Abstract
BACKGROUND: Leydig cell hypoplasia is a rare autosomal recessive condition that interferes with the normal development of male external genitalia in 46,XY individuals. It is mediated by mutations in the lutropin/choriogonadotropin receptor gene, resulting in the impairment of either the binding of hormone or signal transduction. OBJECTIVE/DESIGN: We report a 32-year-old female patient with severe Leydig cell hypoplasia due to a novel homozygote nonsense mutation in exon 10 (c.907C > T, p.Gln303Ter) of the lutropin/choriogonadotropin receptor gene. Interestingly, a second mutation was found (c.935A > G, p.Asn312Ser) downstream of the disruption of the gene sequence. CONCLUSIONS: This case report demonstrates the coexistence of a novel homozygote nonsense mutation with a second mutation in the same hormone binding domain, expanding the genotypic spectrum of lutropin-choriogonadotropic hormone receptor gene mutations. The first diagnosis of this mutation in an adult 46,XY female patient from Morocco underlines the importance of thorough clinical and genetic examination, not only in pre- and post-pubertal children but also in adults originating from conservative socio-cultural backgrounds.
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Richter-Unruh A, Verhoef-Post M, Malak S, et al, 2004 Leydig cell hypoplasia: absent luteinizing hormone receptor cell surface expression caused by a novel homozygous mutation in the extracellular domain. J Clin Endocrinol Metab 89: 5161–5167.
Richter-Unruh A, Martens JW, Verhoef-Post M, et al, 2002 Leydig cell hypoplasia: cases with new mutations, new polymorphisms and cases without mutations in the luteinizing hormone receptor gene. Clin Endocrinol (Oxf) 56: 103–112.
Martens JW, Verhoef-Post M, Abelin N, et al, 1998 A homozygous mutation in the luteinizing hormone receptor causes partial Leydig cell hypoplasia: correlation between receptor activity and phenotype. Mol Endocrinol 12: 775–784.
Themmen AP, Brunner HG, 1996 Luteinizing hormone receptor mutations and sex differentiation. Eur J Endocrinol 134: 533–540.
Ascoli M, Fanelli F, Segaloff DL, 2002 The lutropin/choriogonadotropin receptor, a 2002 perspective. Endocr Rev 23: 141–174.
Richter-Unruh A, Korsch E, Hiort O, et al, 2005 Novel insertion frameshift mutation of the LH receptor gene: problematic clinical distinction of Leydig cell hypoplasia from enzyme defects primarily affecting testosterone biosynthesis. Eur J Endocrinol 152: 255–259.
Kossack N, Simoni M, Richter-Unruh A, et al, 2008 Mutations in a novel, cryptic exon of the luteinizing hormone/chorionic gonadotropin receptor gene cause male pseudohermaphroditism. PLoS Med 5: e88.
Segaloff DL, 2009 Diseases associated with mutations of the human lutropin receptor. Prog Mol Biol Transl Sci 89: 97–114.
Simoni M, 1998 Mutations of the G protein-coupled receptors of the hypothalamo-pituitary-gonadal axis. Where do we stand? Eur J Endocrinol 139: 145–147.
Mitre N, Lteif A, 2009 Treatment of familial male-limited precocious puberty (testot oxicosis) with anastrozole and bicalutamide in a boy with a novel mutation in the luteinizing hormone receptor. J Pediatr Endocrinol Metab 22: 1163–1167.
Xie YB, Wang H, Segaloff DL, 1990 Extracellular domain of lutropin/choriogonadotropin receptor expressed in transfected cells binds choriogonadotropin with high affinity. J Biol Chem 265: 21411–21414.
Fan QR, Hendrickson WA, 2005 Structure of human follicle-stimulating hormone in complex with its receptor. Nature 433: 269–277.
Jiang X, Liu H, Chen X, et al, 2012 Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor. PNAS 109: 12491–12496.
Braun T, Schofield PR, Sprengel R, 1991 Amino-terminal leucine-rich repeats in gonadotropin receptors determine hormone selectivity. EMBO J 10: 1885–1890.
Themmen APN, Huhtaniemi IT, 2000 Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function. Endocr Rev 21: 551–583.
Bruysters M, Verhoef-Post M, Themmen AP, 2008 Asp330 and Tyr331 in the C-terminal cysteine-rich region of the luteinizing hormone receptor are key residues in hormone-induced receptor activation. J Biol Chem 283: 25821–25828.
Nagasaki K, Katsumata N, Ogawa Y, et al, 2010 Novel C617Y mutation in the 7th transmembrane segment of luteinizing hormone/choriogonadotropin receptor in a Japanese boy with peripheral precocious puberty. Endocr J 57: 1055–1060.
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Athanasoulia, A.P., Stalla, G.K. & Auer, M.K. Insights into the coexistence of two mutations in the same LHCGR gene locus causing severe Leydig cell hypoplasia. Hormones 13, 424–429 (2014). https://doi.org/10.14310/horm.2002.1497
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DOI: https://doi.org/10.14310/horm.2002.1497