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Molecular genetic study of congenital adrenal hyperplasia in Serbia: novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations.
J Endocrinol Invest. 2015 Nov; 38(11):1199-210.JE

Abstract

PURPOSE

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease characterized by impaired adrenal steroidogenesis and most often caused by CYP21A2 gene mutations. For the first time, we reported complete spectrum and frequency of CYP21A2 gene mutations in 61 unrelated patients with classical and non-classical CAH from Serbia.

METHODS

Direct DNA sequencing of whole CYP21A2 gene and polymerase chain reaction with sequence-specific primers for detection of CYP21A1P/CYP21A2 chimeras were combined.

RESULTS

We identified 18 different pathogenic alleles-two of them novel. Mutation detection rate was highest in patients with salt-wasting form of CAH (94.7%). The most prevalent mutation was intron 2 splice site mutation, c.290-13A/C>G (18.5%). Other mutation frequencies were: CYP21A1P/CYP21A2 chimeras (13%), p.P30L (13%), p.R356W (11.1%), p.G110fs (7.4%), p.Q318X (4.6%), p.V281L (4.6%), p.I172N (2.8%), p.L307fs (2.8%), p.P453S (1.9%), etc. Mainly, frequencies were similar to those in Slavic populations and bordering countries. However, we found 6.5% of alleles with multiple mutations, frequently including p.P453S. Effects of novel mutations, c.386T>C (p.Leu129Pro) and c.493T>C (p.Ser165Pro), were characterized in silico as deleterious. The effect of well-known mutations on Serbian patients' phenotype was as expected.

CONCLUSIONS

The first comprehensive molecular genetic study of Serbian CAH patients revealed two novel CYP21A2 mutations. This study will enable genetic counseling in our population and contribute to better understanding of molecular landscape of CAH in Europe.

Authors+Show Affiliations

Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, Belgrade, 11010, Serbia.Clinic of Endocrinology, Clinical Center of Serbia, School of Medicine, University of Belgrade, Doktora Subotića 13, Belgrade, 11000, Serbia.Mother and Child Health Care Institute of Serbia "Dr Vukan Cupic", Radoja Dakića 6-8, Belgrade, 11070, Serbia.Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, Belgrade, 11010, Serbia.Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, Belgrade, 11010, Serbia.Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, Belgrade, 11010, Serbia.University Children's Hospital, Tirsova 10, Belgrade, 11000, Serbia.University Clinic for Obstetrics and Gynecology "Narodni Front", Kraljice Natalije 62, Belgrade, 11000, Serbia.Mother and Child Health Care Institute of Serbia "Dr Vukan Cupic", Radoja Dakića 6-8, Belgrade, 11070, Serbia.Mother and Child Health Care Institute of Serbia "Dr Vukan Cupic", Radoja Dakića 6-8, Belgrade, 11070, Serbia.Clinic of Endocrinology, Clinical Center of Serbia, School of Medicine, University of Belgrade, Doktora Subotića 13, Belgrade, 11000, Serbia.Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, Belgrade, 11010, Serbia.Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, Belgrade, 11010, Serbia. maja.stojiljkovic@imgge.bg.ac.rs.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26233337

Citation

Milacic, I, et al. "Molecular Genetic Study of Congenital Adrenal Hyperplasia in Serbia: Novel p.Leu129Pro and p.Ser165Pro CYP21A2 Gene Mutations." Journal of Endocrinological Investigation, vol. 38, no. 11, 2015, pp. 1199-210.
Milacic I, Barac M, Milenkovic T, et al. Molecular genetic study of congenital adrenal hyperplasia in Serbia: novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations. J Endocrinol Invest. 2015;38(11):1199-210.
Milacic, I., Barac, M., Milenkovic, T., Ugrin, M., Klaassen, K., Skakic, A., Jesic, M., Joksic, I., Mitrovic, K., Todorovic, S., Vujovic, S., Pavlovic, S., & Stojiljkovic, M. (2015). Molecular genetic study of congenital adrenal hyperplasia in Serbia: novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations. Journal of Endocrinological Investigation, 38(11), 1199-210. https://doi.org/10.1007/s40618-015-0366-8
Milacic I, et al. Molecular Genetic Study of Congenital Adrenal Hyperplasia in Serbia: Novel p.Leu129Pro and p.Ser165Pro CYP21A2 Gene Mutations. J Endocrinol Invest. 2015;38(11):1199-210. PubMed PMID: 26233337.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular genetic study of congenital adrenal hyperplasia in Serbia: novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations. AU - Milacic,I, AU - Barac,M, AU - Milenkovic,T, AU - Ugrin,M, AU - Klaassen,K, AU - Skakic,A, AU - Jesic,M, AU - Joksic,I, AU - Mitrovic,K, AU - Todorovic,S, AU - Vujovic,S, AU - Pavlovic,S, AU - Stojiljkovic,M, Y1 - 2015/08/02/ PY - 2015/06/07/received PY - 2015/07/20/accepted PY - 2015/8/3/entrez PY - 2015/8/4/pubmed PY - 2016/7/21/medline KW - 21-Hydroxylase deficiency KW - Alleles with multiple mutations KW - CYP21A1P/CYP21A2 chimeras KW - Genotype–phenotype correlation KW - Mutation detection KW - Mutations’ effect SP - 1199 EP - 210 JF - Journal of endocrinological investigation JO - J Endocrinol Invest VL - 38 IS - 11 N2 - PURPOSE: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease characterized by impaired adrenal steroidogenesis and most often caused by CYP21A2 gene mutations. For the first time, we reported complete spectrum and frequency of CYP21A2 gene mutations in 61 unrelated patients with classical and non-classical CAH from Serbia. METHODS: Direct DNA sequencing of whole CYP21A2 gene and polymerase chain reaction with sequence-specific primers for detection of CYP21A1P/CYP21A2 chimeras were combined. RESULTS: We identified 18 different pathogenic alleles-two of them novel. Mutation detection rate was highest in patients with salt-wasting form of CAH (94.7%). The most prevalent mutation was intron 2 splice site mutation, c.290-13A/C>G (18.5%). Other mutation frequencies were: CYP21A1P/CYP21A2 chimeras (13%), p.P30L (13%), p.R356W (11.1%), p.G110fs (7.4%), p.Q318X (4.6%), p.V281L (4.6%), p.I172N (2.8%), p.L307fs (2.8%), p.P453S (1.9%), etc. Mainly, frequencies were similar to those in Slavic populations and bordering countries. However, we found 6.5% of alleles with multiple mutations, frequently including p.P453S. Effects of novel mutations, c.386T>C (p.Leu129Pro) and c.493T>C (p.Ser165Pro), were characterized in silico as deleterious. The effect of well-known mutations on Serbian patients' phenotype was as expected. CONCLUSIONS: The first comprehensive molecular genetic study of Serbian CAH patients revealed two novel CYP21A2 mutations. This study will enable genetic counseling in our population and contribute to better understanding of molecular landscape of CAH in Europe. SN - 1720-8386 UR - https://www.unboundmedicine.com/medline/citation/26233337/Molecular_genetic_study_of_congenital_adrenal_hyperplasia_in_Serbia:_novel_p_Leu129Pro_and_p_Ser165Pro_CYP21A2_gene_mutations_ DB - PRIME DP - Unbound Medicine ER -