title: Interaction of rare illegitimate recombination event and a poly A addition site mutation resulting in a severe form of alpha thalassemia.
abstract: 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.
authors.affiliation: Molecular Biology Diagnostic Unit, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine 19104.
authors.forename: P
authors.initials: P
authors.lastname: Fortina
authors.forename: T
authors.initials: T
authors.lastname: Parrella
authors.forename: M
authors.initials: M
authors.lastname: Sartore
authors.forename: E
authors.initials: E
authors.lastname: Gottardi
authors.forename: V
authors.initials: V
authors.lastname: Gabutti
authors.forename: K
authors.initials: K
authors.lastname: Delgrosso
authors.forename: E
authors.initials: E
authors.lastname: Mansfield
authors.forename: E
authors.initials: E
authors.lastname: Rappaport
authors.forename: E
authors.initials: E
authors.lastname: Schwartz
authors.forename: C
authors.initials: C
authors.lastname: Camaschella
mesh_terms: D001483:Base Sequence; D002648:Child; D005260:Female; D017353:Gene Deletion; D005914:Globins / Q000235:genetics; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D011061:Poly A / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011995:Recombination, Genetic; D015183:Restriction Mapping; D017085:alpha-Thalassemia / Q000235:genetics*
chemical_list: D011061:Poly A; D005914:Globins