Mariam Moalla

Nonstop mutation in the kisspeptin 1 receptor (kiss1r) gene causes normosmic congenital hypogonadotropic hypogonadism

• Authors Details :  
• Mariam Moalla,  
• Faten Hadj Kacem,  
• Abdullah Fahad Al-mutery,  
• Mona Mahfood,  
• Nabila Mejdoub-rekik,  
• Mohamed Abid,  
• Mouna Mnif-feki,  
• Hassen Hadj Kacem

Journal title : Journal of Assisted Reproduction and Genetics

Publisher : Springer Science and Business Media LLC

Online ISSN : 1573-7330

Page Number : 1273-1280

Journal volume : 36

Journal issue : 6

373 Views Original Article

Purpose: Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder mostly characterized by gonadotropins release and/or action deficiencies. Both isolated (idiopathic hypogonadotropic hypogonadism) and syndromic (Kallmann) forms are identified depending on the olfactory ability. Clinical and genetic heterogeneities of CHH have been widely explored, thus improving our understanding of the disease's pathophysiology. This work aims to (1) provide a detailed clinical and hormonal description of normosmic CHH patients and (2) identify the mutation linked to the studied phenotype. Participants and methods: We investigated three affected patients with normosmic CHH, belonging to a consanguineous Tunisian family. Patients underwent an insulin-induced hypoglycemia test. We performed whole exome sequencing to identify the causal mutation. Results: At first diagnosis, a total gonadotropic deficiency was identified in all patients. The insulin-induced hypoglycemia test has also revealed a reduced cortisol secretion and complete growth hormone deficiency. At 20.8 years, one female exhibited a spontaneous recovery of the hypothalamic-pituitary-adrenal axis function, unlike her affected siblings who still depend on corticosteroid replacement therapy. Herein, we identified a novel homozygous nonstop mutation (c.1195T>C) in KISS1R gene in all affected subjects. This mutation led to the substitution of the physiologic stop codon by an arginine (p.X399R). Conclusions: Our study highlights the importance of the KISS1R signaling, in gonadotropin-releasing hormone neurons, in the control of reproductive function. Additionally, our data suggests a complex central and peripheral metabolic control of puberty, through the hypothalamic KISS1R signaling. We suggest a mutual link between the hypothalamic-pituitary-gonadal, -adrenal, and -somatotropic axes.

Article DOI & Crossmark Data

DOI : https://doi.org/10.1007/s10815-019-01468-z

Article Subject Details

• Endocrinology
• Genetics

Article Keywords Details

• KISS1R
• Kisspeptin
• Nonstop mutation
• Normosmic congenital hypogonadotropic hypogonadism
• Whole exome sequencing
• GnRH

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Article References

• (1). Boehm U, Bouloux P-M, Dattani MT, de Roux N, Dodé C, Dunkel L, et al. European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment: expert consensus document. Nat Rev Endocrinol. 2015;11(9):547–64. https://doi.org/10.1038/nrendo.2015.112 .
• (2). Franco B, Guioli S, Pragliola A, Incerti B, Bardoni B, Tonlorenzi R, et al. A gene deleted in Kallmann’s syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature. 1991;353(6344):529–36. https://doi.org/10.1038/353529a0 .
• (3). Topaloglu AK, Kotan LD. Genetics of hypogonadotropic hypogonadism. Endocr Dev. 2016;29:36–49. https://doi.org/10.1159/000438841 .
• (4). Maione L, Dwyer AA, Francou B, Guiochon-Mantel A, Binart N, Bouligand J, et al. GENETICS IN ENDOCRINOLOGY: genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing. Eur J Endocrinol. 2018;178(3):R55–80. https://doi.org/10.1530/EJE-17-0749 .
• (5). Topalo?lu AK. Update on the Genetics of idiopathic hypogonadotropic hypogonadism. J Clin Res Pediatr Endocrinol. 2017;9(Suppl 2):113–22. https://doi.org/10.4274/jcrpe.2017.S010 .
• (6). Kawasaki ES. Sample preparation from blood, cells, and other fluids. NY: Academic Press; 1990. p. 146–52.
• (7). Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, le Poul E, et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem. 2001;276(37):34631–6. https://doi.org/10.1074/jbc.M104847200 .
• (8). Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, et al. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 2001;411(6837):613–7. https://doi.org/10.1038/35079135 .
• (9). Muir AI, Chamberlain L, Elshourbagy NA, Michalovich D, Moore DJ, Calamari A, et al. AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. J Biol Chem. 2001;276(31):28969–75. https://doi.org/10.1074/jbc.M102743200 .
• (10). Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349(17):1614–27. https://doi.org/10.1056/NEJMoa035322 .
• (11). de Roux N, Genin E, Carel J-C, Matsuda F, Chaussain J-L, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A. 2003;100(19):10972–6. https://doi.org/10.1073/pnas.1834399100 .
• (12). Semple RK, Achermann JC, Ellery J, Farooqi IS, Karet FE, Stanhope RG, et al. Two novel missense mutations in g protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2005;90(3):1849–55. https://doi.org/10.1210/jc.2004-1418 .
• (13). Lanfranco F, Gromoll J, von Eckardstein S, Herding EM, Nieschlag E, Simoni M. Role of sequence variations of the GnRH receptor and G protein-coupled receptor 54 gene in male idiopathic hypogonadotropic hypogonadism. Eur J Endocrinol. 2005;153(6):845–52. https://doi.org/10.1530/eje.1.02031 .
• (14). Tenenbaum-Rakover Y, Commenges-Ducos M, Iovane A, Aumas C, Admoni O, de Roux N. Neuroendocrine phenotype analysis in five patients with isolated hypogonadotropic hypogonadism due to a L102P inactivating mutation of GPR54. J Clin Endocrinol Metab. 2007;92(3):1137–44. https://doi.org/10.1210/jc.2006-2147 .
• (15). Nimri R, Lebenthal Y, Lazar L, Chevrier L, Phillip M, Bar M, et al. A novel loss-of-function mutation in GPR54/KISS1R leads to hypogonadotropic hypogonadism in a highly consanguineous family. J Clin Endocrinol Metab. 2011;96(3):E536–45. https://doi.org/10.1210/jc.2010-1676 .
• (16). Breuer O, Abdulhadi-Atwan M, Zeligson S, Fridman H, Renbaum P, Levy-Lahad E, et al. A novel severe N-terminal splice site KISS1R gene mutation causes hypogonadotropic hypogonadism but enables a normal development of neonatal external genitalia. Eur J Endocrinol. 2012;167(2):209–16. https://doi.org/10.1530/EJE-12-0127 .
• (17). Brioude F, Bouligand J, Francou B, Fagart J, Roussel R, Viengchareun S, et al. Two families with normosmic congenital hypogonadotropic hypogonadism and biallelic mutations in KISS1R (KISS1 receptor): clinical evaluation and molecular characterization of a novel mutation. PLoS One. 2013;8(1):e53896. https://doi.org/10.1371/journal.pone.0053896 .
• (18). Demirbilek H, Ozbek MN, Demir K, Kotan LD, Cesur Y, Dogan M, et al. Normosmic idiopathic hypogonadotropic hypogonadism due to a novel homozygous nonsense c.C969A (p.Y323X) mutation in the KISS1R gene in three unrelated families. Clin Endocrinol. 2015;82(3):429–38. https://doi.org/10.1111/cen.12618 .
• (19). Francou B, Paul C, Amazit L, Cartes A, Bouvattier C, Albarel F, et al. Prevalence of KISS1 receptor mutations in a series of 603 patients with normosmic congenital hypogonadotrophic hypogonadism and characterization of novel mutations: a single-centre study. Hum Reprod. 2016;31(6):1363–74. https://doi.org/10.1093/humrep/dew073 .
• (20). Teles MG, Bianco SDC, Brito VN, Trarbach EB, Kuohung W, Xu S, et al. A GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med. 2008;358(7):709–15. https://doi.org/10.1056/NEJMoa073443 .
• (21). Miraoui H, Dwyer AA, Sykiotis GP, Plummer L, Chung W, Feng B, et al. Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet. 2013;92(5):725–43. https://doi.org/10.1016/j.ajhg.2013.04.008 .
• (22). Känsäkoski J, Fagerholm R, Laitinen E-M, Vaaralahti K, Hackman P, Pitteloud N, et al. Mutation screening of SEMA3A and SEMA7A in patients with congenital hypogonadotropic hypogonadism. Pediatr Res. 2014;75(5):641–4. https://doi.org/10.1038/pr.2014.23 .
• (23). Nair S, Jadhav S, Lila A, Jagtap V, Bukan A, Pandit R, et al. Spectrum of phenotype and genotype of congenital isolated hypogonadotropic hypogonadism in Asian Indians. Clin Endocrinol. 2016;85(1):100–9. https://doi.org/10.1111/cen.13009 .
• (24). Colledge WH. Transgenic mouse models to study Gpr54/kisspeptin physiology. Peptides. 2009;30(1):34–41. https://doi.org/10.1016/j.peptides.2008.05.006 .
• (25). Shahab M, Lippincott M, Chan Y-M, Davies A, Merino PM, Plummer L, et al. Discordance in the dependence on Kisspeptin signaling in mini puberty vs adolescent puberty: human genetic evidence. J Clin Endocrinol Metab. 2018;103(4):1273–6. https://doi.org/10.1210/jc.2017-02636 .

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