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Biomedical subjects

A Cao

Publications and source records attributed to A Cao.

At least 163 records · Page 9Linked to original sources
PubMed1992

The HLA DQB1*0502 allele is neutrally associated with insulin-dependent diabetes mellitus in the Sardinian population.

In the Sardinian population a very high incidence of insulin-dependent diabetes mellitus (IDDM) and the lack of HLA-DR2 protective effect due to the high frequency of the A2, Cw7, B17, 3F31, DR2, DQw1 extended haplotype has been reported. This haplotype, carrying a Serine at position 57 of the DQB1*0502 allele, has been previously reported to be underrepresented in patients when compared to controls. In order to provide an explanation for this finding, we defined by RFLP analysis the HLA haplotype of 45 Sardinian IDDM patients and 49 controls. All DR-2DQw1 subjects were molecularly characterized at the HLA DQA and DQB loci. All DR2-positive patients and the vast majority of the DR2-positive controls had the DQB1*0502 allele at the DR2-linked DQB1 locus, with no statistically significant difference between the two groups. All DQA1 genes were the ones expected, with only two exceptions. Nine out of 10 of the DR2-positive patients were compound heterozygotes for DQB1*0201/DQB1*0502 alleles; only this allele combination was significantly increased (p less than 0.0003). Our data suggests that a) the DQB1*0502 allele is neutral for IDDM development and b) the susceptibility to IDDM in our DR2-positive patients is related to the compound heterozygous state between the neutral DQA1*0102/DQB1*0502 and the susceptibility DQA1*0501/DQB1*0201 alleles.

Adolescent↗
PubMed1992

Normal delta-globin gene sequences in Sardinian nondeletional delta beta-thalassemia.

In order to clarify the reasons for the reduced Hb A2 levels in Sardinian delta beta-thalassemia, we characterized, both by cloning and sequence analysis and by direct sequencing of amplified DNA, the delta-globin gene from an individual of Sardinian descent who is a compound heterozygote for the beta zero-thalassemia codon 39 (C-->T) nonsense mutation and the Sardinian delta beta-thalassemia [codon 39(C-->T)/-196(C-->T)A gamma]. The analysis of the delta-globin gene from the delta beta-thalassemia chromosome revealed an entirely normal sequence. The defective function of the delta-globin gene in this determinant is thus likely related to a suppressive effect of the in cis nondeletional high persistence of fetal hemoglobin mutation of the A gamma gene, probably resulting from an increased capability of the relative promoter to interact with the locus control region.

Base Sequence↗
PubMed1992

Prenatal diagnosis of inherited hemoglobinopathies.

This paper reviews the techniques presently available for the prenatal diagnosis of inherited hemoglobinopathies. At the present time, mutations of the globin genes are detected directly in trophoblast DNA, enzymatically amplified by polymerase chain reaction. Known mutations may be defined by restriction endonuclease digestion, non denaturing gradient gel electrophoresis, allele specific oligonucleotide probes or allele specific oligonucleotide primers. Unknown mutations are detected by denaturing gradient gel electrophoresis followed by direct sequencing. Other potentially useful methods for unknown mutations are single strand conformation polymorphism analysis and chemical mismatch cleavage analysis. A potential pitfall for all procedures based on analysis of amplified DNA is the coamplification of maternal sequences. This may be avoided by a careful dissection of maternal decidua from fetal trophoblast, by using an amount of chorionic villi not inferior to 5-10 mg and by reducing the number of amplifying cycles to approximately 20. Monitoring the presence of co-amplified maternal sequences by the analysis of polymorphic sequences is strongly recommended. Future perspectives consist of preimplantation diagnosis by biopsy of the morula or blastula or ova genotyping by analysis of the second polar body.

DNA↗
PubMed1992

Molecular characterization of beta-thalassemia in the Sardinian population.

This study reports the molecular characterization of beta-thalassemia in the Sardinian population. Three thousand beta-thalassemia chromosomes from prospective parents presenting at the genetic service were initially analyzed by dot blot analysis with oligonucleotide probes complementary to the most common beta-thalassemia mutations in the Mediterranean at-risk populations. the mutations which remained uncharacterized by this approach were defined by denaturing gradient gel electrophoresis (DGGE) followed by direct sequence analysis on amplified DNA. We reconfirmed that the predominant mutation in the Sardinian population is the codon 39 nonsense mutation, which accounts for 95.7% of the beta-thalassemia chromosomes. The other two relatively common mutations are frameshifts at codon 6 (2.1%) and at codon 76 (0.7%), relatively uncommon in other Mediterranean-origin populations. In this study we have detected a novel beta-thalassemia mutation, i.e., a frameshift at codon 1, in three beta-thalassemia chromosomes. The DGGE procedure followed by direct sequencing on amplified DNA is a powerful approach for the characterization of unknown mutations in this genetic system. The results herein presented allowed an expansion of the applicability of prenatal diagnosis by DNA analysis, to all couples at risk for beta-thalassemia in our population.

Base Sequence↗
PubMed1991

Molecular characterization of beta-thalassemia intermedia in patients of Italian descent and identification of three novel beta-thalassemia mutations.

In this study, we have defined by dot-blot analysis with allelic specific oligonucleotide probes or direct sequencing on amplified DNA the beta-thalassemia mutations in a large group of patients (23) of Italian descent with thalassemia intermedia. These patients had one parent with either the silent beta-thalassemia carrier phenotype or borderline-normal hemoglobin A2 (HbA2) levels (2.5% to 3.5%). Nearly all were genetic compounds for a severe beta-thalassemia mutation and a beta-thalassemia mutation associated with high residual output of beta-globin chains (beta + intervening sequence [IVS]-I-nt6, beta -87, beta -101), indicating that inheritance of a mild beta-thalassemia allele, even in a single dose, is the most common molecular mechanism producing thalassemia intermedia in the Italian population. In three cases, in whom we failed to define by dot-blot analysis the mutations, we sequenced the beta + globin gene and found three novel beta-thalassemia mutations, which are certainly very rare because they have been hitherto detected solely in a single patient. These mutations consist of: (1) a T-A substitution at position 2 of IVS-I, in a patient compound heterozygote for this mutation and the -87 promoter mutation; (2) a G-C substitution at position 844 of IVS-II, in a patient heterozygous for this mutation who showed normal sequences at the in trans beta-globin gene (The reason for the presence of clinical manifestations in a beta-thalassemia heterozygote has not been defined.); and (3) a deletion of one nucleotide (-T) at codon 126, resulting in a frameshift and readthrough of the 5' untranslated region and most likely producing an elongated Hb molecule of 156 amino acid residues, in a patient heterozygous for this mutation with normal beta-globin gene sequences at the other locus.

Adult↗
PubMed1991

Hemoglobin Cagliari (beta 60 [E4] Val----Glu): a novel unstable thalassemic hemoglobinopathy.

This report describes a patient with thalassemia intermedia-like phenotype born to normal parents in whom globin gene sequencing detected a novel abnormal hemoglobin (Hb) due to a T to A substitution at codon 60 of the beta-globin gene arising as a de novo mutation. Normal sequences were detected at the homologous beta-globin locus. This mutation results in the substitution of a polar (glutamic acid) for a nonpolar (valine) residue near the corner of the heme pocket of the beta-globin chain. The novel variant has been designated Hb Cagliari, from the place of birth of the propositus. Kinetics of globin synthesis performed following splenectomy suggest that this new Hb variant is synthesized at a near normal rate but undergoes rapid breakdown. The extreme lability of the variant explains the clinical and hematologic picture characterized by marked ineffective erythropoiesis, thalassemia-like bone changes, iron overload, high proportion of Hb F in the peripheral blood, reduced beta/alpha-globin chain synthesis ratio in peripheral blood reticulocytes, and absence of the abnormal Hb in peripheral blood at extensive protein structural analysis before splenectomy. This case indicates that a thalassemic hemoglobinopathy should be suspected in the presence of a patient with a thalassemia intermedia-like phenotype born to normal parents, even when protein structural analysis fails to detect an abnormal Hb. DNA sequencing may allow to define the mutation, thus making the proper diagnosis.

Anemia, Hemolytic↗
PubMed1991

Molecular study in von Recklinghausen neurofibromatosis (NF1).

The von Recklinghausen neurofibromatosis (NF1) gene has been mapped to the pericentromeric region of chromosome 17 and various DNA markers have been identified in this region. We have performed a genetic analysis using an anonymous DNA marker, HHH202 (D17S33), tightly linked to the NF1 gene in seven NF1 Italian families. Only one family was fully informative for the HHH202/RsaI polymorphism. In this family this marker can be used for presymptomatic and prenatal diagnosis. However, it is necessary to use additional flanking markers in order to increase informativeness and to obtain better diagnostic accuracy.

Female↗
PubMed1991

Percentile curves for red cell indices of beta zero-thalassaemia heterozygotes in infancy and childhood.

This paper describes the percentile curves for red blood cell (RBC) count, Hb, mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH) values of beta zero-thalassaemia heterozygotes during infancy, childhood and adolescence. Hb values were about 2 g/dl below those of normal controls with a progressive increase with age paralleling the normal developmental trend. The Hb increase with age was due to a progressive rise in the Hb content per cell, the number of RBC remaining nearly constant. MCV and MCH values also increased with age with a pattern parallel to normal control. Because of the high prevalence of alpha-thalassaemia in the Sardinian population, to which all the subjects investigated belong, the 3rd MCH-MCV percentile curves of normal overlap the 97th curve of beta-thalassaemia heterozygotes. The HbA2 levels, however, were always increased as compared to normal. These results confirm in children than screening for heterozygous beta-thalassaemia in populations with a high incidence of alpha and beta-thalassaemia by MCV-MCH determination may overlook a sizeable proportion of beta-thalassaemia carriers. The knowledge of the extent of variation of RBC indices of beta-thalassaemia heterozygotes during infancy, childhood and adolescence, is very useful for the evaluation of a child presenting with a mild microcytic anaemia.

Adolescent↗
PubMed1991

Population-based genetic screening.

A preventive genetic programme aimed to control beta-thalassemia in the Sardinian population is based on a combination of increased awareness of the population, carrier screening, genetic counselling and prenatal diagnosis. As a result, the registry of thalassemia major demonstrated a profound decline in the incidence of this disease from 1 per 250 to 1 per 1200 live births, with 90% of cases effectively prevented.

Adult↗
PubMed1991

Low activity sn-glycerol-3-phosphate dehydrogenase variants in natural populations of Drosophila melanogaster.

Eleven Australian natural populations of Drosophila melanogaster were screened by electrophoresis for evidence of null and/or low activity variants at the Gdph locus. Of 5018 alleles investigated, 57 had markedly lower GDPH activity, as judged by their heterozygous phenotypes, than control alleles. GPDH assays of 13 of these variant alleles showed that whilst they were heterogeneous in their properties and included electrophoretic variants and two categories of low-activity variant, there were no true null alleles. The most common low-activity variants exhibited dominance for GPDH activity in heterozygotes with normal alleles, and were shown to share this property with an allele previously isolated from a London (UK) population (Langley et al., 1981).

Alleles↗
PubMed1991

Molecular basis of beta-thalassemia intermedia in a southern Italian region (Puglia).

We investigated the molecular bases for a mild phenotype by alpha-, beta- and gamma-globin gene analyses in 22 patients with transfusion-independent thalassemia intermedia (15) or a late-presenting form of thalassemia major (7) originating from Puglia, a region of southern Italy. Twenty-two patients with thalassemia major served as controls. The beta+ IVS-I nt 6 of the beta-globin gene and the C----T substitution at position -158 5' of the G gamma-globin gene were detected more frequently in patients with thalassemia intermedia or late-presenting thalassemia major considered together as compared to those affected by typical transfusion-dependent thalassemia major. Three of 15 patients with thalassemia intermedia had the triple alpha-globin gene arrangement in the heterozygous (2) or homozygous state (1) in association with heterozygous beta zero-thalassemia. From these results, we may conclude that the inheritance of a mild beta-thalassemia allele such as the beta+ IVS-I nt 6 mutation, in the homozygous or heterozygous state, the coinheritance with homozygous beta zero-thalassemia of the -158 (C----T) G gamma gene promoter mutation and the presence of heterozygous beta-thalassemia/triple alpha-globin gene arrangement are the most common reasons accounting for the development of attenuated forms of beta-thalassemia in Puglia.

Alpha-Globulins↗
PubMed1991

Early antenatal sonographic diagnosis of conjoined syncephalus-craniothoraco-omphalopagus twins. Case report.

The paper describes the prenatal ultrasonographic diagnosis of conjoined syncephalus-craniothoraco-omphalopagus twins at 13 weeks' gestation. The mother, after genetic counseling, decided to interrupt the pregnancy. The fetal karyotype, the maternal serum and amniotic fluid alpha-fetoprotein levels were normal. The diagnosis was confirmed by pathologic examination of the fetus after termination of pregnancy.

Adult↗