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M C Rosatelli

Publications and source records attributed to M C Rosatelli.

At least 19 recordsLinked to original sources
PubMed2005

Two novel mutations of the AIRE protein affecting its homodimerization properties.

We report two novel mutations, c.230T>C (p.F77S) and c.64_69del (p.V22_D23del) within the HSR domain of the AIRE protein in two patients of Italian descent affected by APECED. Both mutations were found in the compound heterozygous state respectively with c.994+5G>T and c.232T>A (p.W78R). With the two-hybrid assay in the yeast system we found that constructs containing the two mutations fail to interact with the wild-type protein. These findings indicate that both mutations negatively affected the homodimerization properties of the AIRE protein, thereby leading to a defective function.

Adult↗
PubMed2000

High-risk pregnancy in beta-thalassemia major women. Report of three cases.

Reproductive failure is common in beta-thalassemia major patients because of endocrine damage resulting from iron overload. Here 3 full-term pregnancies following spontaneous ovulation in 2 splenectomized beta-thalassemia major women are reported. The main echocardiographic parameters, such as left ventricular end-diastolic and end-systolic diameters, fractional shortening and ejection fraction, were within the normal range before pregnancy, but worsened during gestation, and 1 patient developed pre-congestive heart failure. Deferoxamine therapy was continued throughout 2 pregnancies, while in the other it was stopped after 8 weeks: no abnormalities were noted in the children. Thanks to the currently applied therapies, an increased number of pregnancies may now be expected in beta-thalassemia major women: it is important to find out more about the pregnancy-related problems and their management in these patients.

Adult↗
PubMed2000

A beta-thalassaemia allele with 3 base substitution in codons 4/5 & 6 (ACT CCT GAG-> ACA TCT TAG) detected by denaturing gradient gel electrophoresis & sequencing.

We report the analysis of a beta-thalassaemia gene involving three bases in codons 4/5 and 6 (ACT CCT GAG-> ACA TCT TAG) in a confirmed carrier whose child had beta-thalassaemia major. The fragment of the gene carrying the mutation was detected by denaturing gradient gel electrophoresis (DGGE) using GC clamped primers, followed by direct sequencing. DGGE analysis indicated that one gene was the wild type (normal) while the sequence changes observed were all in the other gene causing beta-thalassaemia major in the child. This confirms a single case report from Lucknow (UP) and adds to the beta-thalassaemia mutations identified in the beta-globin gene in India and will help in the thalassaemia control programme.

Adult↗
PubMed1998

A common mutation in Sardinian autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients.

Autoimmune polyendocrinopathy-candidiasisectodermal dystrophy (APECED; also called APS-1,) is a rare autosomal recessive disorder that is more frequent in certain isolated populations. It is characterized by two of the three major clinical symptoms that may be present: Addison's disease, and/or hypoparathyroidism and/or chronic mucocutaneous candidiasis. We have recently identified the gene for APECED, which we termed AIRE (for autoimmune regulator). AIRE is expressed in thymus, lymph nodes and fetal liver, and encodes a protein with two putative zinc fingers and other motifs suggestive of a transcriptional regulator. Seven mutations have been described to date, including R257X, the predominant Finnish and northern Italian APECED allele, which has also been observed in other patients of diverse origin on different haplotypes. A 13-bp deletion (1094-1106del) has also been observed in several patients of different geo-ethnic origin. The other described mutations appear to be rare. We present mutational analyses of the AIRE gene in ten Sardinian APECED families and show that there is a mutation, R139X, associated with one predominant haplotype unique to the Sardinian patients (18/20 independent alleles). The carrier frequency of R139X in Sardinia is 1.7%, giving an estimated population frequency of APECED of 1/14,400. Using linkage disequilibrium data, the estimated age of the R139X mutation is between 20 and 25 generations. A previously described 13-bp deletion was also observed on an allele of one patient. The identification of a single common Sardinian APECED mutation will facilitate its genetic diagnosis. Given the carrier frequency of R139X in the Sardinian population, AIRE may be implicated in the pathogenesis of other autoimmune diseases in the Sardinian population, particularly those affecting the endocrine system.

DNA Mutational Analysis↗
PubMed1998

Prenatal diagnosis and screening of the haemoglobinopathies.

This paper reviews the most important aspects of carrier detection procedures, genetic counselling, population screening and prenatal diagnosis of the thalassaemias and sickle cell anaemia. Carrier detection can be made retrospectively, following the birth of an affected child, or prospectively. Carrier detection and genetic counselling in at-risk populations for alpha-thalassaemia and sickle cell anaemia is carried out mostly retrospectively. However prospective carrier screening is ongoing in Cuba and Guadeloupe for sickle cell anaemia and, in a very limited way, in some South East Asian populations, for alpha-thalassaemia. For beta-thalassaemia, several programmes, 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 thalassaemia and its prevention by the target population and by the marked decline of the incidence of thalassaemia 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.

Anemia, Sickle Cell↗
PubMed1997

Molecular diagnosis and carrier screening for beta thalassemia.

Thalassemias are common autosomal recessive disorders especially in populations of Mediterranean, Middle Eastern, and Far Eastern descent. Relatively high incidence is also observed in people of Asian Indian origin but the incidence is more limited in those of African descent. Beta Thalassemias are heterogeneous at the molecular level, with more than 150 different molecular defects identified to date. Despite this heterogeneity, each at-risk population has its own spectrum of common mutations, usually from 5 to 10, a finding that simplifies mutation analysis. Homozygosity for beta thalassemias usually results in transfusion-dependent thalassemia major and, rarely, in mild non-transfusion-dependent conditions. Molecular diagnosis may be used to define genotypes associated with mild forms. Advances in carrier diagnosis using hematologic analysis followed by mutation analysis have made possible the population screening of women at childbearing age and prenatal diagnosis. This approach in combination with nondirective genetic counseling has resulted in a consistent decline of the birth of affected homozygotes in several Mediterranean at-risk populations, as well as knowledge of the risks of being a carrier. Molecular diagnosis of homozygotes and identification of carriers of beta thalassemia may lead to improved clinical management of patients with the disorder and prevention of the birth of affected homozygotes.

DNA Mutational Analysis↗
PubMed1997

Molecular analysis of patients of Sardinian descent with Crigler-Najjar syndrome type I.

This study reports the molecular characterisation of the bilirubin UDP-glucuronosyl-transferase gene (UGT1) in a group of patients of Sardinian descent with Crigler-Najjar syndrome type I and their relatives. Sequence analysis of both UGT1A exon 1 and common exons 2-5 was performed in all patients, leading to the detection of AF170 and a novel mutation (470insT), both residing in UGT1A exon 1. All but two heterozygotes for the AF170 mutation showed normal serum bilirubin levels. These two subjects were also heterozygous for the sequence variation A(TA)7TAA in the promoter region of the UGT1A gene.

Adolescent↗
PubMed1996

Control of beta-thalassaemia by carrier screening, genetic counselling and prenatal diagnosis: the Sardinian experience.

Homozygous beta-thalassaemia in a number of at-risk populations (Greek and Turkish Cypriots, Greeks, Continental Italians and Sardinians) has been prevented at the population level by programmes based on carrier screening, genetic counselling and prenatal diagnosis. The Sardinian experience is based on a 20-year programme. Voluntary screening has been offered to prospective parents and, primarily, to women with an ongoing pregnancy. Education of the population at large, training of health personnel, and use of posters and informative booklets have been critical elements for the success of the programme. Genetic counselling has been carried out in a non-directive manner following well-established guidelines. The use of extended family screening magnified the efficacy of the screening programme, allowing the identification of the large majority of parents at risk by screening only 13% of the population at child-bearing age. Following counselling, the large majority of parents accepted prenatal diagnosis. Definition of the parents' mutation and prenatal diagnosis were carried out by a number of PCR-based procedures. The programme was effective, as indicated by the reduction of the birth rate of thalassaemia major from 1:250 live births to 1:4000.

Genetic Counseling↗
PubMed1996

HB Hinwil or beta 38(C4)Thr-->Asn: a new beta chain variant detected in a Swiss family.

This paper reports a new hemoglobin variant which was identified while investigating the cause of a mild erythrocytosis. The abnormal beta-globin chain was detected by reversed phase chromatography. Mutation mapping of the beta-globin gene by polymerase chain reaction and denaturing gradient gel electrophoresis followed by sequence analysis revealed a C-->A transversion at codon 38, predicting a Thr-->Asn substitution. Tryptic peptide mapping by liquid chromatography electrospray mass spectrometry, followed by conventional Edman peptide sequence analysis, confirmed the predicted amino acid substitution. In contrast to the only other known mutation at codon 38, Hb Hazebrouck (Thr-->Pro), this hemoglobin is stable and shows elevated oxygen affinity.

Amino Acid Sequence↗
PubMed1995

A specific cystic fibrosis mutation (T3381) associated with the phenotype of isolated hypotonic dehydration.

We carried out molecular screening for mutations in the cystic fibrosis transmembrane regulator (CFTR) gene in eight children of Sardinian descent seen because of hypotonic dehydration associated with hyponatremia, hypochloremia, hypokalemia, and metabolic alkalosis; none had pulmonary or pancreatic involvement. All the patients had the T3381 mutation either in homozygosity or compound heterozygosity with another CF mutation. The T3381 mutation was not detected in patients with CF who had classic symptoms or in healthy persons of the same descent. These data suggest that the T3381 mutation is associated with a specific mild CF phenotype.

Child↗
PubMed1995

A promoter mutation, C-->T at position -92, leading to silent beta-thalassaemia.

This study describes the clinical phenotype of the C-->T mutation at position -92 of the beta-globin gene. Excluding two cases with HbA2 levels within the range of the beta-thalassemia carrier state, heterozygotes for this mutation showed normal or borderline red blood cells count, Hb levels, MCV, MCH and HbA2 values, and unbalanced globin chain synthesis. Compound heterozygotes for the -92 C-->T mutation and a beta zero-thalassaemia mutation (beta zero 39) (two cases) or severe beta+-thalassaemia (beta+ IVSII nt 745) (two cases) developed thalassaemia intermedia. According to these characteristics, the -92 promoter mutation should be added to the list of silent beta-thalassaemias.

Base Sequence↗
PubMed1994

Genotype-phenotype correlations in beta-thalassemias.

In this paper we review the molecular basis of the marked heterogeneity of the thalassemia syndromes as well as the relative implications for carrier screening and prenatal diagnosis. The classical phenotype of heterozygous beta-thalassemia may be modified by a number of environmental and genetic interacting factors--among which the most relevant are: (1) coinheritance of alpha-thalassemia, which may normalize the red blood cell indices; (2) the presence of a mild beta-thalassemia mutation; (3) cotransmission of delta-thalassemia which may reduce the increase of HbA2 typical of heterozygous beta-thalassemia to normal values and (4) the presence of a silent mutation which can be defined only by imbalanced beta-globin chain synthesis. A number of molecular mechanisms are able to produce the non transfusion dependent attenuated forms of thalassemia syndromes referred to as thalassemia intermedia. The most common are homozygosity for mild beta-thalassemia mutations, coinheritance with homozygous beta-thalassemia of alpha-thalassemia or genetic determinants able to sustain a continuous production of HbF in adult life or the presence of heterozygosity for hyperunstable globin variants.

Amino Acid Sequence↗