to evaluate the effect of the H63D mutation on the ferritin levels of beta-thalassemia carriers. DESIGN AND METHODS: beta-thalassemia carriers have a tendency to increase iron absorption because of mild anemia and slightly increased erythropoiesis. Differences in ferritin levels between homozygotes for H63D and wild type may indicate a modulator effect of the HFE mutation on iron absorption. We studied 152 healthy males, heterozygous for beta-thalassemia. Serum ferritin was measured by chemiluminescence. H63D genotypes were determined by digestion of polymerase chain reaction (PCR) products with MboI restriction enzyme. RESULTS: Forty-five subjects were H63D heterozygotes and four subjects were H63D homozygotes. Ferritin levels were (mean +/- SD): 250 +/- 138 microg/L in homozygotes for the wild type H/H; 295 +/- 186 microg/L in H/D heterozygotes; and 389 +/- 75 microg/L in homozygotes for the mutation D/D. The difference in ferritin values between H/H and D/D is statistically significant (p=0.022). INTERPRETATION AND CONCLUSIONS: beta-thalassemia carriers who are homozygotes for the H63D mutation have higher ferritin levels than beta-thalassemia carriers with the H/H genotype, suggesting that the H63D mutation may have a modulating effect on iron absorption.

Ferritins↗
PubMedDate not supplied

Cloning MafF by recognition site screening with the NFE2 tandem repeat of HS2: analysis of its role in globin and GCSl genes regulation.

The erythroid-specific enhancer within hypersensitivity site 2 (HS2) of the human beta-globin locus control region is required for high level globin gene expression. We used an oligonucleotide of the NF-E2 tandem repeat, within HS2, as recognition site probe to screen a K562 cDNA library for interacting transcription factors. A 2.3 kb full length cDNA encoding the b-zip transcription factor MafF was isolated. MafF can form both homodimers and high affinity heterodimers with Nrf1, Nrf2 and Nf-E2, three members of the CNC-bZip family. Despite obvious structural similarities with the other small Maf proteins, MafF differs in its tissue distribution and its inability to repress transcription when overexpressed as homodimer. In fact, in different cell lines and on different promoters (gamma-globin, beta-globin and glutamylcysteine synthetase genes) the MafF homodimers do not appreciably affect transcription of target promoters, whereas MafF/CNC member heterodimers act as weak transcriptional activators. Even though MafF was cloned using probes derived from the globin LCR, it is in the context of the GCSl promoter and in combination with Jun that MafF shows a rather distinct and specific regulatory role. These observations suggest that a complex network of small Maf and CNC-AP1 protein interactions might be involved in regulating transcription in diverse tissues or developmental stages.

Base Sequence↗
PubMedDate not supplied

Neural tube defects in the offspring of thalassemia carriers.

OBJECTIVES: The risk of neural tube defects (NTDs) is negatively correlated with maternal folate levels in early pregnancy. Thalassemia carriers often have reduced red cell folate contents. The aim of this study was to verify whether thalassemia carriers are at increased risk of having offspring with a NTD. METHODS: We retrospectively evaluated the prevalence of thalassemia carriers among 75 women who had prenatal diagnoses of NTDs made at our center. RESULTS: The prevalence of beta-thalassemia carriers among the affected pregnancies was significantly higher than in the general population (22.5 versus 14%, p < 0.05, chi(2) test). CONCLUSION: Although inconclusive, these data indicate that folate supplementation is mandatory among women with thalassemia who are planning a pregnancy.

Female↗