Steroid 21-hydroxylase (P450c21) naturally occurring mutants I172N, V281L and I236n/V237E/M239K exert a dominant negative effect on enzymatic activity when co-expressed with the wild-type protein.

Steroid 21-hydroxylase deficiency is the major cause of congenital adrenal hyperplasia, an autosomic recessive disorder that affects the synthesis of aldosterone and cortisol. The disease presents a wide spectrum of clinical phenotypes as a result of the combination of different mutant alleles. Due to the adrenal-specific expression of the enzyme, the study of the functional effect of different mutations is only possible through in vitro expression studies. Determination of the functional effect of independent mutations does not always result in clear phenotype-genotype correlations, particularly in those patients with different mutations in the two alleles (compound heterozygotes). In this study we show that co-expression of the mutant proteins I172N, V281L or I236N/V237E/M239K with the wild-type enzyme resulted in an apparent dominant negative effect on the enzymatic activity of the latter, while co-expression with the mutant enzyme R356W does not show this effect.

FMR1 CGG repeat distribution and linked microsatellite-SNP haplotypes in normal Mexican Mestizo and indigenous populations.

The (CGG)n repeat size distribution in the FMR1 gene was studied in healthy individuals: 80 X chromosomes of Mexican Mestizos from Mexico City and 33 X chromosomes of Mexican Amerindians from three indigenous communities (Purepechas, Nahuas, and Tzeltales), along with alleles and haplotypes defined by two microsatellite polymorphic markers (DXS548 and FRAXAC1) and two single nucleotide polymorphisms (FMRA and FMRB). Genetic frequencies of Mestizo and Amerindian subpopulations were statistically similar in almost all cases and thus were considered one population for comparisons with other populations. Sixteen (CGG)n alleles in the 17-38 size range were observed, and the most common were the 25 (38.0%), 26 (28.3%), and 24 (12.3%) repeat alleles. This pattern differs from most other populations reported, but a closer relation to Amerindian, European, and African populations was found, as expected from the historical admixture that gave rise to Mexican Mestizos. The results of the CA repeats analysis at DXS548-FRAXAC1 were restricted to nine haplotypes, of which haplotypes 7-4 (52.2%), 8-4 (23.8%), and 7-3 (11.5%) were predominant. The modal haplotype 7-4, instead of the nearly universal haplotype 7-3, had been reported exclusively in Eastern Asian populations. Likewise, only seven different FRAXAC1-FMRA-FMRB haplotypes were observed, including five novel haplotypes (3TA, 4TA, 3 - A, 4 - A, and 5 - A), compared with Caucasians. Of these, haplotypes - A (78.7%) and 3 - A (13.2%) were the most common in the Mexican population. These data suggest a singular but relatively low genetic diversity at FMR1 in the studied Mexican populations that may be related to the recent origin of Mestizos and the low admixture rate of Amerindians.