Interaction of a rare illegitimate recombination event and a poly A addition site mutation resulting in a severe form of α thalassemia

P. Fortina, T. Parrella, M. Sartore, E. Gottardi, V. Gabutti, K. Delgrosso, E. Mansfield, E. Rappaport, E. Schwartz, C. Camaschella, S. Surrey

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The clinical diversity of thalassemia depends on interaction of diverse genetic defects. We have characterized a severe form of α thalassemia caused by coinheritance of a rare α-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 a severe form of α thalassemia. Southern blot analysis of DNA showed normal as well as aberrant α-globin gene fragments indicating heterozygosity for a deletional form of α thalassemia in the proband and her mother. The coinheritance of a nondeletional form of α thalassemia (αα(T)) was suspected because of the severity of the proband's phenotype and the presence of normal α-globin gene fragments in the father. Selective polymerase chain reaction of the paternal α1- and α2-globin genes in the proband followed by DNA sequence analysis showed an AATAAA to AATGAA mutation in the polyadenylation signal sequence of the α2- 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 α2-globin gene to nucleotide +519 in the α1-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 α2-globin gene and a portion of the 5' end of the α1-globin gene. Sequence characterization of the resultant aberrant truncated α1-globin gene from the proband showed a 27 nucleotide duplication corresponding to the 3' end of the α-globin gene IVS-2 region separated by the insertion of a tetranucleotide (GGTT), suggesting that this deletion is caused by an illegitimate recombination event.

Original languageEnglish
Pages (from-to)3356-3362
Number of pages7
JournalBlood
Volume83
Issue number11
Publication statusPublished - Jun 1 1994

Fingerprint

Poly A
Thalassemia
Globins
Genetic Recombination
Genes
Mutation
Nucleotides
Polymerase chain reaction
DNA Sequence Analysis
Hemoglobin H
Mothers
Abnormal Hemoglobins
Polymerase Chain Reaction
Defects
Polyadenylation
DNA sequences
DNA
Gene Deletion
Protein Sorting Signals
Southern Blotting

ASJC Scopus subject areas

  • Hematology

Cite this

Fortina, P., Parrella, T., Sartore, M., Gottardi, E., Gabutti, V., Delgrosso, K., ... Surrey, S. (1994). Interaction of a rare illegitimate recombination event and a poly A addition site mutation resulting in a severe form of α thalassemia. Blood, 83(11), 3356-3362.

Interaction of a rare illegitimate recombination event and a poly A addition site mutation resulting in a severe form of α thalassemia. / Fortina, P.; Parrella, T.; Sartore, M.; Gottardi, E.; Gabutti, V.; Delgrosso, K.; Mansfield, E.; Rappaport, E.; Schwartz, E.; Camaschella, C.; Surrey, S.

In: Blood, Vol. 83, No. 11, 01.06.1994, p. 3356-3362.

Research output: Contribution to journalArticle

Fortina, P, Parrella, T, Sartore, M, Gottardi, E, Gabutti, V, Delgrosso, K, Mansfield, E, Rappaport, E, Schwartz, E, Camaschella, C & Surrey, S 1994, 'Interaction of a rare illegitimate recombination event and a poly A addition site mutation resulting in a severe form of α thalassemia', Blood, vol. 83, no. 11, pp. 3356-3362.
Fortina P, Parrella T, Sartore M, Gottardi E, Gabutti V, Delgrosso K et al. Interaction of a rare illegitimate recombination event and a poly A addition site mutation resulting in a severe form of α thalassemia. Blood. 1994 Jun 1;83(11):3356-3362.
Fortina, P. ; Parrella, T. ; Sartore, M. ; Gottardi, E. ; Gabutti, V. ; Delgrosso, K. ; Mansfield, E. ; Rappaport, E. ; Schwartz, E. ; Camaschella, C. ; Surrey, S. / Interaction of a rare illegitimate recombination event and a poly A addition site mutation resulting in a severe form of α thalassemia. In: Blood. 1994 ; Vol. 83, No. 11. pp. 3356-3362.
@article{8bd4fed7d34c4aea86f3b67680b47f13,
title = "Interaction of a rare illegitimate recombination event and a poly A addition site mutation resulting in a severe form of α thalassemia",
abstract = "The clinical diversity of thalassemia depends on interaction of diverse genetic defects. We have characterized a severe form of α thalassemia caused by coinheritance of a rare α-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 a severe form of α thalassemia. Southern blot analysis of DNA showed normal as well as aberrant α-globin gene fragments indicating heterozygosity for a deletional form of α thalassemia in the proband and her mother. The coinheritance of a nondeletional form of α thalassemia (αα(T)) was suspected because of the severity of the proband's phenotype and the presence of normal α-globin gene fragments in the father. Selective polymerase chain reaction of the paternal α1- and α2-globin genes in the proband followed by DNA sequence analysis showed an AATAAA to AATGAA mutation in the polyadenylation signal sequence of the α2- 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 α2-globin gene to nucleotide +519 in the α1-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 α2-globin gene and a portion of the 5' end of the α1-globin gene. Sequence characterization of the resultant aberrant truncated α1-globin gene from the proband showed a 27 nucleotide duplication corresponding to the 3' end of the α-globin gene IVS-2 region separated by the insertion of a tetranucleotide (GGTT), suggesting that this deletion is caused by an illegitimate recombination event.",
author = "P. Fortina and T. Parrella and M. Sartore and E. Gottardi and V. Gabutti and K. Delgrosso and E. Mansfield and E. Rappaport and E. Schwartz and C. Camaschella and S. Surrey",
year = "1994",
month = "6",
day = "1",
language = "English",
volume = "83",
pages = "3356--3362",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "11",

}

TY - JOUR

T1 - Interaction of a rare illegitimate recombination event and a poly A addition site mutation resulting in a severe form of α thalassemia

AU - Fortina, P.

AU - Parrella, T.

AU - Sartore, M.

AU - Gottardi, E.

AU - Gabutti, V.

AU - Delgrosso, K.

AU - Mansfield, E.

AU - Rappaport, E.

AU - Schwartz, E.

AU - Camaschella, C.

AU - Surrey, S.

PY - 1994/6/1

Y1 - 1994/6/1

N2 - The clinical diversity of thalassemia depends on interaction of diverse genetic defects. We have characterized a severe form of α thalassemia caused by coinheritance of a rare α-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 a severe form of α thalassemia. Southern blot analysis of DNA showed normal as well as aberrant α-globin gene fragments indicating heterozygosity for a deletional form of α thalassemia in the proband and her mother. The coinheritance of a nondeletional form of α thalassemia (αα(T)) was suspected because of the severity of the proband's phenotype and the presence of normal α-globin gene fragments in the father. Selective polymerase chain reaction of the paternal α1- and α2-globin genes in the proband followed by DNA sequence analysis showed an AATAAA to AATGAA mutation in the polyadenylation signal sequence of the α2- 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 α2-globin gene to nucleotide +519 in the α1-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 α2-globin gene and a portion of the 5' end of the α1-globin gene. Sequence characterization of the resultant aberrant truncated α1-globin gene from the proband showed a 27 nucleotide duplication corresponding to the 3' end of the α-globin gene IVS-2 region separated by the insertion of a tetranucleotide (GGTT), suggesting that this deletion is caused by an illegitimate recombination event.

AB - The clinical diversity of thalassemia depends on interaction of diverse genetic defects. We have characterized a severe form of α thalassemia caused by coinheritance of a rare α-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 a severe form of α thalassemia. Southern blot analysis of DNA showed normal as well as aberrant α-globin gene fragments indicating heterozygosity for a deletional form of α thalassemia in the proband and her mother. The coinheritance of a nondeletional form of α thalassemia (αα(T)) was suspected because of the severity of the proband's phenotype and the presence of normal α-globin gene fragments in the father. Selective polymerase chain reaction of the paternal α1- and α2-globin genes in the proband followed by DNA sequence analysis showed an AATAAA to AATGAA mutation in the polyadenylation signal sequence of the α2- 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 α2-globin gene to nucleotide +519 in the α1-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 α2-globin gene and a portion of the 5' end of the α1-globin gene. Sequence characterization of the resultant aberrant truncated α1-globin gene from the proband showed a 27 nucleotide duplication corresponding to the 3' end of the α-globin gene IVS-2 region separated by the insertion of a tetranucleotide (GGTT), suggesting that this deletion is caused by an illegitimate recombination event.

UR - http://www.scopus.com/inward/record.url?scp=0028308797&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028308797&partnerID=8YFLogxK

M3 - Article

VL - 83

SP - 3356

EP - 3362

JO - Blood

JF - Blood

SN - 0006-4971

IS - 11

ER -