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İdiyopatik Hipogonadotropik Hipogonadizme Neden Olan GNRH1 c.99delA Delesyonunun Klinik ve Genetik İncelemesi

Year 2020, , 73 - 78, 31.03.2020

Leman Damla Kotan Gedik , Erdal Eren İhsan Turan Eda Mengen , Bilgin Yüksel , Ali Kemal Topaloğlu

https://doi.org/10.7240/jeps.615925

Abstract

GNRH1, gonadotropin salgılatıcı hormon
ailesinin üyesi olan bir preprohormonu kodlamaktadır ve idiyopatik
hipogonadotropik hipogonadizm (IHH) hastalık modeli için nedensel genler arasındadır.
Bugüne kadar hastalıkla ilişkili olarak GNRH1’de
oldukça sınırlı sayıda mutasyon bildirilmesine rağmen, homozigot c.99delA delesyonu
farklı etnik kökenlere sahip IHH’li ailelerde tekrarlayan şekilde raporlanmıştır.
Bu çalışmada, GNRH1 c.99delA
mutasyonu taşıyan IHH tanılı üç bağımsız aileden toplam dört hastada ayrıntılı genetik
ve klinik inceleme amaçlanmıştır. Bu ailelerdeki her üç proband da IHH’nin
klinik olarak en ağır manifestasyonu sayılan inmemiş testis/mikropenis ile
başvurmuştur. GNRH1 mutasyonunu
komşulayan homozigot segmentlerin her üç ailede de farklı olması mutasyonun
ortak bir atadan kalıtılmış (founder mutation) olmak yerine, mutasyona eğilimli
bir bölge (mutational hotspot) nedeniyle oluşmuş olduğunu düşündürmektedir. GNRH1 homozigot mutasyonları IHH için
halen nadir görülen nedenlerden biri olmasına rağmen hastalarda nedensel GNRH1 taraması yapılırken c.99delA
mutasyonu öncelikli bakılması gereken noktaların başında gelmektedir. 

Keywords

GNRH1 idiyopatik hipogonadotropik hipogonadizm delesyon çerçeve kayması mutasyonu

Supporting Institution

Çukurova Üniversitesi Bilimsel Araştırma Projeleri

Project Number

4580 ve 11364

References

  • [1] Topaloglu, A.K. (2010). Update on the Genetics of Idiopathic Hypogonadotropic Hypogonadism, J Clin Res Pediatr Endocrinol, 9, 113-122.
  • [2] Chan, Y.M. (2011). A needle in a haystack: mutations in GNRH1 as a rare cause of isolated GnRH deficiency, Mol Cell Endocrinol, 346, 51-56.
  • [3] Bouligand, J., Ghervan, C., Tello, J.A., Brailly-Tabard, S., Salenave, S., Chanson, P., Lombes, M., Millar, R.P., Guiochon-Mantel, A., Young, J. (209). Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation, N Engl J Med, 360, 2742-2748.
  • [4] Chan, Y.M., de Guillebon, A., Lang-Muritano, M., Plummer, L., Cerrato, F., Tsiaras, S., Gaspert, A., Lavoie, H.B., Wu, C.H., Crowley, Jr. W.F., Amory, J.K., Pitteloud, N., Seminara, S.B. (2009). GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism, Proc Natl Acad Sci U S A, 106, 11703-11708.
  • [5] Maione, L., Albarel, F., Bouchard, P., Gallant, M., Flanagan, C.A., Bobe, R., Cohen-Tannoudji, J., Pivonello, R., Colao, A., Brue, T., Millar, R.P., Lombes, M., Young, J., Guiochon-Mantel, A., Bouligand, J. (2013). R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism, PLoS One, 8, e69616.
  • [6] Bouligand, J., Ghervan, C., Trabado, S., Brailly-Tabard, S., Guiochon-Mantel, A., Young, J. (2010). Genetics defects in GNRH1: a paradigm of hypothalamic congenital gonadotropin deficiency, Brain Res, 1364, 3-9.
  • [7] Mengen, E., Tunc, S., Kotan, L.D., Nalbantoglu, O., Demir, K., Gurbuz, F., Turan, I., Seker, G., Yuksel, B., Topaloglu, A.K. (2016). Complete Idiopathic Hypogonadotropic Hypogonadism due to Homozygous GNRH1 Mutations in the Mutational Hot Spots in the Region Encoding the Decapeptide, Horm Res Paediatr, 85, 107-111.
  • [8] Beranova, M., Oliveira, L.M., Bedecarrats, G.Y., Schipani, E., Vallejo, M., Ammini, A.C., Quintos, J.B., Hall, J.E., Martin, K.A., Hayes, J.F., Pitteloud, N., Kaiser, U.B., Crowley, Jr.W.F., Seminara, S.B. (2001). Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism, J Clin Endocrinol Metab, 86, 1580-1588.
  • [9] Kopanos, C., Tsiolkas, V., Kouris, A., Chapple, C.E., Albarca Aguilera, M., Meyer, R., Massouras, A. (2018). VarSome: The Human Genomic Variant Search Engine, Bioinformatics, DOI 10.1093/bioinformatics/bty897.
  • [10] Gupta, A., Singh, T.R. SHIFT: server for hidden stops analysis in frame-shifted translation, BMC research notes, 6, 68.
  • [11] Seligmann, H., Pollock, D.D. (2004). The ambush hypothesis: hidden stop codons prevent off-frame gene reading, DNA Cell Biol, 23, 701-705.
  • [12] Singh, T.R. (2013). Mitochondrial Genomes and Frameshift Mutations: Hidden Stop Codons, their Functional Consequences and Disease Associations, Journal of Clinical & Medical Genomics, 1.
  • [13] Singh, T.R., Pardasani, K.R. (2009). Ambush hypothesis revisited: Evidences for phylogenetic trends, Comput Biol Chem, 33, 239-244.
  • [14] Holbrook, J.A., Neu-Yilik, G., Hentze, M.W., Kulozik, A.E. (2004). Nonsense-mediated decay approaches the clinic, Nat Genet, 36, 801-808.
  • [15] Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W.W., Hegde, M., Lyon, E. Spector, E., Voelkerding, K., Rehm, H.L., A.L.Q.A. Committee, (2015). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, Genetics in medicine : official journal of the American College of Medical Genetics, 17, 405-424.
  • [16] Charoute, H., Bakhchane, A., Benrahma, H., Romdhane, L., Gabi, K., Rouba, H., Fakiri, M., Abdelhak, S., Lenaers, G., Barakat, A. (2015). Mediterranean Founder Mutation Database (MFMD): Taking Advantage from Founder Mutations in Genetics Diagnosis, Genetic Diversity and Migration History of the Mediterranean Population, Hum Mutat, 36, E2441-2453.
  • [17] Botstein, D., Risch, N. (2003). Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease, Nat Genet, 33 Suppl, 228-237.
  • [18] Wakeling, M.N., Laver, T.W., Wright, C.F., De Franco, E., Stals, K.L., Patch, A.M., Hattersley, A.T., Flanagan, S.E., Ellard, S., D.D.D. Study. (2019). Correction: Homozygosity mapping provides supporting evidence of pathogenicity in recessive Mendelian disease, Genetics in medicine : official journal of the American College of Medical Genetics, 21, 766.
  • [19] Rogozin, I.B., Pavlov, Y.I. (2003). Theoretical analysis of mutation hotspots and their DNA sequence context specificity, Mutat Res, 544, 65-85.

Year 2020, , 73 - 78, 31.03.2020

Leman Damla Kotan Gedik , Erdal Eren İhsan Turan Eda Mengen , Bilgin Yüksel , Ali Kemal Topaloğlu

https://doi.org/10.7240/jeps.615925

Abstract

Project Number

4580 ve 11364

References

  • [1] Topaloglu, A.K. (2010). Update on the Genetics of Idiopathic Hypogonadotropic Hypogonadism, J Clin Res Pediatr Endocrinol, 9, 113-122.
  • [2] Chan, Y.M. (2011). A needle in a haystack: mutations in GNRH1 as a rare cause of isolated GnRH deficiency, Mol Cell Endocrinol, 346, 51-56.
  • [3] Bouligand, J., Ghervan, C., Tello, J.A., Brailly-Tabard, S., Salenave, S., Chanson, P., Lombes, M., Millar, R.P., Guiochon-Mantel, A., Young, J. (209). Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation, N Engl J Med, 360, 2742-2748.
  • [4] Chan, Y.M., de Guillebon, A., Lang-Muritano, M., Plummer, L., Cerrato, F., Tsiaras, S., Gaspert, A., Lavoie, H.B., Wu, C.H., Crowley, Jr. W.F., Amory, J.K., Pitteloud, N., Seminara, S.B. (2009). GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism, Proc Natl Acad Sci U S A, 106, 11703-11708.
  • [5] Maione, L., Albarel, F., Bouchard, P., Gallant, M., Flanagan, C.A., Bobe, R., Cohen-Tannoudji, J., Pivonello, R., Colao, A., Brue, T., Millar, R.P., Lombes, M., Young, J., Guiochon-Mantel, A., Bouligand, J. (2013). R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism, PLoS One, 8, e69616.
  • [6] Bouligand, J., Ghervan, C., Trabado, S., Brailly-Tabard, S., Guiochon-Mantel, A., Young, J. (2010). Genetics defects in GNRH1: a paradigm of hypothalamic congenital gonadotropin deficiency, Brain Res, 1364, 3-9.
  • [7] Mengen, E., Tunc, S., Kotan, L.D., Nalbantoglu, O., Demir, K., Gurbuz, F., Turan, I., Seker, G., Yuksel, B., Topaloglu, A.K. (2016). Complete Idiopathic Hypogonadotropic Hypogonadism due to Homozygous GNRH1 Mutations in the Mutational Hot Spots in the Region Encoding the Decapeptide, Horm Res Paediatr, 85, 107-111.
  • [8] Beranova, M., Oliveira, L.M., Bedecarrats, G.Y., Schipani, E., Vallejo, M., Ammini, A.C., Quintos, J.B., Hall, J.E., Martin, K.A., Hayes, J.F., Pitteloud, N., Kaiser, U.B., Crowley, Jr.W.F., Seminara, S.B. (2001). Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism, J Clin Endocrinol Metab, 86, 1580-1588.
  • [9] Kopanos, C., Tsiolkas, V., Kouris, A., Chapple, C.E., Albarca Aguilera, M., Meyer, R., Massouras, A. (2018). VarSome: The Human Genomic Variant Search Engine, Bioinformatics, DOI 10.1093/bioinformatics/bty897.
  • [10] Gupta, A., Singh, T.R. SHIFT: server for hidden stops analysis in frame-shifted translation, BMC research notes, 6, 68.
  • [11] Seligmann, H., Pollock, D.D. (2004). The ambush hypothesis: hidden stop codons prevent off-frame gene reading, DNA Cell Biol, 23, 701-705.
  • [12] Singh, T.R. (2013). Mitochondrial Genomes and Frameshift Mutations: Hidden Stop Codons, their Functional Consequences and Disease Associations, Journal of Clinical & Medical Genomics, 1.
  • [13] Singh, T.R., Pardasani, K.R. (2009). Ambush hypothesis revisited: Evidences for phylogenetic trends, Comput Biol Chem, 33, 239-244.
  • [14] Holbrook, J.A., Neu-Yilik, G., Hentze, M.W., Kulozik, A.E. (2004). Nonsense-mediated decay approaches the clinic, Nat Genet, 36, 801-808.
  • [15] Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W.W., Hegde, M., Lyon, E. Spector, E., Voelkerding, K., Rehm, H.L., A.L.Q.A. Committee, (2015). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, Genetics in medicine : official journal of the American College of Medical Genetics, 17, 405-424.
  • [16] Charoute, H., Bakhchane, A., Benrahma, H., Romdhane, L., Gabi, K., Rouba, H., Fakiri, M., Abdelhak, S., Lenaers, G., Barakat, A. (2015). Mediterranean Founder Mutation Database (MFMD): Taking Advantage from Founder Mutations in Genetics Diagnosis, Genetic Diversity and Migration History of the Mediterranean Population, Hum Mutat, 36, E2441-2453.
  • [17] Botstein, D., Risch, N. (2003). Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease, Nat Genet, 33 Suppl, 228-237.
  • [18] Wakeling, M.N., Laver, T.W., Wright, C.F., De Franco, E., Stals, K.L., Patch, A.M., Hattersley, A.T., Flanagan, S.E., Ellard, S., D.D.D. Study. (2019). Correction: Homozygosity mapping provides supporting evidence of pathogenicity in recessive Mendelian disease, Genetics in medicine : official journal of the American College of Medical Genetics, 21, 766.
  • [19] Rogozin, I.B., Pavlov, Y.I. (2003). Theoretical analysis of mutation hotspots and their DNA sequence context specificity, Mutat Res, 544, 65-85.
There are 19 citations in total.

Details

Primary Language Turkish
Journal Section Research Articles
Authors

Leman Damla Kotan Gedik 0000-0001-6176-8986

Erdal Eren This is me 0000-0002-1684-1053

İhsan Turan This is me 0000-0002-5654-247X

Eda Mengen 0000-0003-1597-8418

Bilgin Yüksel 0000-0003-4378-3255

Ali Kemal Topaloğlu This is me 0000-0003-2931-9552

Project Number 4580 ve 11364
Publication Date March 31, 2020
Published in Issue Year 2020

Cite

APA Kotan Gedik, L. D., Eren, E., Turan, İ., Mengen, E., et al. (2020). İdiyopatik Hipogonadotropik Hipogonadizme Neden Olan GNRH1 c.99delA Delesyonunun Klinik ve Genetik İncelemesi. International Journal of Advances in Engineering and Pure Sciences, 32(1), 73-78. https://doi.org/10.7240/jeps.615925
AMA Kotan Gedik LD, Eren E, Turan İ, Mengen E, Yüksel B, Topaloğlu AK. İdiyopatik Hipogonadotropik Hipogonadizme Neden Olan GNRH1 c.99delA Delesyonunun Klinik ve Genetik İncelemesi. JEPS. March 2020;32(1):73-78. doi:10.7240/jeps.615925
Chicago Kotan Gedik, Leman Damla, Erdal Eren, İhsan Turan, Eda Mengen, Bilgin Yüksel, and Ali Kemal Topaloğlu. “İdiyopatik Hipogonadotropik Hipogonadizme Neden Olan GNRH1 c.99delA Delesyonunun Klinik Ve Genetik İncelemesi”. International Journal of Advances in Engineering and Pure Sciences 32, no. 1 (March 2020): 73-78. https://doi.org/10.7240/jeps.615925.
EndNote Kotan Gedik LD, Eren E, Turan İ, Mengen E, Yüksel B, Topaloğlu AK (March 1, 2020) İdiyopatik Hipogonadotropik Hipogonadizme Neden Olan GNRH1 c.99delA Delesyonunun Klinik ve Genetik İncelemesi. International Journal of Advances in Engineering and Pure Sciences 32 1 73–78.
IEEE L. D. Kotan Gedik, E. Eren, İ. Turan, E. Mengen, B. Yüksel, and A. K. Topaloğlu, “İdiyopatik Hipogonadotropik Hipogonadizme Neden Olan GNRH1 c.99delA Delesyonunun Klinik ve Genetik İncelemesi”, JEPS, vol. 32, no. 1, pp. 73–78, 2020, doi: 10.7240/jeps.615925.
ISNAD Kotan Gedik, Leman Damla et al. “İdiyopatik Hipogonadotropik Hipogonadizme Neden Olan GNRH1 c.99delA Delesyonunun Klinik Ve Genetik İncelemesi”. International Journal of Advances in Engineering and Pure Sciences 32/1 (March 2020), 73-78. https://doi.org/10.7240/jeps.615925.
JAMA Kotan Gedik LD, Eren E, Turan İ, Mengen E, Yüksel B, Topaloğlu AK. İdiyopatik Hipogonadotropik Hipogonadizme Neden Olan GNRH1 c.99delA Delesyonunun Klinik ve Genetik İncelemesi. JEPS. 2020;32:73–78.
MLA Kotan Gedik, Leman Damla et al. “İdiyopatik Hipogonadotropik Hipogonadizme Neden Olan GNRH1 c.99delA Delesyonunun Klinik Ve Genetik İncelemesi”. International Journal of Advances in Engineering and Pure Sciences, vol. 32, no. 1, 2020, pp. 73-78, doi:10.7240/jeps.615925.
Vancouver Kotan Gedik LD, Eren E, Turan İ, Mengen E, Yüksel B, Topaloğlu AK. İdiyopatik Hipogonadotropik Hipogonadizme Neden Olan GNRH1 c.99delA Delesyonunun Klinik ve Genetik İncelemesi. JEPS. 2020;32(1):73-8.