Gene conversion (655G splicing mutation) and the founder effect (Gln318Stop) contribute to the most frequent severe point mutations in congenital adrenal hyperplasia (21‐hydroxylase deficiency) in the Spanish population

Ezquieta, Begoña; Cueva, E; Oyarzábal, M.; Oliver, Antonio; Varela, J.M.; Jariego, C

doi:10.1034/j.1399-0004.2002.620213.x

Cited by 31 publications

(28 citation statements)

References 26 publications

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“…www.eje-online.org A strong positive genotype-phenotype association was verified, similar to that found in other ethnic groups (9,13,14,15,16,17,27,28,29,30,35). The saltwaster frequency was higher in the Null group than in group A, which is also important for clinical decisions in asymptomatic patients (18) during the neonatal period.…”

Section: Discussionsupporting

confidence: 53%

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Molecular CYP21A2 diagnosis in 480 Brazilian patients with congenital adrenal hyperplasia before newborn screening introduction

Carvalho¹,

Miranda²,

Gomes³

et al. 2016

European Journal of Endocrinology

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Background: Most congenital adrenal hyperplasia (CAH) patients carry CYP21A2 mutations derived from conversion events involving the pseudogene, and the remaining carry new mutations. Objective: To review causal mutations and genotype-phenotype correlation in 480 Brazilian patients. Methods: DNA was extracted from 158 salt-wasters (SWs), 116 simple virilizing (SV), and 206 nonclassical (NC) patients. Fourteen point mutations were screened by allele-specific PCR, large rearrangements by Southern blotting/ MLPA, and sequencing was performed in those with incomplete genotype. The gene founder effect was analyzed by microsatellite studies. Patients were divided into six genotypes (Null; A: <2%; B: 3-7%; C: >20% of residual enzymatic activity (EA); D: unknown EA; E: incomplete genotype). Results: Targeted methodologies defined genotype in 87.6% of classical and in 80% of NC patients and the addition of sequencing in 100 and 83.5%, respectively. The most frequent mutations were p.V281L (26.6% of alleles), IVS2-13A/C>G (21.1%), and p.I172N (7.5%); seven rare mutations and one novel mutation (p.E351V) were identified. Gene founder effect was observed in all but one (p.W19X) mutation. Null, A, B, and C genotypes correlated with SW (88%), SW (70%), SV (98%), and NC forms (100%), respectively. In group D, the p.E351V mutation correlated with classical form and group E comprised exclusively NC-patients. ACTH-stimulated 17OHP level of 44.3 ng/mL was the best cutoff to identify NC-patients carrying severe mutations. Conclusions: We identified a good genotype-phenotype correlation in CAH, providing useful data regarding prediction of disease´s severity; moreover, we suggest that ACTH-stimulated 17OHP levels could predict carrier status for severe mutations. Sequencing is essential to optimize molecular diagnosis in Brazilian CAH patients.

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Section: Discussionsupporting

confidence: 53%

“…A high genotype-phenotype correlation of up to 90-95% has been described in several studies (9,13,14,15,16,17). Mutations resulting in up to 2% of residual enzymatic activity correlate with the SW form, 3-10% correlate with the SV form, and 20-50% correlate with the NC form (6,7,8,9,11,16).…”

Section: Introductionmentioning

confidence: 91%

Molecular CYP21A2 diagnosis in 480 Brazilian patients with congenital adrenal hyperplasia before newborn screening introduction

Carvalho¹,

Miranda²,

Gomes³

et al. 2016

European Journal of Endocrinology

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“…This mutation is also the most common worldwide, except in some groups of patients of South Europe (Portugal, Italy and Spain), where it is less common and where mutation V281L has been identified as the most prevalent. Mutation V281L, which confers more than 20% enzymatic activity, is the most common variant associated to the nonclassical form of 21-OH deficiency in South European countries, reaching 34% in Spain (Ezquieta et al, 2002), 28% in Portugal (Friaes et al, 2006) and 24% in Italy (Balsamo et al, 2000). In North Europe, the most frequent mutation in NC alleles is P30L (Table 2).…”

Section: Discussionmentioning

confidence: 99%

CYP21 gene mutations in Brazilian patients with 21-hydroxylase deficiency from the Amazon region

et al. 2008

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Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (P450c21, CYP21) accounts for about 95% of all CAH cases. The incidence of CYP21 gene mutations has been extensively studied in the last years, but in Brazil it has been investigated only in Southeast Brazilian patients. This study is the first report on the distribution of CYP21 mutations in patients from the Amazon region. Direct sequencing of the CYP21 gene identified at least one mutation in 96% of the studied chromosomes. The most common mutations found were IVS2-13A/C > G (36%), Q318X (12%), V281L (12%), 1760_1761insT (9%), Cluster E6 (7%), and P30L (7%). The worldwide most common mutations were identified among patients from the Amazon region at frequencies that may be expected for a population resulting from the admixture of Europeans (predominantly Portuguese), African Blacks and Amerindians, in proportions that differ from those estimated for South Brazilian populations. Interethnic mixture may explain the differences in the frequencies of some mutations between Brazilian patients from the Amazon and from the Southeast of the country. However, the differences found may also be due to variation in the number of patients with the different clinical forms of 21-hydroxylase deficiency in the studies carried out so far.

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“…The 21OHD mild allele V281L is very common in the Mediterranean area, and a frequency of 0.038 (carrier frequency 7.5%) was detected during the neonatal screening of a Spanish population [9]. This mild allele has detectable but reduced (25%) functionality in vitro[6] and is strongly associated with HLAB14 haplotypes; indeed, a founder effect has been described for this and other 21OH-deficient alleles, including some severe mutations [6, 10, 11]. …”

Section: Introductionmentioning

confidence: 99%

Monogenic and Polygenic Models Detected in Steroid 21-Hydroxylase Deficiency-Related Paediatric Hyperandrogenism

et al. 2008

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Aims: Hyperandrogenism, although mostly due to polygenic interactions, is monogenic for some enzymatic adrenal deficiencies. This study evaluates mono- and biallelic 21-hydroxylase deficiency (21OHD)-related hyperandrogenism in pediatric patients. Sensitizing and protective polymorphisms were investigated in carriers and cryptic forms of 21OHD. Methods: The study involved a monogenic analysis of CYP21A2 in patients (375 nonclassical 21OHD [NC21OHD] children; 306 hyperandrogenic 21OHD carriers, n = 306) and a polygenic association study (CAPN10-UCSNP44, PON1-108, TNFR2-M196R, IGF2-ApaI and IRS1-G972R polymorphisms) of 170 hyperandrogenic carriers plus 277 family members (control groups). The metabolic marker 17OH progesterone defined the degree of deficiency; clinical expressivity was determined by pediatric endocrinologists. Results: The group of 21OHD carriers manifesting hyperandrogenism was enriched in the CAPN-UCSNP44 rare variant in homozygosity (4.9 vs. 0.4%, NCBI data for the general population; p = 0.004). In our patients and controls, contrasting distributions were observed for this and another polymorphism, TNFR2-196R. In a recessive model, their rare variants were more frequently detected among the forms with high (p = 0.048) and low (p = 0.034) expressivity respectively. Conclusions: 21OHD-related pediatric hyperandrogenism follows monogenic and polygenic models. The opposite behaviors in terms of clinical expressivity detected for CAPN-UCSNP44 and TNFR2-M196R rare variants suggest these variants to be sensitizing and protective factors respectively in adrenal hyperandrogenism.

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Gene conversion (655G splicing mutation) and the founder effect (Gln318Stop) contribute to the most frequent severe point mutations in congenital adrenal hyperplasia (21‐hydroxylase deficiency) in the Spanish population

Cited by 31 publications

References 26 publications

Molecular CYP21A2 diagnosis in 480 Brazilian patients with congenital adrenal hyperplasia before newborn screening introduction

Molecular CYP21A2 diagnosis in 480 Brazilian patients with congenital adrenal hyperplasia before newborn screening introduction

CYP21 gene mutations in Brazilian patients with 21-hydroxylase deficiency from the Amazon region

Monogenic and Polygenic Models Detected in Steroid 21-Hydroxylase Deficiency-Related Paediatric Hyperandrogenism

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