Molecular genetic study of congenital adrenal hyperplasia in Serbia: novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations
Само за регистроване кориснике
2015
Аутори
Milacić, I.Barac, M.
Milenković, T.
Ugrin, Milena
Karan-Đurašević, Teodora
Skakić, Anita
Jesić, M.
Joksić, I.
Mitrović, K.
Todorović, S.
Vujović, S.
Pavlović, Sonja
Stojiljković, Maja
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
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 gt 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 gt C (p.Leu129Pro) and c.493T gt 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.
Кључне речи:
Mutations' effect / Mutation detection / Genotype-phenotype correlation / CYP21A1P/CYP21A2 chimeras / Alleles with multiple mutations / 21-Hydroxylase deficiencyИзвор:
Journal of Endocrinological Investigation, 2015, 38, 11, 1199-1210Издавач:
- Springer, New York
Финансирање / пројекти:
- Ретке болести: молекуларна патофизиологија, дијагностички и терапијски модалитети и социјални, етички и правни аспекти (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41004)
DOI: 10.1007/s40618-015-0366-8
ISSN: 0391-4097
PubMed: 26233337
WoS: 000362681800007
Scopus: 2-s2.0-84944066083
Институција/група
Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Milacić, I. AU - Barac, M. AU - Milenković, T. AU - Ugrin, Milena AU - Karan-Đurašević, Teodora AU - Skakić, Anita AU - Jesić, M. AU - Joksić, I. AU - Mitrović, K. AU - Todorović, S. AU - Vujović, S. AU - Pavlović, Sonja AU - Stojiljković, Maja PY - 2015 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/828 AB - 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 gt 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 gt C (p.Leu129Pro) and c.493T gt 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. PB - Springer, New York T2 - Journal of Endocrinological Investigation T1 - Molecular genetic study of congenital adrenal hyperplasia in Serbia: novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations EP - 1210 IS - 11 SP - 1199 VL - 38 DO - 10.1007/s40618-015-0366-8 ER -
@article{ author = "Milacić, I. and Barac, M. and Milenković, T. and Ugrin, Milena and Karan-Đurašević, Teodora and Skakić, Anita and Jesić, M. and Joksić, I. and Mitrović, K. and Todorović, S. and Vujović, S. and Pavlović, Sonja and Stojiljković, Maja", year = "2015", 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 gt 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 gt C (p.Leu129Pro) and c.493T gt 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.", publisher = "Springer, New York", journal = "Journal of Endocrinological Investigation", title = "Molecular genetic study of congenital adrenal hyperplasia in Serbia: novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations", pages = "1210-1199", number = "11", volume = "38", doi = "10.1007/s40618-015-0366-8" }
Milacić, I., Barac, M., Milenković, T., Ugrin, M., Karan-Đurašević, T., Skakić, A., Jesić, M., Joksić, I., Mitrović, K., Todorović, S., Vujović, S., Pavlović, S.,& Stojiljković, M.. (2015). Molecular genetic study of congenital adrenal hyperplasia in Serbia: novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations. in Journal of Endocrinological Investigation Springer, New York., 38(11), 1199-1210. https://doi.org/10.1007/s40618-015-0366-8
Milacić I, Barac M, Milenković T, Ugrin M, Karan-Đurašević T, Skakić A, Jesić M, Joksić I, Mitrović K, Todorović S, Vujović S, Pavlović S, Stojiljković M. Molecular genetic study of congenital adrenal hyperplasia in Serbia: novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations. in Journal of Endocrinological Investigation. 2015;38(11):1199-1210. doi:10.1007/s40618-015-0366-8 .
Milacić, I., Barac, M., Milenković, T., Ugrin, Milena, Karan-Đurašević, Teodora, Skakić, Anita, Jesić, M., Joksić, I., Mitrović, K., Todorović, S., Vujović, S., Pavlović, Sonja, Stojiljković, Maja, "Molecular genetic study of congenital adrenal hyperplasia in Serbia: novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations" in Journal of Endocrinological Investigation, 38, no. 11 (2015):1199-1210, https://doi.org/10.1007/s40618-015-0366-8 . .