title: Mutational spectrum of delta-globin gene in the Portuguese population.
abstract: The phenotype of increased Hb A2 typical of beta-thalassaemia (beta-thal) carriers can be reduced to normal or borderline values because of the co-inheritance of a delta-globin gene (HBD, MIM #142000) mutation, which may lead to misinterpretation of diagnostic results. To know the spectrum of delta-globin mutations in the Portuguese population we performed a mutational analysis of the delta-globin gene in a group of 51 Portuguese beta-thal carriers presenting microcytosis, hypochromia and a normal/borderline Hb A2 level and in another group of 15 individuals suspected to have delta-globin structural abnormalities. The heterozygosity for the beta(+)IVS-I-6T-->C (HBB:c. 92+6T>C) mutation was the main cause for the mentioned atypical beta-thal carrier phenotype. Furthermore, eight individuals were double heterozygous for one common beta-thal mutation and the delta(+)Cd27G-->T mutation (Hb A2-Yialousa; HBD:c.82G>T). One of them also presented a novel delta-globin gene promoter mutation,-80G-->A (HBD:c.-130G>A), responsible for about 25% decrease of the promoter activity in transient expression assays. One the other hand, in the other group of 15 individuals suspected to have delta-globin structural abnormalities observed by biochemical methods, some known Hb A2 variants were identified - Hb A2' (HBD:c.49G>C), Hb A2-Babinga (HBD:c.410G>A), and Hb A2-Wrens (HBD:c.295G>A), and the novel Hb A2-Fogo [delta64(E8)(Gly-->Ser); (HBD:c.193G>A)]. This novel Hb A2 variant was observed segregating in linkage with Hb E (HBB:c.79G>A) in a three generation family. In conclusion, six different delta-globin mutations were found, being two of them new molecular defects. All delta-alleles identified were found linked to the expected beta-globin cluster haplotype. All mutations caused a low Hb A2 level and through this could lead to misdiagnosis when inherited together with a beta-thal allele.
authors.affiliation: Centro de Genética Humana, Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Morgado
authors.forename: Isabel
authors.initials: I
authors.lastname: Picanço
authors.forename: Susana
authors.initials: S
authors.lastname: Gomes
authors.forename: Armandina
authors.initials: A
authors.lastname: Miranda
authors.forename: Margarida
authors.initials: M
authors.lastname: Coucelo
authors.forename: Filomena
authors.initials: F
authors.lastname: Seuanes
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Seixas
authors.forename: Luísa
authors.initials: L
authors.lastname: Romão
authors.forename: Paula
authors.initials: P
authors.lastname: Faustino
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D006580:Genetic Carrier Screening; D005914:Globins / Q000235:genetics*; D006239:Haplotypes; D006443:Hemoglobin A2 / Q000235:genetics; D006454:Hemoglobins / Q000235:genetics; D006455:Hemoglobins, Abnormal / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D010957:Plasmids; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011174:Portugal / Q000453:epidemiology; D011401:Promoter Regions, Genetic; D014162:Transfection; D017086:beta-Thalassemia / Q000208:ethnology / Q000235:genetics*
chemical_list: D006454:Hemoglobins; D006455:Hemoglobins, Abnormal; C032001:hemoglobin D; D005914:Globins; D006443:Hemoglobin A2; C020622:hemoglobin B; D008156:Luciferases