Clinical and genetic heterogeneity in black patients with homozygous
beta-thalassemia from the southeastern United States
JM Gonzalez-Redondo, TA Stoming, KD Lanclos, YC Gu, A Kutlar, F Kutlar, T Nakatsuji, B Deng, IS Han and VC McKie
Department of Cell and Molecular Biology, Medical College of Georgia,
Augusta 30912-2100.
The presence of various substitutions and deletions resulting in beta-
thalassemia was studied in 19 black patients with homozygous beta-
thalassemia and in numerous relatives; all patients were from Georgia,
South Carolina, and Alabama. Methodology included gene mapping,
amplification of genomic DNA with Taq polymerase, identification of known
nucleotide substitutions or a single nucleotide deletion through
hybridization with synthetic oligonucleotides, cloning and sequencing of a
beta-globin gene, and sequencing of amplified genomic DNA. Of the 38
chromosomes tested, 21 (55%) had the A----G substitution at nt -29, eight
(21%) had the C----T substitution at nt -88, three (8%) had the
substitution at codon 24, while one each of the following abnormalities
were also detected: frameshift at codon 6, a C----A mutation at nt 848 of
the beta IVS-II (new), an A----T mutation at codon 61 (new), a deletion of
1.35 kilobases including the 5' end of beta, a Ggamma(Agammadelta beta)
degree-thalassemia, and one thalassemia determinant that remained
unidentified. The C----A mutation at nt 848 of IVS-II occurred at a
position 3 nucleotides 5' to the third exon, adjacent to the invariant AG
dinucleotide of the acceptor sequence. The A----T mutation in codon 61
(AAG----TAG) resulted in the creation of a stop codon and thus in beta
degree-thalassemia. The various mutations occurred on chromosomes with
different haplotypes; however, chromosomes with a specific mutation but
with different haplotypes belonged to one specific framework, which
suggested that crossovers were responsible for these different types.
Hemoglobin (Hb) F levels were generally high (55% to 75% with 98.5% in one
patient with beta degree/beta degree); a few patients with specific
haplotypes and an alpha-thalassemia-2 heterozygosity had a lower Hb F
level. The Ggamma in the Hb F was consistently high when the C----T
mutation occurred at nt -158 to the Cap site of the Ggamma-globin gene;
seven patients with +/+ at this site had an average Ggamma of 73.8%, eight
patients with +/- had 64.8%, and one patient with -/- had 34.2%. Variations
in hematologic values and in Hb F, Ggamma, and Hb A2 levels of relatives
with a beta- thalassemia heterozygosity depended to some extent on the
types of mutations or deletions and on the haplotypes of the chromosomes
with the beta-thalassemia determinant.
Volume 72,
Issue 3,
pp. 1007-1014,
09/01/1988
Copyright © 1988 by The American Society of Hematology
