Juvenile hereditary hemochromatosis is a genetically heterogeneous disorder transmitted as an autosomal recessive trait. It is most often caused by mutations in the HJV gene and rarely in the HAMP gene. Hepcidin is considered to constitute a negative regulator of iron absorption, and its production is increased in inflammatory states and iron overload. We report the detection of a new mutation in the HAMP gene leading to juvenile hemochromatosis in 2 members of a Portuguese family. The mutation lies in the 5-UTR (untranslated region) of the gene and creates a new initiation codon in the context of a Kozak sequence. We found no trace of hepcidin protein in the patients' urine, suggesting that ribosomes select the mutant initiation codon for translation. The decrease of hepcidin production would thus lead to increased iron absorption, resulting in iron deposition in parenchymal tissues. Phlebotomy therapy of the 2 patients resulted in impressive clinical
We report a Swiss-Spanish family three members of which have the clinical picture of thalassemia intermedia. Restriction endonuclease mapping of the alpha-globin cluster and digestion with Mae I of the in vitro amplified 5' segment of the beta-globin gene shows a combination of triplicated alpha globin locus, anti-3.7 kb type, with heterozygous codon 39 C----T beta (0) thalassemic mutation. These, as well as 16 similar cases reported in the literature, permit the following conclusion: a single extra alpha-globin gene gives rise to a clinically significant degree of dyserythropoietic anemia only when it interacts with a severe beta(+) or beta(0) thalassemic mutation.
Summary.We describe a new case of an association of aglobin gene quadruplication of the anti-4.2 type with b Њ-thalassaemia. The patient, a young woman of mixed Brazilian-Portuguese origin, suffered from chronic haemolytic anaemia with splenomegaly. Bone marrow supravital staining with brilliant cresyl blue and electron microscopy studies showed large inclusion bodies in about 3% of erythroblasts. Upon immunofluorescent staining these inclusions reacted with a monoclonal antibody to a-but not to b-globin. Analysis of a-globin cluster by Southern blotting showed the presence of pathologic fragments specific for the anti-4.2 a-globin gene quadruplication. a/b mRNA ratio was higher than in cases combining a-globin triplication and bЊ-thalassaemia or in cases of bЊ-thalassaemia heterozygous state alone (18, 14·7 and 10·1 respectively). Our data confirmed the hypothesis that the clinically detectable haemolysis in this bЊ-thalassaemic patient was due to an unusually high amount of precipitated a-globin in erythroid precursors. This considerable excess of a-globin chains was due partly to the b-globin deficit caused by the presence of the bЊ-thalassaemic gene, but also to the presence of 6 active a-globin genes resulting from a-globin gene quadruplication in one chromosome.Keywords: a-globin gene quadruplication, inclusion body bthalassaemia, a/b mRNA ratio, globin mRNA quantification, thalassaemia intermedia.Rearrangements in the human a-globin cluster are amongst the most common genetic abnormalities observed in human populations. Deletions are the most common type of modification and involve the a-genes or larger areas of the cluster. However a-globin triplications are also encountered, and are a result of non-reciprocal crossing-over events (Weatherall, 1994).Association of such a-globin haplotypes (aaa/) with bЊ-thalassaemias strongly suggests that all genes are functioning, since these patients present a thalassaemia intermedia phenotype (Beris et al, 1991b;Ho et al, 1998). a-globin gene quadruplication is exceptional. To date, clinical and haematological data have been reported for six cases belonging to two families presenting this haplotype, but the information given was scanty and incomplete (Gu et al, 1987).We report a new case of a-globin gene quadruplication in association with a bЊ-thalassaemia, in a patient presenting large erythroblastic inclusions, severe ineffective erythropoiesis and haemolysis.The inclusion bodies were investigated by electron microscopy and immunofluorescence staining, using monoclonal antibodies against the a-and b-globin chains. Only the first antibody was found to react with the inclusions. Globin mRNA ratio quantification was performed, revealing, as expected, a great excess of a-globin mRNA. CASE REPORT, MATERIALS AND METHODSThe patient, a young woman of mixed Brazilian-Portuguese origin, was initially referred to our service because of chronic fatigue. Upon examination chronic haemolytic anaemia and splenomegaly were revealed with: Hb 8·4 g/dl, RBC 4·09 ×
Microcytosis is a highly prevalent finding during blood examination. This study investigates the causes of microcytosis (defined as mean corpuscular volume (MCV)<82 fl) in 466 patients referred to our laboratory for suspected hemoglobinopathy. The following data were obtained: Hb, MCV, serum iron, transferrin, ferritin, HbA2, HbF, isoelectric focusing of the Hb, gene mapping of chromosome 16 with Xba I and Bgl II and hybridization with an α‐ and a ζ‐probe, inflammatory status. Results show that iron deficiency remains the first cause of microcytosis (35.2% of our patients), even in a selected population such as ours. Deletional α‐thalassemia, probably the most frequent hemoglobinopathy throughout the world, represents the second most frequent cause of microcytosis (31.1%), followed by β‐thalassemia heterozygous state (18.9%). Of our patients, 1.3% had microcytosis due to the presence of an abnormal hemoglobin (HbC, Hb S/C, HbE). Three cases (0.6%) had other possible causes of microcytosis. Of the remaining 60 cases, 28 had an inflammatory state. Finally, 32 cases (6.9%) remain unexplained; taking into consideration the origin of these cases, their hematological parameters and their family history, we postulate that these cases are at high risk for non‐deletional α‐thalassemia.
Investigation of microcytic anemia with normal ferrous status in two members (father and daughter) of a Swiss family originating from Bern revealed high levels of HbA2 (4%, 7.3%) and HbF (3.2%, 3.1%). Direct sequence analysis of asymmetrically amplified DNA showed the ATG-->ACG mutation in the intiation codon of the beta-globin gene. Heterozygous beta-thalassemia was not found in either of the propositus's parents or in any of his brothers and sisters. Extended restriction fragment length polymorphism haplotyping of the beta chromosomes led us to the conclusion of a recent spontaneous mutation in the paternal germ cell. The results of routine HLA and blood group testing supported the stated paternity. We also found that the intragenic sequence polymorphisms (frameworks) are not always in linkage disequilibrium with the Bam HI polymorphism downstream from the beta-globin gene as previously observed. This is the second family found to carry this initiation codon mutation in the beta-globin gene. Unlike the first reported family, of Yugoslavian origin, our patients have high HbF levels and this in the absence of a C-->T substitution at -158 site 5' to G gamma.
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