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21.05.2018 | Original Article

Genetic analysis of the human insulin-like 3 gene in pediatric patients with testicular torsion

verfasst von: Anna Paola Capra, Elisa Ferro, Maria Angela La Rosa, Silvana Briuglia, Tiziana Russo, Salvatore Arena, Carmelo Salpietro Damiano, Carmelo Romeo, Pietro Impellizzeri

Erschienen in: Pediatric Surgery International | Ausgabe 7/2018

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Abstract

Purpose

Testicular torsion (TT) mainly affects boys under 18 years old. To avoid orchiectomy, TT requires an immediate operative management. The etiology of TT is still controversial. Observed familiar recurrence suggests the presence of a genetic involvement. The INSL3 gene consists of two exons, and it is specifically expressed in fetal and adult Leydig cells. In transgenic mice, deletion of this gene was observed an increased testicular mobility and testicular torsion. We have hypothesized the possible involvement of the INSL3 gene as a predisposing factor of human TT.

Methods

We performed genetic analysis in 25 pediatric patients with unilateral and intravaginal TT (left, n = 13, 56%; right, n = 12, 48%). The age of the patients ranged from 1 to 16 years (median age n = 10.4 ± 5.46 years). In this study, we included two first male cousins affected by TT. Venous peripheral blood samples was obtained after parental written informed consent.

Results

The Thr60Ala polymorphism was detected in exon 1 of INSL3 gene and other 2 rarer variants (rs1047233 and rs1003887) were identified in the 3′ untranslated region. These variants are prevalent in patients with TT instead of healthy subjects.

Conclusions

Additional studies in a larger population are needed to better understand the clinical consequence of the INSL 3 variations founded. This would allow in the future to identify the patients at risk of TT to improve clinical management.

[Yang C, Song B, Tan J, Liu X, Wei GH (2011) Testicular torsion in children: a 20-year retrospective study in a single institution. Sci World J 11:362–368. https://doi.org/10.1100/tsw.2011.39 CrossRef

DrlÌk M, Kočvara R (2013) Torsion of spermatic cord in children: a review. J Pediatr Urol 3:259–266. https://doi.org/10.1016/j.jpurol.2012.05.016 CrossRef

Zhao LC, Lautz TB, Meeks JJ, Maizels M (2011) Pediatric testicular torsion epidemiology using a national database: incidence, risk of orchiectomy and possible measures toward improving the quality of care. J Urol 186(5):2009–2013. https://doi.org/10.1016/j.juro.2011.07.024 CrossRefPubMed

DaJusta DG, Granberg CF, Villanueva C, Baker LA (2013) Contemporary review of testicular torsion: new concepts, emerging technologies and potential therapeutics. J Pediatr Urol 9(6 Pt A):723–730. https://doi.org/10.1016/j.jpurol.2012.08.012 CrossRefPubMed

Arap MA, Vicentini FC, Cocuzza M, Hallak J, Athayde K, Lucon AM, Arap S, Srougi M (2007) Late hormonal levels, semen parameters, and presence of antisperm antibodies in patients treated for testicular torsion. J Androl 28(4):528–532. https://doi.org/10.2164/jandrol.106.002097 CrossRefPubMed

Schneck FX, Bellinger MF (1970) Abnormalities of the testes and scrotum and their surgical management. In: Campbell MF (ed) Anomalies of the kidney, vol 2, 3rd edn. WB Saunders, Philadelphia, pp 1447–1452

Shteynshlyuger A, Yu J (2013) Familial testicular torsion: a meta analysis suggests inheritance. J Pediatr Urol 9(5):683–690. https://doi.org/10.1016/j.jpurol.2012.08.002 CrossRefPubMed

Bowlin PR, Gatti JM, Murphy JP (2017) Pediatric testicular torsion. Surg Clin N Am 97(1):161–172. https://doi.org/10.1016/j.suc.2016.08.012 CrossRefPubMed

Fènichel P, Lahlou N, Coquillard P, Panaia-Ferrari P, Wagner-Mahler K, Brucker-Davis F (2015) Cord blood insulin-like peptide 3 (INSL3) but not testosterone is reduced in idiopathic cryptorchidism. Clin Endocrinol 82(2):242–247. https://doi.org/10.1111/cen.12500 CrossRef

10.

Vinci G, Anjot MN, Trivin C, Lottmann H, Brauner R, McElreavey K (2004) An analysis of the genetic factors involved in testicular descent in a cohort of 14 male patients with anorchia. J Clin Endocrinol Metab 89(12):6282–6285. https://doi.org/10.1210/jc.2004-0891 CrossRefPubMed

11.

Ferlin A, Simonato M, Bartoloni L, Rizzo G, Bettella A, Dottorini T, Dallapiccola B, Foresta C (2003) The INSL3-LGR8/GREAT ligand-receptor pair in human cryptorchidism. J Clin Endocrinol Metab 88:4273–4279. https://doi.org/10.1210/jc.2003-030359 CrossRefPubMed

12.

Bay K, Andersson AM (2011) Human testicular insulin-like factor 3: in relation to development, reproductive hormones and andrological disorders. Int J Androl 34(2):97–109. https://doi.org/10.1111/j.1365-2605.2010.01074.x CrossRefPubMed

13.

Nef S, Parada LF (1999) Cryptorchidism in mice mutant for Insl3. Nat Genet 22:295–299. https://doi.org/10.1038/10364 CrossRefPubMed

14.

Zimmermann S, Steding G, Emmen JM, Brinkmann AO, Nayernia K, Holstein AF, Engel W, Adham IM (1999) Targeted disruption of the Insl3 gene causes bilateral cryptorchidism. Mol Endocrinol 13(5):681–691. https://doi.org/10.1210/mend.13.5.0272 CrossRefPubMed

15.

Huang X, Jia J, Sun M, Li M, Liu N (2016) Mutational screening of the INSL3 gene in azoospermic males with a history of cryptorchidism. Andrologia 48(7):835–839. https://doi.org/10.1111/and.12522 CrossRefPubMed

16.

Koskimies P, Virtanen H, Lindstrom M, Kaleva M, Poutanen M, Huhtaniemi I, Toppari J (2000) A common polymorphism in the human relaxin-like factor (RLF) gene: no relationship with cryptorchidism. Pediatr Res 47:538–541CrossRefPubMed

17.

Krausz C, Quintana-Murci L, Fellous M, Siffroi JP, McElreavey K (2000) Absence of mutations involving the INSL3 gene in human idiopathic cryptorchidism. Mol Hum Reprod 6:298–302CrossRefPubMed

18.

Tomboc M, Lee PA, Mitwally MF, Schneck FX, Bellinger M, Witchel SF (2000) Insulin-like 3/relaxin-like factor gene mutations are associated with cryptorchidism. J Clin Endocrinol Metab 85(11):4013–4018. https://doi.org/10.1210/jcem.85.11.6935 PubMedCrossRef

19.

Lim HN, Raipert-de Meyts E, Skakkebaek NE, Hawkins JR, Hughes IA (2001) Genetic analysis of the INSL3 gene in patients with maldescent of the testis. Eur J Endocrinol 144:129–137CrossRefPubMed

20.

Marin P, Ferlin A, Moro E, Garolla A, Foresta C (2001) Different insulin-like 3 (INSL3) gene mutations not associated with human cryptorchidism. J Endocrinol Invest 24:RC13-RC15. https://doi.org/10.1007/BF03343848 CrossRef

21.

Takahashi I, Takahashi T, Komatsu M, Matsuda J, Takada G (2001) Ala/Thr60 variant of the Leydig insulin-like hormone is not associated with cryptorchidism in the Japanese population. Pediatr Int 43:256–258CrossRefPubMed

22.

Baker LA, Nef S, Nguyen MT, Stapleton R, Nordenskjold A, Pohl H, Parada LF (2002) The insulin-3 gene: lack of a genetic basis for human cryptorchidism. J Urol 167:2534–2537CrossRefPubMed

23.

Canto P, Escudero I, Soderlund D, Nishimura E, Carranza-Lira S, Gutierrez J, Nava A, Mendez JP (2003) A novel mutation of the insulin-like 3 gene in patients with cryptorchidism. J Hum Genet 48:86–90. https://doi.org/10.1007/s100380300012 CrossRefPubMed

24.

Ferlin A, Bogatcheva NV, Gianesello L, Pepe A, Vinanzi C, Agoulnik AI, Foresta C (2006) Insulin-like factor 3 gene mutations in testicular dysgenesis syndrome: clinical and functional characterization. Mol Hum Reprod 12:401–406. https://doi.org/10.1093/molehr/gal043 CrossRefPubMed

25.

Ferlin A, Zuccarello D, Zuccarello B, Chirico MR, Zanon GF, Foresta C (2008) Genetic alterations associated with cryptorchidism. JAMA 300(19):2271–2276. https://doi.org/10.1001/jama.2008.668 CrossRefPubMed

26.

Feng S, Cortessis VK, Hwang A, Hardy B, Koh CJ, Bogatcheva NV, Agoulnik AI (2004) Mutation analysis of INSL3 and GREAT/ LGR8 genes in familial cryptorchidism. Urology 64:1032–1036. https://doi.org/10.1016/j.urology.2004.06.051 CrossRefPubMed

27.

Foresta C, Ferlin A (2004) Role of INSL3 and LGR8 in cryptorchism and testicular functions. Reprod Biomed Online 9(3):294–298CrossRefPubMed

28.

El Houate B, Rouba H, Sibai H, Barakat A, Chafik A, Chadli el B, Imken L, Bogatcheva NV, Feng S, Agoulnik AI, McElreavey K (2007) Novel mutations involving the INSL3 gene associated with cryptorchidism. J Urol 177:1947–1951. https://doi.org/10.1016/j.juro.2007.01.002 CrossRefPubMed

29.

Yamazawa K, Wada Y, Sasagawa I, Aoki K, Ueoka K, Ogata T (2007) Mutation and polymorphism analyses of INSL3 and LGR8/GREAT in 62 Japanese patients with cryptorchidism. Horm Res 67:73–76. https://doi.org/10.1159/000096089 PubMedCrossRef

30.

Mamoulakis C, Georgiou I, Dimitriadis F, Tsounapi P, Giannakis I, Chatzikyriakidou A, Antypas S, Sofras F, Takenaka A, Sofikitis N (2014) Genetic analysis of the human Insulin-like 3 gene: absence of mutations in a Greek paediatric cohort with testicular maldescent. Andrologia 46(9):986–996. https://doi.org/10.1111/and.12184 CrossRefPubMed

31.

Sozubir S, Barber T, Wang Y, Ahn C, Zhang S, Verma S, Lonergan D, Lorenzo AJ, Nef S, Baker LA (2010) Loss of Insl3: a potential predisposing factor for testicular torsion. J Urol 183(6):2373–2379. https://doi.org/10.1016/j.juro.2010.02.2390 CrossRefPubMed

32.

Romeo C, Impellizzeri P, Arrigo T, Antonuccio P, Valenzise M, Mirabelli S, Astra Borruto F, Scalfari G, Arena F, De Luca F (2010) Late hormonal function after testicular torsion. J Pediatr Surg 45(2):411–413. https://doi.org/10.1016/j.jpedsurg.2009.10.086 CrossRefPubMed

33.

Ivell R, Balvers M, Domagalski R, Ungefroren H, Hunt N, Schulze W (1997) The relaxin-like factor: a highly specific and constitutive new marker for Leydig cells in the human testis. Mol Hum Reprod 3(6):459–466CrossRefPubMed

34.

Ivell R, Anand-Ivell R (2009) Biology of insulin-like factor 3 in human reproduction. Hum Reprod Update 15(4):463–476. https://doi.org/10.1093/humupd/dmp011 CrossRefPubMed

35.

Ivell R, Agoulnik AI, Anand-Ivell R (2017) Relaxin-like peptides in male reproduction—a human perspective. Br J Pharmacol 174(10):990–1001. https://doi.org/10.1111/bph.13689 CrossRefPubMedPubMedCentral

36.

Foresta C, Zuccarello D, Garolla A, Ferlin A (2008) Role of hormones, genes, and environment in human cryptorchidism. Endocr Rev 29(5):560–580. https://doi.org/10.1210/er.2007-0042 CrossRefPubMed

37.

Bogatcheva NV, Truong A, Feng S, Engel W, Adham IM, Agoulnik AI (2003) GREAT/LGR8 is the only receptor for insulin-like 3 peptide. Mol Endocrinol 17(12):2639–2646. https://doi.org/10.1210/me.2003-0096 CrossRefPubMed

38.

Ivell R, Heng K, Anand-Ivell R (2014) Insulin-like factor 3 and the HPG axis in the male. Front Endocrinol (Lausanne) 27(5):6. https://doi.org/10.3389/fendo.2014.00006 CrossRef

39.

Shaikh N, Dadachanji R, Meherji P, Shah N, Mukherjee S (2016) Polymorphisms and haplotypes of insulin-like factor 3 gene are associated with risk of polycystic ovary syndrome in Indian women. Gene 577(2):180–186. https://doi.org/10.1016/j.gene.2015.11.033 CrossRefPubMed

Titel: Genetic analysis of the human insulin-like 3 gene in pediatric patients with testicular torsion
verfasst von: Anna Paola Capra
Elisa Ferro
Maria Angela La Rosa
Silvana Briuglia
Tiziana Russo
Salvatore Arena
Carmelo Salpietro Damiano
Carmelo Romeo
Pietro Impellizzeri
Publikationsdatum: 21.05.2018
Verlag: Springer Berlin Heidelberg
Erschienen in: Pediatric Surgery International / Ausgabe 7/2018
Print ISSN: 0179-0358
Elektronische ISSN: 1437-9813
DOI: https://doi.org/10.1007/s00383-018-4280-y

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Genetic analysis of the human insulin-like 3 gene in pediatric patients with testicular torsion

Abstract

Purpose

Methods

Results

Conclusions

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