Interaction of rare illegitimate recombination event and a poly A addition site mutation resulting in a severe form of alpha thalassemia
| Autor: | V Gabutti, Paolo Fortina, Eric F. Rappaport, E. S. Mansfield, Elias Schwartz, M. Sartore, C Camaschella, E Gottardi, T Parrella, Kathleen Delgrosso |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 1994 |
| Předmět: |
Male
Proband Thalassemia Molecular Sequence Data Restriction Mapping Immunology Alpha-thalassemia Biology medicine.disease_cause Polymerase Chain Reaction Biochemistry alpha-Thalassemia hemic and lymphatic diseases Gene duplication medicine Humans Globin Child Gene Southern blot Recombination Genetic Genetics Mutation Base Sequence Cell Biology Hematology medicine.disease Molecular biology Globins Female Poly A Gene Deletion |
| Popis: | The clinical diversity of thalassemia depends on interaction of diverse genetic defects. We have characterized a severe form of alpha thalassemia caused by coinheritance of a rare alpha-globin gene deletion and a nondeletional defect in a southern Italian family. The proband, a 7-year-old girl, exhibited an abnormal hemoglobin electrophoresis pattern with hemoglobin H and hemoglobin Barts, indicating inheritance of H and hemoglobin Barts, indicating inheritance of a severe form of alpha thalassemia. Southern blot analysis of DNA showed normal as well as aberrant alpha-globin gene fragments indicating heterozygosity for a deletional form of alpha thalassemia in the proband and her mother. The coinheritance of a nondeletional form of alpha thalassemia (alpha alpha T) was suspected because of the severity of the proband's phenotype and the presence of normal alpha-globin gene fragments in the father. Selective polymerase chain reaction of the paternal alpha 1- and alpha 2-globin genes in the proband followed by DNA sequence analysis showed an AATAAA to AATGAA mutation in the polyadenylation signal sequence of the alpha 2-globin gene. Genomic DNA mapping and sequence analysis of a unique polymerase chain reaction product generated across the deletion breakpoint of the maternal allele showed a 5,201-bp deletion extending from 870 nucleotides 5′ of the alpha 2-globin gene to nucleotide +519 in the alpha 1-globin gene. This deletion is similar to that previously suggested by blotting studies in a Greek family (Pressley et al, Nucleic Acids Res 8:4889, 1980) and removes the entire alpha 2-globin gene and a portion of the 5′ end of the alpha 1-globin gene. Sequence characterization of the resultant aberrant truncated alpha 1-globin gene from the proband showed a 27 nucleotide duplication corresponding to the 3′ end of the alpha-globin gene IVS-2 region separated by the insertion of a tetranucleotide (GGTT), suggesting that this deletion is caused by an illegitimate recombination event. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|