Screening of CYP21 gene mutations in 129 French patients affected by steroid 21-hydroxylase deficiency

Abstract

The frequency of 12 different mutations of the steroid 21-hydroxylase gene (CYP21) was investigated in 129 French patients affected by congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency. Eighty-nine percent of the CAH chromosomes were characterized. The most frequent mutations were a C-G substitution in intron 2, the deletion of the CYP21 gene and a T-A substitution in exon 4 in the severe form of the disease, and a G-T substitution in exon 7 in the nonclassic form. The correlation between the genotypes and the clinical forms of the disease showed marked variation in the phenotype from a single genotype, suggesting that individual variation and undetected additional mutations on the same CAH chromosome accounted for the phenotype. In 65 informative meioses of CAH families, no de novo mutation was found.

Ethnic-specific distribution of mutations in 716 patients with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency

“…However, we found the large deletion in only 5% of 38 alleles in our East Indian patients, while Mathur at el found 16% of 46 alleles [41]. The mutation frequencies in our French patients match previous reports [42][43][44][45], with the exception of the IVS2 AS -13 (A/C to G) mutation. We found 41% of 32 alleles with the IVS2 AS -13 (A/C to G) mutation, whereas previous reports showed only 14% to 23%.…”

Prenatal Diagnosis of Steroid 21 -Hydroxylase Deficiency by the Modified Polymerase Chain Reaction to Detect Splice Site Mutation in the CYP21 Gene.

“…Our study describes a sensitive method without radioactive probe that allows the I2G mutation to be visualized rapidly rather than by allele-specific dot blot. Because the I2G mutation is the most frequent cause of 21-hydroxylase deficiency [2][3][4][5][6][7][8] and the frequency of the I2G mutation in Japanese population is higher than that in Caucasian, this method is useful for the carrier detection and prenatal diagnosis of the approximately 25% of Japanese families [2,7], in which the disorder results from homozygosity for the I2G mutation. And for those families in which the affected individuals are compound heterozygotes for the I2G mutation and a different gene conversion event [2][3][4][5][6][7][8], this method could be combined in the future with a similar approach to detect the other known mutations of the CYP21 gene.…”

“…Among several point mutations, the most frequently identified point mutation in the CYP21 gene in salt-wasting (SW) and simple virilizing (SV) patients with steroid 21-hydroxylase deficiency is an A-> G transition at nucleotide 656, causing aberrant splicing [2][3][4][5][6][7][8][9]. This mutation is detected in approximately 60% of Caucasian and Japanese patients [2][3][4][5][6][7][8][9]. In this disease, prenatal diagnosis and treatment are advocated to prevent ambiguious genitalia in female newborns [1].…”

CYP21 and CYP21P variability in steroid 21-hydroxylase deficiency patients and in the general population in the Netherlands

“…Polymerase chain reaction (PCR) amplification of CYP21 and CYP21P followed by oligonucleotide hybridisation 17,18,[27][28][29] was used to determine sequence variability. Three overlapping parts of either CYP21 or CYP21P (see following sections 1, 2 and 3; Figure 1) were specifically amplified using the primers listed in Table 1.…”

“…They vary among different populations. 8,17,18,22,[26][27][28][29][30][31][32][33][34][35][36][37] However, information on the variability of the CYP21P pseudogene, especially in association with the TaqI/BglII haplotypes that define the overall structure of the region, is rather limited. 18,38 Such information is highly relevant to the hypotheses describing the origin of the different categories of disease-causing mutations in CYP21: the location of crossover sites and the extent of conversion zones depend on the composition of the CYP21P gene involved.…”