The beta-thalassemia mutation/haplotype distribution in the moroccan population.

The present study compiles the results of our own research and of a prior study on beta-thalassemia (thal) in Morocco, comprising a total of 187 beta-thalassemic chromosomes. Six major mutations: (beta0) codon 39 (C --> T), (beta+) IVS-I-6 (T --> C), (beta0) frameshift codon (FSC) 6 (-A), (beta0) FSC 8 (-AA), (beta0) IVS-I-1 (G --> A) and (beta+) -29 (A --> G) account for 75.7% of the independent chromosomes studied.

Spectrum of beta thalassemia mutations and HbF levels in the heterozygous Moroccan population.

A comprehensive hematological and molecular analysis of 57 beta thalassemic heterozygotes, 28 homozygotes, 18 double heterozygotes, 3 compound heterozygotes beta thal/beta S and one compound heterozygote beta thal/Hb Newcastle, in 46 Moroccan families with at least one beta thalassemia patient is reported. Six major mutations: beta(0)39 (C-->T), beta(0)FsCD8(-AA), beta(+)IVS1,nt6 (T-->C) and beta(0)IVS1,nt1 (G-->A), beta(0)FsCD6 (-A) and beta(+)-29 (A-->G) cap site account for 75% of the 86 independent beta thal chromosomes studied. For the first time, an extensive mutation/haplotype study has been performed on the Moroccan population, and data are consistent with the geographical location of the country and historical links with both the Mediterranean and the Sub-Saharan Africa communities.

A novel rearrangement of the human fetal globin genes leading to a six gamma-globin gene haplotype.

Haematological as well as gene mapping data are reported for three members of a Portuguese Caucasian family with high G(gamma)-globin levels. A gamma-globin gene sextuplication of the G(gamma)AG(gamma)AG(gamma)AG(gamma)AG(gamma)A(gamma) type was present in the proband and her father. Comparison of gene mapping data with quantitative results of fetal haemoglobin (HbF) analysis provided an explanation for the extremely high G(gamma)-globin levels (> 90%) in the HbF from the two mentioned individuals.

Fetal hemoglobin elevation in Hb Lepore heterozygotes and its correlation with beta globin cluster linked determinants.

We have analysed, at the hematological and molecular level, 51 Hb lepore heterozygotes and three compound heterozygotes for Hb Lepore and HbS (HbLep/HbS) in 26 unselected Portuguese families. The Lepore Boston variant was present in one family, in association with classical haplotype V. All of the other Lepore alleles present haplotype III in association with XmnI (+)5' of (G)gamma gene, in tight linkage disequilibrium to the major mutation found in the Portuguese population, the Lepore Baltimore variant ( delta(68Leu)-beta(84Thr)).

Identification of a new WT1 mutation in a sporadic Wilms' tumour.

A new mutation in WT1 is described in a sporadic unilateral Wilms' tumour consisting of a 17 bp duplication in exon 7 generating a stop codon. The second allele is either partially deleted or presents the same alteration. LOH analysis at 11p15.

Dominantly transmitted beta-thalassemia arising from the production of several aberrant mRNA species and one abnormal peptide.

We describe a dominantly inherited beta-thalassemia intermedia phenotype observed in a five-generation Portuguese family. Carriers are characterized by moderate anemia, hypochromia, microcytosis, elevated hemoglobin (Hb)A2 and HbF levels, splenomegaly, hepatomegaly, and inclusion bodies in peripheral red blood cells after splenectomy. The molecular basis of this condition is a small deletion within the 5' consensus splicing sequence of the second intron of the beta-globin gene, IVS-II-4,5 (-AG).

A novel mosaic Bantu/Benin/Bantu beta s haplotype found in several African populations.

In a survey of the chromosomal backgrounds associated with the sickle cell gene in Portuguese-speaking populations from Europe and Africa, a discordance between the classical haplotype and the predicted allele at the RsaI polymorphism 5' to the beta globin gene was observed in four patients. Extensive typing of the corresponding beta s chromosomes at simple polymorphic repeat motifs revealed a novel "extended" haplotype that appeared to be a mosaic of (1) a Bantu-type DNase I hypersensitive site 2 within the beta globin gene cluster locus control region, (2) a Benin 5' subhaplotype, and (3) a Bantu 3' subhaplotype. We propose two alternative schedules for the generation of yet another chromosomal background of the sickle cell gene.

Insertional inactivation of the WT1 gene in tumour cells from a patient with WAGR syndrome.

The WT1 gene was analysed using DNA from a Wilms' tumour derived from a patient with the WAGR syndrome using single strand conformation polymorphism analysis and polymerase chain reaction sequencing. A 14-bp insertion was found in the intron part of the splice donor site of exon 7 and was a tandem duplication of an upstream exon sequence. This mutation would be expected to disrupt the correct processing of the WT1 mRNA and is predicted to result in a non-functional protein.

Importation route of the sickle cell trait into Portugal: contribution of molecular epidemiology.

To elucidate the origin and spread of the sickle cell trait into the Portuguese population, we examined nine polymorphic DNA markers within the beta globin gene cluster defining the haplotype. The population sample included 64 sickle-cell-gene-bearing individuals from defined Portuguese-speaking white, black, and Asian Indian populations. The nature and geographic distribution of the different beta S haplotypes in Portugal suggest that the sickle cell trait has been imported twice: between the eighth and the thirteenth centuries from the Mediterranean basin (in association with the Benin haplotype) and after the fifteenth century from black Africa over an Atlantic route (Senegal and Bantu haplotypes).

Novel promoter and splice junction defects add to the genetic, clinical or geographic heterogeneity of beta-thalassaemia in the Portuguese population.

In order to delineate the spectrum and the relative abundance of beta-globin gene defects causing thalassaemia in the Portuguese population, a representative sample was analysed including 51 beta-thalassaemia carriers along with 26 patients representing different clinical phenotypes. Seven mutations were identified, four of which [codon 39 (C----T), 39%; intervening sequence (IVS) 1 nucleotide (nt) 1 (G----A), 26%; IVS 1 nt 110 (G----A), 17%; IVS 1 nt 6 (T----C), 15%] account for 97% of 93 beta-thalassaemia chromosomes. Two previously undescribed mutations, namely a C----T substitution at position--90 in the proximal CACCC box, and the deletion of nucleotides 4 and 5 (AG) in IVS2 were identified.

Alpha-thalassemia resulting from deletion of regulatory sequences far upstream of the alpha-globin structural genes.

We describe an alpha-thalassemia determinant in which alpha-globin expression is silenced by a deletion located 27 kb 5' to the transcription start site of the alpha 2-globin gene. This alpha-thalassemic determinant, (alpha alpha)MM, is a member of a newly described group of thalassemic mutations resulting from deletion of locus-controlling sequences critical to globin gene expression.