Mutational spectrum of steroid 21-hydroxylase and the genotype-phenotype association in Middle European patients with congenital adrenal hyperplasia.
ABSTRACT To analyze the mutational spectrum of steroid 21-hydroxylase (CYP21) and the genotype- phenotype correlation in patients with congenital adrenal hyperplasia (CAH) registered in the Middle European Society for Pediatric Endocrinology CAH database, and to design a reliable and rational approach for CYP21 mutation detection in Middle European populations.
Molecular analysis of the CYP21 gene was performed in 432 CAH patients and 298 family members. Low-resolution genotyping was performed to detect the eight most common point mutations. High-resolution genotyping, including Southern blotting and sequencing was performed to detect CYP21 gene deletions, conversions, point mutations or other sequence changes.
CYP21 gene deletion and In2 and Ile172Asn mutation accounted for 72.7% of the affected alleles in the whole study group. A good genotype-phenotype correlation was observed, with the exception of Ile172Asn and Pro30Leu mutations. In 37% of patients low resolution genotyping could not identify the causative mutation or distinguish homozygosity from hemizygosity. Using high-resolution genotyping, the causative mutations could be identified in 341 out of 348 analyzed patients. A novel mutation Gln315Stop was found in one simple virilising CAH (SV-CAH) patient from Austria. In the remaining seven patients polymorphisms were identified as the leading sequence alteration. The presence of elevated basal and ACTH-stimulated 17-hydroxyprogesterone, premature pubarche, advanced bone age and clitoral hypertrophy directly implicated Asn493Ser polymorphism in the manifestation of nonclassical- (NC) and even SV-CAH.
By genotyping for the most common point mutations, CYP21 gene deletion/conversion and the 8 bp deletion in exon 3, it should be possible to identify the mutation in 94-99% of the diseased alleles in any investigated Middle European population. In patients with a mild form of the disease and no detectable mutation CYP21 gene polymorphisms should be considered as a plausible disease-causing mutation.
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ABSTRACT: Aim: Hereditary endocrinopathies in Cyprus exhibit evidence of a founder effect and display the influence of past migration patterns. The genetic frequency and mutation pattern of a specific disorder of sex development (DSD), which is classified as 46,XX DSD or 46,XY DSD, and the non-classic form of congenital adrenal hyperplasia (NC-CAH) outline a type of genetic drift. Results: Not only the high prevalence of the NC-CAH p.V281L mutation but also the rarity of CAH large lesions present a genetic diversity similar to that observed in the Middle Eastern countries. In addition, both the high frequency of the 5-alpha steroid reductase deficiency (5αSRD) IVS1-2A>G mutation and the carrier frequency of the 17-beta hydroxysteroid dehydrogenase 3 (17β-HSD-3) p.R80Q mutation are good examples of a founder effect. p.R80Q can be considered a founder mutation, even though it has been identified in patients of Dutch, Brazilian, and Portuguese origin. This has led to the speculation that it has a Phoenician origin. Phoenicians as ancient traders migrated around 750 BC from present day Syria, Lebanon, and Israel toward Portugal, Spain, and also to nearby Cyprus. While the 5αSRD IVS1-2A>G mutation has already been extensively reported in Turkish patients, it is very common in the Eastern Mediterranean region. Conclusion: This short article portrays clearly, through specific endocrine genetic disorders, the past migration trends in Cyprus that shaped the present-day gene pool of the Greek-Cypriot population.Genetic Testing and Molecular Biomarkers 08/2012; 16(9):1073-9. DOI:10.1089/gtmb.2011.0381 · 1.15 Impact Factor
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ABSTRACT: The aim of this study was to identify the molecular defect in a group of 37 unrelated Greek Cypriot patients affected by NC-CAH and evaluate the relationship between the genotype, phenotype and adrenal androgen levels. Clinical evaluation, biochemical analysis of 17-OHP, Testosterone, Androstenedione, DHEA-S, direct DNA sequencing and MLPA analyses. Eleven known mutations were identified with the p.V281L being the most predominant and observed in 68.9% of the alleles. There was no difference between the two genotypes (mild/mild and mild/severe) with clinical presentation, whereas a proportional relationship between the type of mutation and adrenal androgen levels was found. The frequency of the underlying genetic defect in our patients with NC-CAH is similar to that observed in most Mediterranean populations. Although the genotype cannot solely explain the clinical expression of NC-CAH, discrimination between mild and severe alleles is crucial in antenatal diagnosis and genetic counselling.Clinical biochemistry 05/2011; 44(12):959-63. DOI:10.1016/j.clinbiochem.2011.05.013 · 2.23 Impact Factor
Conference Paper: A new rule-based method of automatic phonetic notation on polyphones[Show abstract] [Hide abstract]
ABSTRACT: In this paper, a new rule-based method of automatic phonetic notation on the 220 polyphones whose appearing frequency exceeds 99% is proposed. Firstly, all the polyphones in a sentence are classified beforehand. Secondly, rules are extracted based on eight features. Lastly, automatic phonetic notation is applied according to the rules. The paper puts forward a new concept of prosodic functional part of speech in order to improve the numerous and complicated grammatical information. The examples and results of this method are shown at the end of this paper. Compared with other approaches dealt with polyphones, the results show that this new method improves the accuracy of phonetic notation on polyphones.Signal Processing, 2004. Proceedings. ICSP '04. 2004 7th International Conference on; 10/2004