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The antithrombin III gene polymorphism in Japan: examination for haplotypes relevant to disordered antithrombin III
Y Oguma1, N Sakuragawa, K Hiraga
1Department of Clinical Laboratory Medicine, Toyama Medical and Pharmaceutical University School of Medicine, Japan.
Insights
This study investigated genetic variations in the antithrombin III (AT III) gene in Japanese populations. Restriction fragment length polymorphisms (RFLPs) were analyzed to understand congenital AT III deficiency, revealing potential genetic markers for the condition.
Area of Science:
- Genetics
- Molecular Biology
- Biochemistry
Background:
- Congenital antithrombin III (AT III) deficiency is a significant risk factor for thrombosis.
- Restriction fragment length polymorphisms (RFLPs) in the human AT III gene have been previously identified in Caucasian populations.
- These RFLPs have been instrumental in linkage analysis for congenital AT III abnormalities.
Purpose of the Study:
- To examine the existence and distribution of known AT III gene RFLPs in the Japanese population.
- To utilize these RFLPs for the molecular survey of individuals with AT III deficiency, including the AT III Toyama kindred and four type Ia deficient families.
- To investigate the genetic basis of decreased AT III levels in affected families.
Main Methods:
- Isolation of an AT III cDNA clone to serve as a hybridization probe.
- Analysis of intragenic (+/- alleles) and 5'-length (S/F alleles) polymorphisms using Southern blotting.
- Genotyping of individuals within the AT III Toyama kindred and four type Ia deficient families.
Main Results:
- The intragenic (+/-) and 5'-length (S/F) RFLPs were found to be evenly distributed in the Japanese population.
- A disproportionate association was observed between specific alleles: + with S, and - with F.
- The AT III Toyama kindred exhibited a homozygous -/F genotype; affected members of deficient families showed no detectable alterations on Southern blots, suggesting subtle genetic defects or regulatory issues.
Conclusions:
- The identified RFLPs are conserved in the Japanese population and can be utilized for molecular genetic studies of AT III deficiency.
- The lack of gross alterations in Southern blots suggests that inherited AT III deficiency in these families may stem from subtle gene defects or trans-acting regulatory mechanisms.
- The RFLPs provide potential linkage markers for identifying abnormal AT III genes, particularly on specific haplotypes, aiding in the determination of structural changes in two heterozygous deficient families.
Abstract:
In the human antithrombin III (AT III) gene of Caucasian, two restriction fragment length polymorphism (RFLPs) have been identified and used for the linkage analysis of many congenital AT III abnormality and deficiency. In the present study, we attempted to examine the existence and distribution of these RFLPs in Japanese and utilize them for the molecular survey of the members in the AT III Toyama kindred and 4 type Ia deficient families. An AT III cDNA clone was isolated by ourselves and served as a hybridization probe. In Japanese, the intragenic polymorphism, which is referred to + and - alleles, was evenly distributed (.49: .51), and the 5'-length polymorphism, designated as S and F alleles, was also conserved at a ratio of .4 to .6. However, the combined genotypes of both polymorphisms revealed disproportionate, and + and S, and - and F alleles seemed mainly to coexist. AT III genes of the AT III Toyama kindred showed the homozygous genotype of -/F, and all affected members of the deficient families demonstrated no distinguishable alterations on Southern blots, suggesting that a subtle defect in the AT III gene or the "trans-acting" disordered mechanism is responsible for the decreased AT III levels. According to some reports that a defective AT III gene is the cause of inherited AT III deficiency, it was implied that the abnormal AT III gene was located on the haplotype of -/F in 3 families and +/F in one. In two deficient families with heterozygous genotypes, the RFLPs were considered to bring a clue to determine the structural changes.
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