Introduction

b-Thalassemia constitutes one of the most serious health problems worldwide, accounting for a major number of childhood deaths per year primarily in regions of the world endemic for malaria (WHO, 1983). The disease results from mutations in and around the b-globin gene located as a cluster on the short arm of chromosome #11. b-Thalassemia is an autosomal recessive disorder characterized by microcytosis and hemolytic anemia. It results from a variety of molecular defects that reduce (b⁺-thalassemia) or abolish (b⁰-thalassemia) the synthesis of the b-globin chains of hemoglobin (Weatherall and Clegg, 1981).

Homozygotes and compound heterozygotes for b-thalassemia have a wide spectrum of clinical phenotypes, ranging from an undetectable to a life-threatening transfusion-dependent disease (Table 1). Generally, most b-thalassemia patients present with a severe, transfusion-dependent anemia within the first two years of life and later suffer from the long-term consequences of iron overload (thalassemia major). However, some other patients may have minor clinical manifestations that may not require transfusion (thalassemia intermedia).

Heterozygous b-thalassemia subjects (carriers) are usually asymptomatic. Their hematology is characterized by a slight to moderate anemia with marked hypochromia, microcytosis, a slightly raised level of the minor adult hemoglobin HbA₂, and an unbalanced a/b globin chain synthesis ratio (thalassemia minor; Lin et al., 1994).

At present, more than 180 mutations produce b-thalassemia (Huisman et al., 1997). They affect not only the actual amino acid coding regions of the b-globin exons, but also sites surrounding the gene and even within the non-coding introns. Most of these mutations cause defects in transcription, RNA splicing, RNA modification and translation due to frameshifts and nonsense codons. Other mutations produce highly unstable b-globin products (Huisman et al., 1997).

b-Thalassemia mutations differ greatly in their phenotypic effects; these range from the extremely mild mutations, which are both clinically and phenotypically silent in the heterozygous state (silent b-thalassemia; Rosatelli et al., 1994), to those which are rare and produce a phenotype of thalassemia intermedia due to the inheritance of a single copy of abnormal gene (dominant b-thalassemia; Thein, 1992). Between these two extremes lie the majority of b-thalassemia mutations whose carriers are asymptomatic, whereas homozygotes and compound heterozygotes suffer from a transfusion dependent anemia (reviewed by Weatherall et al., 1989).

A Brief History of b-Thalassemia Research in Turkey

The first two patients with b-thalassemia major in Turkey, were reported in 1941 (reviewed in Aksoy, 1991). However, the importance of b-thalassemia as a health problem was brought to the attention of physicians only after 1950 (Aksoy, 1959). Common problems encountered in Turkish b-thalassemia major patients included: below-average height, growth retardation (mainly in patients of 10 years of age or more), delay in bone age, and delayed puberty (Yesilipek et al., 1993). These results showed that growth and endocrine disturbances have significant negative effects in the quality of life of thalassemic patients. The first report about the prevalence of b-thalassemia carriers in Turkey was published in 1971 in which the incidence rate was stated to be 2 per cent (Cavdar et al., 1971). Dincol et al. were the first investigators to indicate regional differences in the prevalence rate of b-thalassemia trait in Turkey and to demonstrate the presence of both b+- and b0-thalassemia genes in the country (Dincol et al., 1979). Studies conducted in the years 1980 and 1995, confirmed this observation and noted a frequency variability ranging between 3.4 (East Anatolia) and 11 per cent (Western Thrace and Antalya; Aksoy et al., 1980; Aksoy et al., 1985; Kurkcuoglu et al., 1986; Bircan et al., 1993; Kocak et al., 1995). Due to this relatively high incidence of b-thalassemia in the Turkish population, the presence of patients co-inheriting b-thalassemia along with another congenital disorder is not surprising. So far, there has been several reports about the co-inheritance of b-thalassemia along with Immerslund-Grasbeck Syndrome (Sayli et al., 1994), Fanconi anemia (Altay et al., 1996a), and familial Mediterranean fever (Canatan D., unpublished observations). The co-inheritance of b-thalassemia and HbS, that is usually expressed as a severe type of disease in Turkish patients (Altay et al., 1997), cannot be neglected either (reviewed in Altay and Basak, 1995).

It was only in the year 1987 that the first study discussing the molecular basis of b-thalassemia in the Turkish population was published (Akar et al., 1987). Progress in the methodology to analyze mutations of the b-globin gene has made it possible to understand some of the mechanisms that are responsible for the occurrence of b-thalassemia in Turkey. Since then, several country-scale studies have been conducted in order to elucidate the molecular basis of b-thalassemia (Diaz-Chico et al., 1988; Gurgey et al., 1989; Aulehla-Scholz et al., 1990; Oner et al., 1990; Basak et al., 1992a; Atalay, et al., 1993; Altay and Basak, 1995; Nisli et al., 1997; Tadmouri et al., 1998a). These studies showed that the molecular basis of b-thalassemia in Turkey is quite heterogeneous and that more than 30 different mutations are behind the great variability in clinical expression of this disorder. In addition to these studies, many reports of single cases of Turkish b-thalassemia patients, either living in Turkey or abroad, contributed to the wealth of information about the presence of many rare and several novel b-globin mutations responsible for the disease in the Turkish population (Diaz-Chico et al., 1987; Gonzalez-Redondo et al., 1989a; Gonzalez-Redondo et al., 1989b; Schnee et al., 1989; Oner et al., 1991; Basak et al., 1992b; Ozcelik et al., 1993; Basak et al., 1993; Jankovic et al., 1994; Tadmouri et al., 1997; Tuzmen et al., 1997; Tadmouri et al., 1998b; Tadmouri et al., 1998c; Tadmouri et al., 1998d). Furthermore, several other papers described non-common forms of molecular alterations leading to b-thalassemia such as a deletion/inversion rearrangement of the b-globin gene cluster in a Turkish family with db0-thalassemia intermedia (Kulozik, et al., 1992; Oner et al., 1997) and a new type of b-thalassemia major with homozygosity for two non-consecutive 7.6 Kb deletions of the yb and b-genes (Oner et al., 1995). By April 1998, the total number of b-thalassemia alleles described in the Turkish population was 43 (Table 1) and they can surely be considered as a testimony of past colonizations that inhabited the Anatolian lands.

Molecular and Population Genetic Analyses of b-Thalassemia in Turkey

Of the 43 b-thalassemia mutations present in the Turkish population, at least 25 have been described in our laboratory (Tadmouri et al., 1998a). The experimental strategy that was followed while investigating the occurrence of these mutations was based on PCR amplification of the b-globin gene followed by dot-blot hybridization with 18 probes specific for the Mediterranean populations. Denaturing gradient gel electrophoresis (DGGE), restriction endonuclease analysis, and the amplification refractory mutation system (ARMS) were also used. DNA samples, in which a mutation was not revealed by these methods, were subjected to genomic sequencing (Tadmouri et al., 1998a).

Our results show that the IVS-I-110 (G-A) mutation is the most common b-thalassemia defect in Turkey (39.3%), followed in decreasing order by IVS-I-6 (T-C), FSC-8 (-AA), IVS-I-1 (G-A), IVS-II-745 (C-G), IVS-II-1 (G-A), Cd 39 (C-T), -30 (T-A), and FSC-5 (-CT) lesions, all of which have frequencies above 2% (Tadmouri et al., 1998a).

Table 1. b-Globin Gene Mutations Described in Turks

A comparison of the mutation frequencies in different regions of Turkey demonstrates that the distribution of b-thalassemia alleles differs within each area with marked local variations. When the regional results are compared with the overall frequency prevalent in the country, it can be noticed that the western and southern parts of Turkey are in good accordance with the overall distribution, whereas the northern and eastern parts have a more region/population-specific profile. The ethnic identities of the latter regions seem to be more preserved than the western and southern coastal parts of the country, which display a greater heterogeneity. On the other hand, although less heterogeneous, the northern, eastern and southeastern parts of Turkey seem to have their own battery of mutations, e.g. -30 (T-A), -87 (C-G), FSC-8/9 (+G) and IVS-II-745 (C-G) have a significantly high occurrence in these regions (Tadmouri et al., 1998a).

Prenatal Diagnosis of Thalassemia in Turkey

Although there are excellent treatment modalities today, like hypertransfusion therapy and administration of iron chelating agents for control of the accumulated excess iron, there is no definitive cure for b-thalassemia yet. Drugs to enhance the g-globin gene expression, bone marrow transplantation and gene therapy seem to be very promising, however, they are not in routine use yet. Thus, emphasis has to be given to prevention programs, like carrier screening and prenatal diagnosis.

Advances in the molecular understanding of b-thalassemia in Turkey did greatly improve preventive medical services such as genetic counseling and prenatal diagnosis and shed light on understanding the clinical and hematological variations of this disorder. For this, specialized medical centers at different universities were established to conduct treatment and investigation of b-thalassemic patients. Despite the difficulties imposed by the presence of various kinds of mutations leading to b-thalassemia in Turkey, prenatal diagnosis is feasible when early methods of fetal sampling are combined with the advent of PCR-based techniques such as, allele specific oligonucleotide hybridization, the amplification refractory mutation system, restriction endonuclease digestion analysis, DNA sequencing (Tuzmen et al., 1996), and, more recently, the reverse dot-blot hybridization technique. At present, prenatal diagnosis of b-thalassemia and sickle cell disease (SCD) are performed in several centers in Turkey, some of which are, Hacettepe University (Ankara; Gurgey et al., 1996), Bogazici University (Istanbul), and Cukorova University (Adana; reviewed by Altay and Basak, 1995).

During the years 1990-1998 (April), 94 pregnancies at risk for b-thalassemia and SCD have been successfully completed in the framework of a prenatal diagnosis program conducted in our laboratory. Until 1995, molecular screening was carried out using the methods mentioned previously. In 1996, the reverse dot-blot method was introduced (b-Globin StripA^ssay Kit, Vienna Labs). This method, which is capable of handling in a non-radioactive format the screening of a single sample for many mutation sites, is rapid, accurate, reliable, and cost-effective.

In addition to the elevated rate of consanguineous marriages (21%) within certain communities having a high incidence of thalassemia (Basaran et al., 1988), Turkey is one of the countries showing the highest rates of population increase in the world (36:1000, Census 1994). Both figures appear to contribute drastically to the frequency of affected births. The expected number of infants born annually with b-thalassemia and SCD in Turkey has been calculated to be around 150 and 40, respectively. Hence, approximately 800 pregnant women should seek prenatal diagnosis each year. Unfortunately, the total number of prenatal diagnoses performed in all operating centers barely exceeds 1/8^th of the expected value each year (reviewed by Altay and Basak, 1995). This indicates the need for implementing a comprehensive genetic preventive program for the eradication of b-thalassemia and SCD in Turkey like those going on in many Mediterranean countries. This could be performed either by screening of reproductive couples when they register for marriage (Altay et al., 1996b) or by educating the population at risk and their physicians. Intensive involvement of the population, e.g., community education and informed genetic counseling, is an important prerequisite (Tuzmen et al., 1996).

The Origin and Spread of b-Thalassemia in Turkey and the Mediterranean

By far the most common readily detectable type of variation between individuals in the globin loci is produced by neutral DNA sequence differences named ‘polymorphisms’. Such polymorphisms are estimated to occur every hundred bases or so throughout the genome (Jeffreys, 1979), representing a huge reservoir of genetic variation. Many polymorphisms have been found in the b-globin gene cluster (reviewed by Labie and Elion, 1996). Given the considerable number of such polymorphisms found in the b-globin cluster, it may be calculated that, potentially, a very large number of combinations of these sites along a chromosome, i.e., ‘haplotypes’, might exist. DNA haplotypes in the b-globin gene can be used for a) the discrimination between diverse epistatic events linked to the b-gene that may modulate the phenotypic expression of a structural mutation and b) the determination of the date of origin and track of gene flow of a particular b-globin gene mutation (reviewed by Labie and Elion, 1996).

Recently, DNA sequence variation in the intergenic domain upstream to the b-globin gene has attracted an increased attention. A large group of studies have accumulated in the last few years, most of which aimed at deducing the possible origins of some b-globin gene mutations through the analysis of several nucleotide polymorphisms and the (AT)_xT_y motif 5’ to the b-globin gene (reviewed by Labie and Elion, 1996). In a yet unpublished study of Trabuchet et al. (UCBLI, France), conducted over 3000 subjects living in a remote village in Senegal with a history of consanguineous marriages (90%), over 36 different b-globin haplotypes were characterized. This demonstrates two main facts:

• The populations in Africa today are recognized as the most diverse, irrespective of the level of genetic analyses.
• This result also shows the relative variability in the studied polymorphic region, making it one of the most ideal tools to study relationships between different populations.

In order to deduce the possible origins for the different b-thalassemia mutations in Turkey, we are, presently, analyzing a 790 bp DNA fragment located 400 bp 5’ to the b-globin gene that contains nine polymorphic nucleotides (-1069, -989, -780, -710, -703, -551, -543, -521, -491) and one hypervariable microsatellite of composite sequence (AT)_xT_y.

By comparing our preliminary results concerning the spectrum of the b-globin gene haplotypes in Turkey (Table I) with those, of Perrin et al. in Algeria (1998) some conclusions may be reached:

• The IVS-I-110 mutation is associated in Turkey with two distinct haplotypes ACATTTCCA (AT)7T7 (haplotype I) and GCATTTCCA (AT)7T7 (haplotype R). In Algeria, where haplotype R was not found at all (Perrin et al., 1998), a third haplotype is present [ACATCCCCA (AT)9T5 (haplotype V)]. Although these results may suggest that IVS-I-110 has multiple origins, we propose that the mutation originally occurred on haplotype I (predominating in IVS-I-110 alleles from both countries) and the observed haplotypic diversity is mainly due to recombination events between the ancestral b-thalassemia chromosome and other chromosomes, such as haplotype R that seems to be common in normal alleles from Turkey. The haplotype I encountered in Algeria agrees well with an Ottoman importation, between the 16^th and 19^th centuries, thus favoring an East Mediterranean origin for IVS-I-110.
• Some other mutations, e.g., -87 (C-G) and IVS-I-130 (G-A), had more specific associations with unique haplotypes indicating differences in their origins in respect to time and place. As for the IVS-I-130 (G-A), we found that this rare mutation is associated with either haplotypes GCTTCC(AT)₇T₇CA or GCTCCC(AT)₇T₇CA. The first of these haplotypes has been observed in Algerian b-thalassemia chromosomes carrying the -29 (A-G) and the FSC-6 (-A) alleles encountered in high frequencies in this country (Perrin et al., 1998). The second sequence haplotype, however, seems to be strictly associated with the Algerian IVS-I-2 (T-C) mutation (Perrin et al., 1998). In conjunction with this, the fact that the mutation IVS-I-130 (G-A) was described once in an Egyptian patient (Deidda et al., 1990) could be a good indication favoring a North-Eastern African origin, and then we would expect to find a similar sequence haplotype in the Egyptian patient. Confirmation would need a deep screening of thalassemic mutations in countries like Egypt or Libya (Tadmouri et al., 1998c).
• Another interesting observation is the association of the ‘Chinese’ IVS-II-654 (T-C) mutation, we encountered in a Turkish family, with the (AT)₉(T)₅ type of microsatellite and the ACATCCCCA sequence. Chinese IVS-II-654 chromosomes, however, are strongly linked to the (AT)₈(T)₅ type of arrangement (Zhou et al., 1995). To the best of our knowledge, the ACATCCCCA (AT)₉(T)₅ compound motif was thus far described in only three IVS-I-110 (G-A) b-thalassemia patients from the Oran region (Algeria; Perrin et al., 1998), in one Cd 39 (C-T) heterozygote from Western Thrace, as well as in several normal b-globin genes from France (Perrin P., personal communication, Jan. 1998). This line of evidence strongly suggests a Western Mediterranean, thus, an independent origin for the IVS-II-654 (C-T) mutation occurring in our family (Tadmouri et al., 1998d).

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