Caucasian mutant allele

Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber C-M, Saragosti S, Lapoumeroulie C, Cognaux J, Forceille C, Muyldermans G, Verhofstede C, Burtonboy G, Georges M, Imai T, Rana S, Yi Y, Smyth RJ, Collman RG, Dorns RW, Vassart G, Parmentier M (1996) Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382 722-725... 

Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber CM et al. Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 1996 382 722-725. 

Thiopurine S-methyltransferase deficiency two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Am J Hum Genet 1996 58 694-702. 

Based on the population genotype-phenotype studies performed to date, assays for the molecular diagnosis of TPMT deficiency have focussed on alleles TPMT 2, TPMT 3A and TPMT 3C, as these represent 80-95% of all mutant alleles of this gene in Caucasians [46, 50]. However, the frequency and pattern of mutant alleles of this gene is different among various ethnic populations. For example, Southwest Asians (Indian, Pakistani) have a lower frequency of mutant TPMT alleles and all mutant alleles identified to date are TPMT 3A (Table 24.1) [52]. This is in contrast to Kenyans and Ghanaians where the frequency of mutant alleles is similar to Caucasians, and all mutant alleles are TPMT 3C (Table 24.1) [53, 54]. Among African Americans, TPMT 3C is the most prevalent allele, but TPMT 2... 

TPMT 3C accounted for 100% of the mutant alleles observed in the Ghanaian subjects. This is similarly found in 101 Kenyans and 192 Chinese subjects, as well as in Sudanese and Filipino subjects (Table 24.1 Figure 24.2) [52, 54]. This contrasts with the Caucasian (British, American, French) subjects, where 5.7, 5.5 and 11.4% of variant alleles were TPMT 3C, respectively (Table 24.1). TPMT 3 A was not detected in the African or Asian populations, but accounted for 84.9, 81.4 and 88.9% of variant alleles in British, American, and French Caucasians, respectively. Therefore, mutations at nucleotide 719 (TPMT 3C) is common in all populations studied to date, but occurs most often in the presence of a simultaneous mutation at nucleotide 460 (TPMT 3A) in Caucasian subjects (Table 24.1). 

The TPMT 2 allele (G238C) accounted for 9.4, 7.1 and 5.5% of the mutant alleles in the British, French and American populations, respectively. However, this allele was not found in any of the Ghanaian subjects and was not detected in the other African or Asian subjects. These findings are consistent with those of a recent study, which found that the TPMT 2 allele was present in British Caucasians and not in Chinese or Southwest Asian subjects [52]. In addition, the TPMTk2 allele was not detected in Kenyan subjects [54]. This suggests that TPMTk2 is either very rare in non-Caucasian populations or specific to Caucasians, or both. The recently identified TPMT mutant alleles TPMT 4- 8 appear to be relatively rare in Caucasian subjects. Their contribution to variant alleles in other ethnic groups has yet to be defined. 

Comparison of Mutant Alleles Across the Three Major Ethnic Croups (African, Asian and Caucasian)... 

Tai, H. L., Krynetski, E. Y., Yates, C. R., et al. (1996) Thiopuiine S-methyltransferase deficiency two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. American Journal of Human Genetics. 58, 694-702. 

The distribution of TPMT mutant alleles differs significantly among ethnic populations. In the Caucasian population, TPMT 3A, 2, and 3C are the most frequently observed variant alleles which, altogether, account for more than 95% of variant alleles (Table 2) (64,170). In Asian and African populations, TPMT 3C is the most frequent variant allele (171,172). Comprehensive work was done to investigate the functional consequences of TPMT variants and recently alleles including 13 non-synonymous TPMT SNPs were transiently expressed in COS-1 cells and enzyme activity and protein quantity were determined (173). 

The most comprehensive analysis of TPMT phenotype versus genotype published to date was conducted by Schaeffeler et al. (140). In their study, RBC TPMT activity and genotype TPMT 2 and 3 alleles) were analyzed in 1214 healthy Caucasian blood donors. Discordant cases between phenotype and genotype were systematically sequenced. The frequencies of the mutant alleles were 4.4% for TPMT 3A, 0.4% for TPMT 3C, and 0.2% for TPMT 2. All seven TPMT-deficient subjects identified by Schaeffeler and colleagues were homozygous or compound heterozygous carriers for these alleles. 

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