Turkiye Klinikleri Journal of Medical Sciences

.: ORIGINAL RESEARCH
Embriyonik Beyin Gelişiminde Görevli DCX ve PAFAH1B1 Genlerinde Meydana Gelen SNP'lerin İn Silico Değerlendirilmesi: Biyoinformatik Çalışma
In Silico Evaluation of SNPs Occurring in DCX and PAFAH1B1 Genes Involved in Embryonic Brain Development: Bioinformatic Study
Ahmet TAMERa
aÜsküdar Üniversitesi Sağlık Bilimleri Enstitüsü, Nörobilim ABD, İstanbul, Türkiye
Turkiye Klinikleri J Med Sci. 2022;42(2):119-29
doi: 10.5336/medsci.2021-86727
Article Language: TR
Full Text
ÖZET
Amaç: DCX geni, sinir sisteminin gelişimi sırasında nöronların mikrotübüllerine bağlanan doublecortin proteinini kodlamaktadır. Doublecortin, göç eden nöronlarda mikrotübülleri bağlar ve stabilize eder. Bu gen ailesinin üyeleri tarafından düzenlenen hücresel süreçler; nöronal göç, nörogenez ve göz reseptör gelişimini de içermektedir. PAFAH1B1 geni nöronal göç sırasında hücre nükleusunun göçünden sorumludur. Literatürde bu genlerde tek nükleotid polimorfizmlerinin etkilerini in silico analizlerle bildiren bir çalışma kaydedilmemiştir. Bu araştırmanın amacı çeşitli hücresel süreçleri düzenleyen Doublecortin-X (DCX) ve PAFAH1B1 genlerindeki tek nükleotid polimorfizmlerinin in silico analizlerle değerlendirilmesidir. Gereç ve Yöntemler: Bu çalışmada DCX ve PAFAH1B1 genlerinde oluşan SNP'lerin, bu genlerin kodladıkları proteinlerin fonksiyonel etkileri, stabilite analizleri ve modellemeleri; SIFT, PolyPhen, Provean, PhD-SNP, Mutation assesor, SNPs&GO, SNAP2, I-Mutant 3.0, MuPro, HOPE veritabanları ile yapıldı. GeneMANIA ile bu genlerin diğer genlerle etkileşimde olduğu gösterildi. Bu genlerdeki mikroRNA işlevlerinin, merkezi sinir sisteminde oluşan hastalıklarla ilişkisine bakmak için Human Disease MicroRNA Database 3.0 kullanıldı. Bulgular: Çeşitli veri tabanları ile yapılan bu çalışmada DCX ve PAFAH1B1 genlerindeki SNP'lerin protein fonksiyonuna zararlı olduğu, stabilite analizlerinde protein kararlılığının bozulmasına neden olduğu sonucuna ulaşıldı. Proteinlerde boyut, yük ve hidrofobisite farklılığı oluştuğu sonucuna ulaşıldı. Sonuç: Boyut, yük ve hidrofobisite değişimi proteinlerin çekirdeğine uyum sağlayamamasına, yük farkıyla etkileşimde olduğu molekülleri iteceği ve hidrofobisite farkından dolayı hidrojen bağlarının doğru pozisyonda oluşamamasına dolayısıyla protein katlanma sorunlarına yol açabileceği sonucuna ulaşıldı. GeneMANIA ile bu genlerin birçok genle etkileşimde olup, çeşitli süreçleri düzenlediği ve bu genlerin mikroRNA'larında değişimin şizofreni, otizm, glioblastoma, beyin neoplazmaları, iskemi, epilepsi, nöroblastoma gibi merkezi sinir sistemi hastalıklarıyla ilişkili olduğu gösterildi.

Anahtar Kelimeler: DCX ve PAFAH1B1 geni; kortikal malformasyonlar; tek nükleotid polimorfizmi; in silico
ABSTRACT
Objective: The DCX gene encodes the doublecortin protein that binds to the microtubules of neurons during the development of the nervous system. Doublecortin binds and stabilizes microtubules in migrating neurons. Cellular processes regulated by members of this gene family; it also includes neuronal migration, neurogenesis and eye receptor development. The PAFAH1B1 gene is responsible for the migration of the cell nucleus during neuronal migration. There is no study in the literature reporting the effects of single nucleotide polymorphisms in these genes by in silico analysis. The aim of this research is to evaluate single nucleotide polymorphisms in Doublecortin-X (DCX) and PAFAH1B1 genes, which regulate various cellular processes, by in silico analysis. Materials and Methods: In this study, the functional effects, stability analyzes and modeling of the SNPs formed in DCX and PAFAH1B1 genes and the proteins encoded by these genes; SIFT, PolyPhen, Provean, PhD-SNP, Mutation assessor, SNPs&GO, SNAP2, I-Mutant 3.0, MuPro, HOPE databases. These genes were shown to interact with other genes with GeneMANIA. Human Disease MicroRNA Database 3.0 was used to look at the relationship between microRNA functions in these genes and diseases in the central nervous system. Findings: In this study conducted with various databases, SNPs in DCX and PAFAH1B1 genes are harmful to protein function, in stability analyzes, it was concluded that it caused deterioration of protein stability. It was concluded that there were differences in dimension, charge and hydrophobicity in proteins. Conclusion: It was concluded that the change in dimension, charge and hydrophobicity may cause the proteins to not adapt to their nuclei, repel the molecules with which they interact with the charge difference, and the hydrogen bonds cannot be formed in the correct position due to the hydrophobicity difference, thus leading to protein folding problems. With GeneMANIA, it has been shown that these genes interact with many genes and regulate various processes, and that changes in the microRNAs of these genes are associated with central nervous system diseases such as schizophrenia, autism, glioblastoma, brain neoplasms, ischemia, epilepsy, and neuroblastoma.

Keywords: DCX and PAFAH1B1 gene; cortical malformation; single nucleotide polymorphism; in silico
REFERENCES:
  1. Zare I, Paul D, Moody S. Doublecortin mutation in an adolescent male. Child Neurol Open. 2019;6:2329048X19836589. [Crossref]  [PubMed]  [PMC] 
  2. Aydın K. Bölüm 14: Çocuklarda kortikal gelişimsel malformasyonlar. Tatlı B, Özmen M, editörler. Yenidoğan Nörolojisi. İstanbul: Nobel Tıp Kitabevleri; 2016. p.201-28.
  3. Dijkmans TF, van Hooijdonk LW, Fitzsimons CP, Vreugdenhil E. The doublecortin gene family and disorders of neuronal structure. Cent Nerv Syst Agents Med Chem. 2010;10(1):32-46. [Crossref]  [PubMed] 
  4. Dobyns WB, Andermann E, Andermann F, Czapansky-Beilman D, Dubeau F, Dulac O, et al. X-linked malformations of neuronal migration. Neurology. 1996;47(2):331-9. [Crossref]  [PubMed] 
  5. Pinard JM, Motte J, Chiron C, Brian R, Andermann E, Dulac O. Subcortical laminar heterotopia and lissencephaly in two families: a single X linked dominant gene. J Neurol Neurosurg Psychiatry. 1994;57(8):914-20. [Crossref]  [PubMed]  [PMC] 
  6. Pilz DT, Matsumoto N, Minnerath S, Mills P, Gleeson JG, Allen KM, et al. LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation. Hum Mol Genet. 1998;7(13):2029-37. [Crossref]  [PubMed] 
  7. Poirier K, Keays DA, Francis F, Saillour Y, Bahi N, Manouvrier S, et al. Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A). Hum Mutat. 2007;28(11):1055-64. [Crossref]  [PubMed] 
  8. Guedes-Dias P, Holzbaur ELF. Axonal transport: driving synaptic function. Science. 2019;366(6462):eaaw9997. [Crossref]  [PubMed]  [PMC] 
  9. Tanrıdağ O. Dil, Konuşma ve Davranışlar Açısından Çocuk Beyninin Gelişimi ve Nörogelişimsel Problemler. Bölüm 4. Beyin gelişiminden psikiyatriye ve geriatriye giden yol. 1. Baskı. İstanbul: Üsküdar Üniversitesi Yayınları; 2018. p.67-70.
  10. Geschwind DH, Robidoux J, Alarcón M, Miller BL, Wilhelmsen KC, Cummings JL, et al. Dementia and neurodevelopmental predisposition: cognitive dysfunction in presymptomatic subjects precedes dementia by decades in frontotemporal dementia. Ann Neurol. 2001;50(6):741-6. [Crossref]  [PubMed] 
  11. Murray RM, Lewis SW. Is schizophrenia a neurodevelopmental disorder? Br Med J (Clin Res Ed). 1987;295(6600):681-2. [Crossref]  [PubMed]  [PMC] 
  12. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215-33. [Crossref]  [PubMed]  [PMC] 
  13. Pappalardo F, Russo G, Tshinanu FM, Viceconti M. In silico clinical trials: concepts and early adoptions. Brief Bioinform. 2019;20(5):1699-708. [Crossref]  [PubMed] 
  14. Gleeson JG, Allen KM, Fox JW, Lamperti ED, Berkovic S, Scheffer I, et al. Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell. 1998;92(1):63-72. [Crossref]  [PubMed] 
  15. Pramparo T, Youn YH, Yingling J, Hirotsune S, Wynshaw-Boris A. Novel embryonic neuronal migration and proliferation defects in Dcx mutant mice are exacerbated by Lis1 reduction. J Neurosci. 2010;30(8):3002-12. [Crossref]  [PubMed]  [PMC] 
  16. Tokuoka SM, Ishii S, Kawamura N, Satoh M, Shimada A, Sasaki S, et al. Involvement of platelet-activating factor and LIS1 in neuronal migration. Eur J Neurosci. 2003;18(3):563-70. [Crossref]  [PubMed] 
  17. Bai J, Ramos RL, Paramasivam M, Siddiqi F, Ackman JB, LoTurco JJ. The role of DCX and LIS1 in migration through the lateral cortical stream of developing forebrain. Dev Neurosci. 2008;30(1-3):144-56. [Crossref]  [PubMed] 
  18. Pilz DT, Kuc J, Matsumoto N, Bodurtha J, Bernadi B, Tassinari CA, et al. Subcortical band heterotopia in rare affected males can be caused by missense mutations in DCX (XLIS) or LIS1. Hum Mol Genet. 1999;8(9):1757-60. [Crossref]  [PubMed] 
  19. Caspi M, Coquelle FM, Koifman C, Levy T, Arai H, Aoki J, et al. LIS1 missense mutations: variable phenotypes result from unpredictable alterations in biochemical and cellular properties. J Biol Chem. 2003;278(40):38740-8. [Crossref]  [PubMed] 
  20. Mineyko A, Doja A, Hurteau J, Dobyns WB, Das S, Boycott KM. A novel missense mutation in LIS1 in a child with subcortical band heterotopia and pachygyria inherited from his mildly affected mother with somatic mosaicism. J Child Neurol. 2010;25(6):738-41. [Crossref]  [PubMed] 
  21. Shen XM, Brengman JM, Edvardson S, Sine SM, Engel AG. Highly fatal fast-channel syndrome caused by AChR ε subunit mutation at the agonist binding site. Neurology. 2012;79(5):449-54. [Crossref]  [PubMed]  [PMC] 
  22. Felekkis K, Touvana E, Stefanou Ch, Deltas C. microRNAs: a newly described class of encoded molecules that play a role in health and disease. Hippokratia. 2010;14(4):236-40. [PubMed]  [PMC] 
  23. Friocourt G, Koulakoff A, Chafey P, Boucher D, Fauchereau F, Chelly J, et al. Doublecortin functions at the extremities of growing neuronal processes. Cereb Cortex. 2003;13(6):620-6. [Crossref]  [PubMed] 
  24. Gleeson JG, Lin PT, Flanagan LA, Walsh CA. Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron. 1999;23(2):257-71. [Crossref]  [PubMed] 

Login



Contact


Ortadoğu Reklam Tanıtım Yayıncılık Turizm Eğitim İnşaat Sanayi ve Ticaret A.Ş.

.: Address

Turkocagi Caddesi No:30 06520 Balgat / ANKARA
Phone: +90 312 286 56 56
Fax: +90 312 220 04 70
E-mail: info@turkiyeklinikleri.com

.: Manuscript Editing Department

Phone: +90 312 286 56 56/ 2
E-mail: yaziisleri@turkiyeklinikleri.com

.: English Language Redaction

Phone: +90 312 286 56 56/ 145
E-mail: tkyayindestek@turkiyeklinikleri.com

.: Marketing Sales-Project Department

Phone: +90 312 286 56 56/ 142
E-mail: reklam@turkiyeklinikleri.com

.: Subscription and Public Relations Department

Phone: +90 312 286 56 56/ 118
E-mail: abone@turkiyeklinikleri.com

.: Customer Services

Phone: +90 312 286 56 56/ 118
E-mail: satisdestek@turkiyeklinikleri.com

1. TERMS OF USE

1.1. To use the web pages with http://www.turkiyeklinikleri.com domain name or the websites reached through the sub domain names attached to the domain name (They will be collectively referred as "SITE"), please read the conditions below. If you do not accept these terms, please cease to use the "SITE." "SITE" owner reserves the right to change the information on the website, forms, contents, the "SITE," "SITE" terms of use anytime they want.

1.2. The owner of the "SITE" is Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. (From now on it is going to be referred as "Turkiye Klinikleri", shortly) and it resides at Turkocagi cad. No:30, 06520 Balgat Ankara. The services in the "SITE" are provided by "Turkiye Klinikleri."

1.3. Anyone accessing the "SITE" with or without a fee whether they are a natural person or a legal identity is considered to agree these terms of use. In this contract hereby, "Turkiye Klinikleri" may change the stated terms anytime. These changes will be published in the "SITE" periodically and they will be valid when they are published. Any natural person or legal identity benefiting from and reaching to the "SITE" are considered to be agreed to any change on hereby contract terms done by "Turkiye Klinikleri."

1.4. The "Terms of Use" hereby is published in the website with the last change on March 30th 2014 and the "SITE" is activated by enabling the access to everyone. The "Terms of Use" hereby is also a part of the any "USER Contract" was and/or will be done with the users using "Turkiye Klinikleri" services with or without a fee an inseparable.

2. DEFINITIONS

2.1. "SITE": A website offering different kind of services and context with a certain frame determined by "Turkiye Klinikleri" and it is accessible on-line on http://www.turkiyeklinikleri.com domain name and/or subdomains connected to the domain name.

2.2. USER: A natural person or a legal identity accessing to the "SITE" through online settings.

2.3. LINK: A link enabling to access to another website through the "SITE", the files, the context or through another website to the "SITE", the files and the context.

2.4. CONTEXT: Any visual, literary and auditory images published in the "Turkiye Klinikleri", "SITE" and/or any website or any accessible information, file, picture, number/figures, price, etc.

2.5. "USER CONTRACT": An electronically signed contract between a natural or a legal identity benefiting from special services "Turkiye Klinikleri" will provide and "Turkiye Klinikleri".

3. SCOPE OF THE SERVICES

3.1. "Turkiye Klinikleri" is completely free to determine the scope and quality of the services via the "SITE".

3.2. To benefit the services of "Turkiye Klinikleri" "SITE", the "USER" must deliver the features that will be specified by "Turkiye Klinikleri". "Turkiye Klinikleri" may change this necessity any time single-sided.

3.3. Not for a limited number, the services "Turkiye Klinikleri" will provide through the "SITE" for a certain price or for free are;

- Providing scientific articles, books and informative publications for health industry.

- Providing structural, statistical and editorial support to article preparation stage for scientific journals.

4. GENERAL PROVISIONS

4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com