International Journal of
-Thalassemia in the Korean Population
Sung Sup Park, Han-Ik Cho
Department of Clinical Pathology, Seoul National University College of Medicine,
Seoul National University Hospital Clinical Research Institute, Seoul, Korea
-Thalassemia is uncommon in the Korean population, however it must be considered in the differential diagnosis
of hypochromic anemia. The molecular characterization of -Thalassemia is absolutely necessary for molecular
diagnosis as well as any genetic epidemiological study in this region. We analyzed the molecular basis of
-thalassemia in 47 Korean families. Using direct sequencing of genomic DNA amplified through PCR and haplotype
analysis, 44 -thalassemia genes were characterized, all of which were heterozygous. Fourteen different mutations
were identified. The common mutations noted included the initiation codon (CD) ATG- AGG (23.4%), CD 17 A-
T (21.2%), and IVS-II-1 G- A (12.7%). Interestingly, mutations causing dominantly inherited -thalassemia were
common (17.0%). All cases of IVS-II-1 G- A mutations were linked to the silent mutation of CD 91 C- T of the
-globin gene. The initiation CD ATG- AGG and IVS-II-1 G- A with CD 91 C- T were found in the Far East
only, and may be inherited from a common origin for each mutation, at least in Koreans. CD17 A- T and CDs
41/42 -TTCT were suggested to be introduced by gene-flow from southern China. Otherwise, Hb Korea , CDs 89/90
-GT and a novel -thalassemia mutation, CD 131 CAG- TAG, were only identified in Koreans. This mutation
spectrum is characteristic of the low prevalent area of -thalassemia, however it is quite different even from the
adjacent countries, Japan or China.
1. Introduction assumed to be about 0.1% like Japan. We have carried
out a detailed genetic analysis of -thalassemia in the
-Thalassemia is prevalent in regions previously Korean population, which may be another example of
endemic for malaria including the Mediterranean, Middle the -thalassemia mutation spectrum of a low-preva-
East, parts of Africa, India, the Southeast Asia, and lence area.
southern China . Molecular analysis of the -thalas-
semia genes has demonstrated a striking heterogeneity, 2. The spectrum of -thalassemia alleles
and population studies indicate that probably only 20
-thalassemia alleles account for 80% of the To date, we characterized 44 -thalassaemic alleles in
-thalassemia mutations worldwide. This is due to the 47 families with -thalassemia minor or intermedia, and
phenomenon of geographical clustering, where each identified fourteen types of mutations including a case
population has a few common mutations together with a analyzed in the other institute previously . The pa-
varying number of rarer ones [2,3]. tients were identified throughout South Korea, and this
On the contrary, -thalassemia is uncommon in data may represent the overall trend of -thalassemia in
countries of a temperate climate, such as Britain, the Korean population.
northern Europe, Japan and Korea, possibly due to the Table 1 shows the molecular spectrum of -thalas-
absence of selection in favor of the -thalassemia semia in Koreans, demonstrating heterogeneity compared
genes. In this respect, it is interesting to compare the to the endemic areas. Recently we found a novel -
spectrum of -thalassemia alleles in high-frequency thalassemia mutation, CD 131 CAG- TAG. Intere-
areas with that seen in regions where -thalassemia is stingly, all cases with IVS-II-1 G- A were linked to
uncommon . the silent mutation, CD 91 C- T of the -globin gene.
It is known that -thalassemia does occur in Koreans Three mutations were relatively common: the initiation
[4-7] and the -thalassemia gene frequency is roughly CD ATG- AGG (23.4%), CD 17 A- T (21.2%), and
Table 1. Table 2.
M o lecular S pectrum o f -thalassem ia in the K o rean P op ulation. -Thalassaem ic M utatio ns and Their A sso ciated H aplo types and
ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Fram ew orks in K o reans.
M utatio n N o . o f alleles % ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ
ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ N um b er
Initiatio n co d o n A TG - A G G 11 23.4 M utatio n -H aplotyp e Fram ew o rk
o f alleles
C o d ons 8/9 + G 1 2.1 ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ
C o d on 17 A - T 10 21.2 Initiatio n co d o n A TG - A G G 3 -+ -+ + -+ FW 3A
IVS -I-130 G - A 1 2.1 6 n.d . FW 3A
IVS -I-130 G - C 2 4.2 C o d ons 8/9 + G 1 + ---- + + FW 1
C o d ons 33/34 -G G T (H b K orea) 1 2.1 C o d on 17 A - T 2 + ---- -+ FW 3A
C o d ons 41/42 TTC T 2 4.2 2 n.d . FW 3A
C o d ons 89/90 G T 2 4.2 IVS -I-130 G - C 1 n.d . FW 3A
IVS -II-1 G - A w ith co d on 91 C - T 6 12.7 IVS -I-130 G - A 1 n.d . FW 1
IVS -II-849 A - G 1 2.1 C o d ons 41/42 TTC T 1 + ---- + + FW 1
C o d on 114 T- C (H b B rescia) 1 2.1 1 + ---- -+ FW 3A
C o d on 121 G - T 4 8.5 C o d ons 89/90 G T 1 -+ + -+ + - FW 1
C o d on 127 C A G - C G G (H b D ieppe) 1 2.1 1 FW 2
C o d on 131 C A G - TA G 1 2.1 IVS -II-1 G - A w ith co d on
U nknow n 3 6.3 91 C - T 4 n.d . FW 2
ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ C o d on 114 T- C (H b B rescia) 1 + ---- + - FW 2
To tal 47 100 C o d on 121 G - T 1 n.d . FW 2
*n.d .: not d eterm ined
IVS-II-1 G- A (12.7%). Mutations causing dominantly
inherited -thalassemia were common (17.0%): CD 121 Unfortunately, there were no comparable reports on the
G- T, CDs 33/34 -GGT (Hb Korea), CD 114 T- C haplotype and framework analysis in the Chinese or the
(Hb Brescia), CD 127 CAG- CGG (Hb Dieppe), and Japanese populations.
CD131 CAG- TAG. CD 17 A- T nonsense mutation is one of the most
common mutations in southern China and Southeast
3. Association of -thalassemia with -globin Asia. This mutation has been linked to FW2 and/or to
haplotypes and other polymorphisms the haplotype of [+---- -+] in the all of four families
available in this study, and also in the Chinese and the
All of the cases with the three common mutations, Thai . It suggests that this mutation was introduced
the initiation CD ATG- AGG, CD 17 A- T, and by gene-flow from southern China.
IVS-II-1 G- A, were shown to be linked to the same The IVS-II-1 G- A mutation has been identified
haplotype and/or framework (Table 2). These results from different ethnic groups . Surprisingly, this
suggested that at least three common mutations may be mutation was linked to CD 91 C- T in all of six
inherited from the same origin for each mutation. CDs unrelated Korean families and four Japanese families
41/42 -TTCT and CDs 89/90 -GT were shown to be previously reported [10,15]. However, this type of
from different haplotypes in two families. The silent linkage has not been reported in other ethnic groups.
mutation, CD 91 C- T that was linked to all cases All Korean families had FW2, and all four Japanese
with IVS-II-1 G- A was not found in any of the 550 cases showed the same haplotype [-+--+ +-] and FW2.
normal individuals (1100 chromosomes), and it was These results strongly suggest that this type of mutation
thought as a very rare polymorphism. in Koreans and Japanese may be inherited from an
4. Characteristics of the -thalassemia We found five types of -thalassemia mutations that
Mutations Found in Koreans are dominantly inherited in eight probands (17.0%). CD
121 C- T was found in four of the Korean families
The molecular epidemiology of the initiation CD studied (8.5%) and is probably the most common domi-
ATG- AGG mutation is very interesting. Geographi- nant -thalassemia allele in other ethnic groups as well
cally, this mutation is quite unique to the population of . Otherwise, Hb Brescia and Hb Dieppe has been
the Far East Asia. So far, all 27 probands reported, observed very rarely in several racial populations, and
including those in this report, have been restricted to Hb Korea and CD 131 CAG- TAG were found in
the Chinese, the Japanese and the Korean populations Koreans only. A Korean proband with CD 121 C- T
[5,6,8,9,11-13]. In this study, RFLP haplotypes and had FW2 and Japanese patients with the mutation
framework linked to the mutation were type IV [-+-++ showed haplotype [+---- -+] and/or FW2 [10,17], which
-+] in all of three available families, and the FW3 was different from the British -haplotype [-++-+ +-]
Asian type in nine probands. These results suggest a linked with CD 121 G- T . These findings support
common origin of this mutation, at least in Koreans. the hypothesis that most of dominant -thalassemia
mutations have an independent origin and are sometimes 4. Park SS, Barnetson R, Kim SW, Weatherall DJ, Thein SL. A
caused by spontaneous mutations . spontaneous deletion of beta 33/34 Val in exon 2 of the beta
globin gene (Hb Korea) produces the phenotype of dominant
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