Background: Heterozygous SOX2 mutations have been reported to cause isolated hypogonadotropic hypogonadism (HH) in addition to ocular and brain abnormalities. Objective: We report a novel missense SOX2 (Y110C) mutation in an HH patient with mild ocular malformation. Patients: The 20-year-old male was referred because of typical signs of complete hypogonadism, with small intrascrotal testes (2 ml), no pubic hair (P1), and a micropenis. Hormone assays revealed very low plasma testosterone levels and very low levels of plasma gonadotropin. He was found to have retinal detachment in his right eye and surgery was performed at the age of 14 years. Results: Using a next-generation sequencing strategy, we identified a novel heterozygous SOX2 mutation, c.329A>G (p.Y110C). Y110C SOX2 had reduced transactivation and no dominant negative effect. Subcellular localization revealed no significant difference between wild-type and mutant SOX2. EMSA experiments showed that the Y110C SOX2 abrogated DNA-binding ability. Conclusion: The Y110C mutation affects a critical residue in the SOX2 protein. This study extends our understanding of the phenotypic features, molecular mechanism, and developmental course associated with mutations in SOX2. When multiple genes need to be analyzed for mutations simultaneously, targeted sequence analysis of interesting genomic regions is an attractive approach.

Keywords:
SOX2, Hypogonadotropic hypogonadism, HMG domain, Targeted next-generation sequencing
1.
Karges B, de Roux N: Molecular genetics of isolated hypogonadotropic hypogonadism and Kallmann syndrome. Endocr Dev 2005;8:67-80.
2.
de Roux N: GnRH receptor and GPR54 inactivation in isolated gonadotropic deficiency. Best Pract Res Clin Endocrinol Metab 2006;20:515-528.
3.
Silveira LF, Trarbach EB, Latronico AC: Genetics basis for GnRH-dependent pubertal disorders in humans. Mol Cell Endocrinol 2010;324:30-38.
4.
Bouligand J, Ghervan C, Tello JA, Brailly-Tabard S, Salenave S, Chanson P, Lombès M, Millar RP, Guiochon-Mantel A, Young J: Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation. N Engl J Med 2009;360:2742-2748.
5.
Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, Porter KM, Serin A, Mungan NO, Cook JR, Ozbek MN, Imamoglu S, Akalin NS, Yuksel B, O'Rahilly S, Semple RK: TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nat Genet 2009;41:354-358.
6.
Topaloglu AK, Tello JA, Kotan LD, Ozbek MN, Yilmaz MB, Erdogan S, Gurbuz F, Temiz F, Millar RP, Yuksel B: Inactivating KISS1 mutation and hypogonadotropic hypogonadism. N Engl J Med 2012;366:629-635.
7.
Kelberman D, Rizzoti K, Avilion A, Bitner-Glindzicz M, Cianfarani S, Collins J, Chong WK, Kirk JM, Achermann JC, Ross R, Carmignac D, Lovell-Badge R, Robinson IC, Dattani MT: Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans. J Clin Invest 2006;116:2442-2455.
8.
Kelberman D, de Castro SC, Huang S, Crolla JA, Palmer R, Gregory JW, Taylor D, Cavallo L, Faienza MF, Fischetto R, Achermann JC, Martinez-Barbera JP, Rizzoti K, Lovell-Badge R, Robinson IC, Gerrelli D, Dattani MT: SOX2 plays a critical role in the pituitary, forebrain, and eye during human embryonic development. J Clin Endocrinol Metab 2008;93:1865-1873.
9.
Fantes J, Ragge NK, Lynch SA, McGill NI, Collin JR, Howard-Peebles PN, Hayward C, Vivian AJ, Williamson K, van Heyningen V, FitzPatrick DR: Mutations in SOX2 cause anophthalmia. Nat Genet 2003;33:461-463.
10.
Williamson KA, Hever AM, Rainger J, Rogers RC, Magee A, Fiedler Z, Keng WT, Sharkey FH, McGill N, Hill CJ, Schneider A, Messina M, Turnpenny PD, Fantes JA, van Heyningen V, FitzPatrick DR: Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome. Hum Mol Genet 2006;15:1413-1422.
11.
Schneider A, Bardakjian T, Reis LM, Tyler RC, Semina EV: Novel SOX2 mutations and genotype-phenotype correlation in anophthalmia and microphthalmia. Am J Med Genet A 2009;149A:2706-2715.
12.
Leiden University Medical Center. Leiden Open Variation Database. MRC Human Genetics Unit LOVD at MRC IGMM. Leiden University Medical Center website. http://lsdb.hgu.mrc.ac.uk/home.php.
13.
Woods KS, Cundall M, Turton J, Rizotti K, Mehta A, Palmer R, Wong J, Chong WK, Al-Zyoud M, El-Ali M, Otonkoski T, Martinez-Barbera JP, Thomas PQ, Robinson IC, Lovell-Badge R, Woodward KJ, Dattani MT: Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism. Am J Hum Genet 2005;76:833-849.
14.
Sato N, Kamachi Y, Kondoh H, Shima Y, Morohashi K, Horikawa R, Ogata T: Hypogonadotropic hypogonadism in an adult female with a heterozygous hypomorphic mutation of SOX2. Eur J Endocrinol 2007;156:167-171.
15.
Mihelec M, Abraham P, Gibson K, Krowka R, Susman R, Storen R, Chen Y, Donald J, Tam PP, Grigg JR, Flaherty M, Gole GA, Jamieson RV: Novel SOX2 partner-factor domain mutation in a four-generation family. Eur J Hum Genet 2009;17:1417-1422.
16.
Kamachi Y, Cheah KS, Kondoh H: Mechanism of regulatory target selection by the SOX high-mobility-group domain proteins as revealed by comparison of SOX1/2/3 and SOX9. Mol Cell Biol 1999;19:107-120.
17.
Pitteloud N, Durrani S, Raivio T, Sykiotis GP: Complex genetics in idiopathic hypogonadotropic hypogonadism. Front Horm Res 2010;39:142-153.
18.
Sykiotis GP, Plummer L, Hughes VA, Au M, Durrani S, Nayak-Young S, Dwyer AA, Quinton R, Hall JE, Gusella JF, Seminara SB, Crowley WF Jr, Pitteloud N: Oligogenic basis of isolated gonadotropin-releasing hormone deficiency. Proc Natl Acad Sci USA 2010;34:15140-15144.
© 2014 S. Karger AG, Basel
2014
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.