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ABSTRACT: The Cri du Chat Syndrome (CdCS) is one of the most common deletion syndromes, involving the short arm of chromosome 5, with an incidence of 1 in 50.000 live births. The following are the characteristic features of this syndrome: microcephaly, hypertelorism, round face, micrognatia, epicanthic folds, prominent nasal bridge, hypotonia and severe psychomotor retardation. Patients also show a high pitched cry similar to the mewing of a cat. Deletions and duplications of chromosome 5p have been described in the literature. Mosaicism represents only 3% of this cytogenetic aberration. Up to date, only cases of de novo 5p mosaic anomalies involving two or three rearranged cell lines, with deletions and duplications, have been described. Herein, we report the first case of a patient affected by multiple congenital anomalies and a mosaicism, with two rearranged cell lines: one with a 5p deletion; the other with a 5p deletion/duplication. Our patient did not show the characteristic features described in patients with 5p duplications, but a phenotype compatible with the CdCS. Our case represents the first description of a mosaicism with deletion and deletion/duplication of a portion of the short arm of chromosome 5.
Genetic counseling (Geneva, Switzerland) 02/2008; 19(4):381-6. · 0.50 Impact Factor
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Annals of the New York Academy of Sciences 12/2006; 612(1):90 - 97. · 3.15 Impact Factor
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ABSTRACT: During the switch from human gamma- (fetal) to beta- (adult) globin gene expression, the gamma and beta genes are expressed competitively by an alternating transcription mechanism. The -50 region of the gamma gene promoter has been proposed to be responsible for the early competitive advantage of the gamma genes and to act as a stage selector element (SSE) in hemoglobin switching. We analyzed the effect of mutating the -50 region of the gamma gene in the presence of a competing beta gene in transgenic mice. This shows that the -50 region does not affect silencing of the beta gene in early development and does not act as a stage selector. However, it affects the ratio of gamma versus beta gene expression in the early, but not later, stages of fetal development. Interestingly, both the wild-type and mutant minilocus constructs show a higher frequency of alternate transcription than observed in the complete locus, suggesting that sequences normally present between the gamma and beta genes facilitate the interaction of the locus control region (LCR) and beta-globin gene in the complete locus.
The EMBO Journal 10/2001; 20(18):5242-9. · 9.20 Impact Factor
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American Journal of Hematology 06/2001; 67(1):58. · 4.67 Impact Factor
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L Crisponi,
M Deiana,
A Loi,
F Chiappe,
M Uda,
P Amati,
L Bisceglia,
L Zelante,
R Nagaraja,
S Porcu, [......],
M Rocchi,
M Nicolino,
A Lienhardt-Roussie,
A Nivelon,
A Verloes,
D Schlessinger,
P Gasparini,
D Bonneau,
A Cao,
G Pilia
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ABSTRACT: In type I blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), eyelid abnormalities are associated with ovarian failure. Type II BPES shows only the eyelid defects, but both types map to chromosome 3q23. We have positionally cloned a novel, putative winged helix/forkhead transcription factor gene, FOXL2, that is mutated to produce truncated proteins in type I families and larger proteins in type II. Consistent with an involvement in those tissues, FOXL2 is selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it appears predominantly in the ovary. FOXL2 represents a candidate gene for the polled/intersex syndrome XX sex-reversal goat.
Nature Genetics 03/2001; 27(2):159-66. · 35.53 Impact Factor
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Hemoglobin 09/2000; 24(3):239-44. · 1.30 Impact Factor
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ABSTRACT: This paper presents allele frequencies of two short tandem repeats (CD4 and F13A1) in three anthropologically defined populations: Sardinians (Italy), Corsicans (France) and Piaroa Indians (Venezuela). The comparison shows some relevant differences both in number and distribution of the CD4 and F13A1 alleles.
Gene geography: a computerized bulletin on human gene frequencies 05/1996; 10(1):51-63.
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Blood 10/1995; 86(5):2055-6. · 9.90 Impact Factor
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ABSTRACT: In sheep as in man and most other mammals, there are two alpha-globin genes (I alpha and II alpha), which are expressed at different levels, the upstream gene being the most efficient. In alpha-globin gene triplication and quadruplication, this trend is confirmed, i.e., the alpha-chain output of the downstream genes progressively decreases. In this study, we have determined the complete sequence of the cDNAs and of both the introns in a triple-alpha haplotype in which each gene could be recognized for the presence of distinct alleles. The sequence analysis reveals that the bodies of the three alpha-globin genes are essentially identical (99.9% homology) and moreover indicates that the down-regulation of additional alpha-globin genes in sheep is not the effect of sequence variation from the Cap to the Poly(A) addition sites. This striking similarity among alpha-genes is higher than that seen in other mammals and is probably sustained by particularly efficient mechanisms of gene conversion and cross-over fixation.
Journal of Molecular Evolution 05/1995; 40(4):349-53. · 2.27 Impact Factor
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ABSTRACT: We previously found that in sheep alpha alpha-, alpha alpha alpha-, and alpha alpha alpha alpha-globin gene haplotypes, in which individual genes encode distinct allelic variants, the gene expression determined at protein level progressively decreases from the 5' to the 3' end. In the present study, through direct DNA analysis, we definitively established the gene relative position in the cluster and we verified the occurrence of the gradient also at the mRNA level. We measured the relative abundance of the alpha 113His-mRNA in alpha alpha and alpha alpha alpha haplotypes, in which the gene coding for the alpha 113His chain occupies the second and the third position, respectively. The alpha 113His-mRNA levels were about 20% and 8% to 9%, respectively, which closely paralleled alpha-chain levels. We conclude that the expression gradient occurs also at the mRNA level and is most likely of transcriptional origin.
Blood 05/1994; 83(8):2317-22. · 9.90 Impact Factor
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Human Mutation 02/1992; 1(2):169-71. · 5.69 Impact Factor
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ABSTRACT: This paper describes four families of Italian descent in each of which the propositus had the clinical phenotype of thalassaemia intermedia, resulting from the compound heterozygous state for high HbA2 beta thalassaemia and type I silent beta thalassaemia. Direct sequencing on amplified DNA and/or oligonucleotide analysis detected, in all families but one, the compound heterozygous state for codon 39 nonsense mutation and the C-T substitution at position -101 in the distal CACCC box of the beta-globin gene promoter (beta th-101). Members of these families who are heterozygous for high HbA2 beta thalassaemia showed the codon 39 nonsense mutation, while those with the clinical phenotype of silent beta thalassaemia had the beta th-101 mutation. In the remaining family, the propositus and one of his siblings had the compound heterozygous state for a molecularly undefined high HbA2 beta thalassaemia and the beta th-101 mutation in combination with the triple alpha globin gene arrangement. These patients showed a more severe thalassaemia intermedia like clinical phenotype as compared to those with the same beta-globin genotype and a normal alpha-globin gene arrangement. In the families investigated the beta th-101 was always associated with haplotype I. A group of patients with thalassaemia intermedia from Southern Italy, either homozygous or heterozygous for haplotype I and in whom previous studies had failed to define the mutation in one of the beta thalassaemia globin genes, were screened by oligonucleotide analysis for the presence of the beta th-101. Three out of nine were positive. These results indicate that the beta th-101 mutation is a common cause of the type I silent beta thalassaemia phenotype in the Southern Italian population.
British Journal of Haematology 05/1990; 74(4):480-6. · 4.94 Impact Factor
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Blood 04/1990; 75(6):1378-9. · 9.90 Impact Factor
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M. S. Ristaldi,
S. Murru,
G. Loudianos,
L. Casula,
S. Porcu,
D. Pigheddu,
B. Fanni,
G. V. Sciarratta,
S. Agosti,
M. I. Parodi,
D. Leone,
C. Camaschella,
A. Serra,
M. Pirastu,
A. Cao
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ABSTRACT: This paper describes four families of Italian descent in each of which the propositus had the clinical phenotype of thalassaemia intermedia, resulting from the compound heterozygous state for high HbA2β thalassaemia and type I silent β thalassaemia. Direct sequencing on amplified DNA and/or oligonucleotide analysis detected, in all families but one, the compound heterozygous state for codon 39 nonsense mutation and the C-T substitution at position – 101 in the distal CACCC box of the β-globin gene promoter (βth–101). Members of these families who are heterozygous for high HbA2β thalassaemia showed the codon 39 nonsense mutation, while those with the clinical phenotype of silent β thalassaemia had the βth–101 mutation. In the remaining family, the propositus and one of his siblings had the compound heterozygous state for a molecularly undefined high HbA2β thalassaemia and the βth–101 mutation in combination with the triple α globin gene arrangement. These patients showed a more severe thalassaemia intermedia like clinical phenotype as compared to those with the same β-globin genotype and a normal α-globin gene arrangement. In the families investigated the βth–101 was always associated with haplotype I. A group of patients with thalassaemia intermedia from Southern Italy, either homozygous or heterozygous for haplotype I and in whom previous studies had failed to define the mutation in one of the β thalassaemia globin genes, were screened by oligonucleotide analysis for the presence of the βth–101. Three out of nine were positive. These results indicate that the βth–101 mutation is a common cause of the type I silent β thalassaemia phenotype in the Southern Italian population.
British Journal of Haematology 03/1990; 74(4):480 - 486. · 4.94 Impact Factor
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ABSTRACT: Hemophilia A (HA), a common inherited bleeding disorder in humans, is due to the deficiency or absence of the factor VIII (FVIII) activity. The cloning of the FVIII gene has made molecular probes available for the characterization of the basic defect in this disease. In this study we describe six different mutations in the FVIII gene detected by DNA analysis of 100 HA patients of Italian descent. In two of them, with a severe clinical picture, we identified two novel deletions, one in the middle of the FVIII gene from exons 7 to 22 and the other encompassing the entire factor VIII gene. Both of these patients produced antibodies to factor VIII. In a patient with mild HA we detected a duplication of exon 13, which is a rearrangement not yet described within the FVIII gene. A possible explanation for the mild phenotype in this patient is that the molecular defect results in the production of an unstable FVIII protein with residual 10% FVIII activity. Screening by Taq I restriction endonuclease detected three mutations that were further characterized by direct sequencing on amplified DNA: a C-T substitution at codon 1960, in exon 18, converting the codon for arginine to a non-sense codon; and a G-A substitution at codon 2228 and 2326, in exons 24 and 26 respectively, resulting in the substitution of glutamine for arginine. All three of these mutations have been previously described. The non-sense mutation and the codon 2228 G-A mutation was found in patients with severe HA, while the codon 2326 G-A mutation was associated with a quite severe condition. These results confirm that the molecular bases of HA are very heterogeneous and provide further evidence that recurrent mutations are not uncommon in this system.
Blood 03/1990; 75(3):662-70. · 9.90 Impact Factor
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Blood 02/1990; 75(2):526-8. · 9.90 Impact Factor
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ABSTRACT: This paper reviews the molecular pathology of a heterogeneous group of beta-thalassemia heterozygotes which may be referred to as atypical beta-thalassemia. This group includes four different categories of heterozygous beta-thalassemia, which are characterized, respectively, by (1) normal MCV and MCH; (2) normal Hb A2; (3) normal MCV, MCH, and Hb A2 and imbalanced globin chain synthesis only or, (4) the presence of clinical manifestations. The first group is represented by a limited proportion of double heterozygotes for alpha- and beta-thalassemia. The second group includes two categories. One category is double heterozygotes for delta- and beta-thalassemia with the delta-thalassemia mutation in cis or in trans to beta-thalassemia. A number of delta-thalassemia mutations which produce this phenotype by interacting with beta-thalassemia have been described. The other category within the second group is heterozygotes for some mild beta(+)-thalassemia mutations. Within the third group, conclusive evidence for a mutation within the beta-globin gene cluster producing the silent beta-thalassemia phenotype has been obtained solely for a C----T substitution at -101 within the CACCC box of the beta-globin gene. Possible candidates are the complex rearrangements (-T, +ATA; -T, +ATATA) found at position -530 from the cap site. In the group of thalassemic hemoglobinopathies, a series of mutations mostly located in the third exon and producing elongated or truncated molecules have been recently reported. Most of the mutations are silent at the protein level, produce inclusion bodies in peripheral erythrocytes, and show a dominant transmission pattern or occur sporadically.
Annals of the New York Academy of Sciences 02/1990; 612:90-7. · 3.15 Impact Factor
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ABSTRACT: In this paper we review the characteristics and effectiveness of a program aimed at preventing homozygous beta-thalassemia in the Sardinian population. The target population for screening were couples at marriage, conception or early pregnancy. Awareness of the problem and the involvement of the population were achieved via the mass media or by personal approaches through lectures or discussions. Parents' Associations were consulted and have made themselves available to prospective couples in several critical areas. Education on thalassemias was introduced into the school curriculum. Counseling was based on private interviews at which the several options available were discussed with the individual carrier or the couples. Prenatal diagnosis was chosen by the large majority of couples counseled. The introduction of 1st trimester diagnosis resulted in a striking increase of the acceptance rate from 93.2 to 99.1%. Prenatal diagnosis was carried out initially by fetal blood analysis and thereafter by trophoblast or amniocyte DNA analysis. Direct detection of the mutation by oligonucleotide hybridization on agarose gel separated DNA fragments or by dot-blot analysis with allelic specific oligonucleotide probes on enzymatically amplified DNA was used. This program resulted in a decline in thalassemia major births of 90%. The reasons for residual cases were mostly lack of information and, less frequently, misdiagnoses or refusal of fetal diagnosis.
Clinical Genetics 12/1989; 36(5):277-85. · 3.13 Impact Factor
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ABSTRACT: In this study, we describe a simple strategy to detect beta-thalassaemia mutations in prospective parents and to make prenatal diagnosis in pregnancies at risk in the Mediterranean population. Screening of prospective parents is carried out by dot blot analysis on enzymatically amplified DNA with a set of oligonucleotide probes complementary to the most common mutations in this population. Prenatal diagnosis is accomplished by the same procedure on enzymatically amplified amniocyte or trophoblast DNA. The main advantages of this procedure are the simplicity, sensitivity (0.05 micrograms of DNA), and rapidity (12-24 h). Further simplification is obtained by amplification of the DNA from crude amniotic cell lysate. The very low amount of fetal material necessary for this analysis eliminates the need to culture amniotic fluid cells and may decrease the fetal loss rate associated with trophoblast sampling. The number of specific DNA sequences obtained by the amplification procedure allowed us to use non-radioactive labelled oligonucleotide probes, which have several advantages compared to radioactive probes.
Prenatal Diagnosis 10/1989; 9(9):629-38. · 2.11 Impact Factor
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ABSTRACT: In the Mediterranean area, 50% of the beta thalassaemia mutations abolish or create a restriction endonuclease site in the beta globin gene. This study describes a new procedure for prenatal detection of these beta thalassaemia defects based on the direct visualisation, on an ethidium bromide stained polyacrylamide gel, of the discrete DNA fragments produced by restriction endonuclease digestion of fetal DNA, enzymatically amplified using the DNA polymerase from the thermophilus bacterium Thermus aquaticus. We applied this procedure to the Sardinian population to detect the nonsense mutation at codon 39 and the frameshift at codon 6 of the beta globin gene; these are the most frequent beta thalassaemia mutations in this population, accounting for 95% and 2.2% of the beta thalassaemia chromosomes. The main advantages of this procedure are simplicity (no radioactivity), sensitivity (0.2 microgram of DNA), and rapidity (12 hours). The very small amount of fetal material required makes amniotic fluid cell culture unnecessary and may decrease the fetal loss rate associated with trophoblast sampling. By circumventing the use of radioactive and non-radioactive probes, the spread of this technology to the high risk areas will be facilitated.
Journal of Medical Genetics 07/1989; 26(6):363-7. · 6.36 Impact Factor
