Yalçın BAŞARAN, Hilmi Umut ÜNAL, Şinasi Erol BOLU, Rahşan İlikçi SAĞKAN

Analysis of KAL1, FGFR1, GPR54, and NELF copy number variations by multiplex ligation dependent probe amplification in male patients with idiopathic hypogonadotropic hypogonadism

Hypogonadotropic hypogonadism is a production failure of gonadal hormones due to a lack of gonadotropin secretion. Here, we aimed to determine the prevalence of genomic rearrangements in the KAL1, FGFR1, GPR54, and NELF genes in patients diagnosed with hypogonadotropic hypogonadism. Materials and methods: The study included 86 male patients with idiopathic hypogonadotropic hypogonadism (76 diagnosed with normosmic idiopathic hypogonadotropic hypogonadism and 10 with Kallmann syndrome). Additionally, 95 healthy controls were recruited to investigate rearrangements in the KAL1, FGFR1, GPR54, and NELF genes, using multiplex ligation dependent probe amplification. Results: From the 86 patients, 3 patients with Kallmann syndrome had heterozygous deletions in exon 9 of the KAL1 gene (probe target sequence: 5941-L05940), and 1 of these patients also had a duplication in exon 11 of the same gene (probe target sequence: 4427-L03813). Additionally, 1 patient with nIHH had a duplication in exons 14 and 18 of the FGFR1 gene (probe target sequences: 4440-L03826 and 4441-L03827, respectively). No deletions/duplications were identified in the GPR54 and NELF genes and no genomic rearrangement was detected in the control subjects. Conclusion: To improve our understanding of this complex condition and also for better genetic counseling and directing therapy, defining the genetic basis of these disorders is essential.

Anahtar Kelimeler:

Key words: Normosmic idiopathic hypogonadotropic hypogonadism, Kallmann syndrome, KAL1, FGFR1, GPR54, NELF, multiplex ligation dependent probe amplification

Analysis of KAL1, FGFR1, GPR54, and NELF copy number variations by multiplex ligation dependent probe amplification in male patients with idiopathic hypogonadotropic hypogonadism

Keywords:

Kallmann syndrome, KAL1, FGFR1, GPR54, NELF, multiplex ligation dependent probe amplification, Normosmic idiopathic hypogonadotropic hypogonadism,

PDF

___

Akdağ T, Tiftik AM, Sarıyıldız L. A comparative investigation of anti-Müllerian hormone (AMH) and various biochemical parameters in patients with cryptorchidism, oligospermia, or varicocele. Turk J Med Sci 2012; 42: 411–5. 2. Kallmann FJ, Schoenfeld WA, Barrera SE. The genetic aspects of primary eunuchoidism. Am J Ment Defic 1944; 48203–36.
De Morsier G. Median craioencephalic dysraphias and olfactogenital dysplasia. World Neurol 1962; 3485–506.
Naftolin F, Harris G, Bobrow M. Effect of purified luteinizing hormone releasing factor on normal and hypogonadotrophic anosmic men. Nature 1971; 232: 496–7.
Schwanzel-Fukuda M, Bick D, Pfaff D. Luteinizing hormone- releasing hormone (LHRH)-expressing cells do not migrate normally in an inherited hypogonadal (Kallmann) syndrome. Brain Res Mol Brain Res 1989; 6: 311–26.
Schwanzel-Fukuda M. Origin and migration of luteinizing hormone-releasing hormone neurons in mammals. Microsc Res Tech 1999; 44: 2–10.
González-Martínez D, Kim S, Hu Y, Guimond S, Schofield J, Winyard P et al. Anosmin-1 modulates fibroblast growth factor receptor 1 signaling in human gonadotropin-releasing hormone olfactory neuroblasts through a heparan sulfate- dependent mechanism. J Neurosci 2004; 24: 10384–92.
Tsai P, Gill J. Mechanisms of disease: insights into X-linked and autosomal-dominant Kallmann syndrome. Nat Clin Pract Endocrinol Metab 2006; 2: 160–71.
Hardelin J, Levilliers J, Castillo I del, Cohen-Salmon M, Legouis R, Blanchard S et al. X chromosome-linked Kallmann syndrome: stop mutations validate the candidate gene. Proc Natl Acad Sci USA 1992; 89: 8190–4.
Dodé C, Teixeira L, Levilliers J, Fouveaut C, Bouchard P, Kottler M et al. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet 2006; 2: 175.
Sato N, Katsumata N, Kagami M, Hasegawa T, Hori N, Kawakita S et al. Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients. J Clin Endocrinol Metab 2004; 89: 1079–88.
Albuisson J, Pêcheux C, Carel J, Lacombe D, Leheup B, Lapuzina P et al. Kallmann syndrome: 14 novel mutations in KAL1 and FGFR1 (KAL2). Hum Mutat 2005; 25: 98–9.
Doty R, Shaman P, Kimmelman C, Dann M. University of Pennsylvania Smell Identification Test: a rapid quantitative olfactory function test for the clinic. Laryngoscope 1984; 94: 176–8.
Lee D, Nguyen T, O’Neill G, Cheng R, Liu Y, Howard A et al. Discovery of a receptor related to the galanin receptors. FEBS Lett 1999; 446: 103–7.
De Roux N, Genin E, Carel J, Matsuda F, Chaussain J, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA 2003; 100: 10972–6.
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: 1137–44.
Bianco S, Kaiser U. The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism. Nat Rev Endocrinol 2009; 5: 569–76.
Cerrato F, Shagoury J, Kralickova M, Dwyer A, Falardeau J, Ozata M et al. Coding sequence analysis of GNRHR and GPR54 in patients with congenital and adult-onset forms of hypogonadotropic hypogonadism. Eur J Endocrinol 2006; 155: S3–S10.
Miura K, Acierno JJ, Seminara S. Characterization of the human nasal embryonic LHRH factor gene, NELF, and a mutation screening among 65 patients with idiopathic hypogonadotropic hypogonadism (IHH). J Hum Genet 2004; 49: 265–8.
Pedersen-White J, Chorich L, Bick D, Sherins R, Layman L. The prevalence of intragenic deletions in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Mol Hum Reprod 2008; 14: 367–70.
Schouten J, McElgunn C, Waaijer R, Zwijnenburg D, Diepvens F, Pals G. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 2002; 30: e57.