Alla A, Ongoth FEM, Tahiri A, Karrou M, Rouf S, Benhaddou H, Kamaoui I, McElreavey K, Latrech H (2022) Novel homozygous inactivating mutation in the luteinizing hormone receptor gene (LHCGR) associated with 46, XY DSD in a Moroccan family. J Pediatr Endocrinol Metab 35:1215–1221

Article  PubMed  Google Scholar 

Ascoli M, Fanelli F, Segaloff DL (2002) The lutropin/choriogonadotropin receptor, a 2002 perspective. Endocr Rev 23:141–174

Article  CAS  PubMed  Google Scholar 

Casarini L, Santi D, Brigante G, Simoni M (2018) Two hormones for one receptor: evolution, Biochemistry, actions, and pathophysiology of LH and hCG. Endocr Rev 39:549–592

Article  PubMed  Google Scholar 

Charmandari E, Guan R, Zhang M, Silveira LG, Fan QR, Chrousos GP, Sertedaki AC, Latronico AC, Segaloff DL (2016) Misfolding ectodomain mutations of the lutropin receptor increase efficacy of hormone stimulation. Mol Endocrinol 30:62–76

Article  CAS  PubMed  Google Scholar 

Hassan HA, Essawi ML, Mekkawy MK, Mazen I (2020) Novel mutations of the LHCGR gene in two families with 46,XY DSD causing Leydig cell hypoplasia I. Horm (Athens) 19:573–579

Article  Google Scholar 

He WB, Du J, Yang XW, Li W, Tang WL, Dai C, Chen YZ, Zhang YX, Lu GX, Lin G, Gong F, Tan YQ (2019) Novel inactivating mutations in the FSH receptor cause premature ovarian insufficiency with resistant ovary syndrome. Reprod Biomed Online 38:397–406

Article  CAS  PubMed  Google Scholar 

Karakaya AA, Çayır A, Unal E, Beştaş A, Solmaz AE, Haspolat YK (2022) A rare cause of primary amenorrhea: LHCGR gene mutations. Eur J Obstet Gynecol Reproductive Biology 272:193–197

Article  Google Scholar 

Kossack N, Troppmann B, Richter-Unruh A, Kleinau G, Gromoll J (2013) Aberrant transcription of the LHCGR gene caused by a mutation in exon 6A leads to Leydig cell hypoplasia type II. Mol Cell Endocrinol 366:59–67

Article  CAS  PubMed  Google Scholar 

Latronico AC, Anasti J, Arnhold IJ, Rapaport R, Mendonca BB, Bloise W, Castro M, Tsigos C, Chrousos GP (1996) Brief report: testicular and ovarian resistance to luteinizing hormone caused by inactivating mutations of the luteinizing hormone-receptor gene. N Engl J Med 334:507–512

Article  CAS  PubMed  Google Scholar 

Laue L, Wu S-M, Kudo M, Hsueh AJ, Cutler GB Jr, Griffin JE, Wilson JD, Brain C, Berry AC, Grant DB (1995) A nonsense mutation of the human luteinizing hormone receptor gene in Leydig cell hypoplasia. Hum Mol Genet 4:1429–1433

Article  CAS  PubMed  Google Scholar 

Laue LL, Wu SM, Kudo M, Bourdony CJ, Cutler GB Jr., Hsueh AJ, Chan WY (1996) Compound heterozygous mutations of the luteinizing hormone receptor gene in Leydig cell hypoplasia. Mol Endocrinol 10:987–997

CAS  PubMed  Google Scholar 

Martens JW, Verhoef-Post M, Abelin N, Ezabella M, Toledo SP, Brunner HG, Themmen AP (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

Article  CAS  PubMed  Google Scholar 

Mazen I, Mekkawy M, Kamel A, Essawi M, Hassan H, Abdel-Hamid M, Amr K, Soliman H, El-Ruby M, Torky A, El Gammal M, Elaidy A, Bashamboo A, McElreavey K (2021) Advances in genomic diagnosis of a large cohort of Egyptian patients with disorders of sex development. Am J Med Genet A 185:1666–1677

Article  CAS  PubMed  Google Scholar 

McFarland K, Sprengel R, Phillips HS, Köhler M, Rosemblit N, Nikolics K, Segaloff DL, Seeburg PH (1989) Lutropin-choriogonadotropin receptor: an unusual member of the G protein-coupled receptor family. Science 245:494–499

Article  CAS  PubMed  Google Scholar 

Min L, Ascoli M (2000) Effect of activating and inactivating mutations on the phosphorylation and trafficking of the human lutropin/choriogonadotropin receptor. Mol Endocrinol 14:1797–1810

Article  CAS  PubMed  Google Scholar 

Muller T, Gromoll J, Simoni M (2003) Absence of exon 10 of the human luteinizing hormone (LH) receptor impairs LH, but not human chorionic gonadotropin action. J Clin Endocrinol Metab 88:2242–2249

Article  CAS  PubMed  Google Scholar 

Nagashima T, Murakami M, Onigata K, Morimura T, Nagashima K, Mori M, Morikawa A (2001) Novel inactivating missense mutations in the thyrotropin receptor gene in Japanese children with resistance to thyrotropin. Thyroid 11:551–559

Article  CAS  PubMed  Google Scholar 

Pandurangan AP, Blundell TL (2020) Prediction of impacts of mutations on protein structure and interactions: SDM, a statistical approach, and mCSM, using machine learning. Protein Sci 29:247–257

Article  CAS  PubMed  Google Scholar 

Parthiban V, Gromiha MM, Schomburg D (2006) CUPSAT: prediction of protein stability upon point mutations. Nucleic Acids Res 34:W239–242

Article  CAS  PubMed  PubMed Central  Google Scholar 

Pires DE, Ascher DB, Blundell TL (2014) DUET: a server for predicting effects of mutations on protein stability using an integrated computational approach. Nucleic Acids Res 42:W314–319

Article  CAS  PubMed  PubMed Central  Google Scholar 

Potorac I, Trehan A, Szymańska K, Fudvoye J, Thiry A, Huhtaniemi I, Daly AF, Beckers A, Parent A-S, Rivero-Müller A (2019) Compound heterozygous mutations in the luteinizing hormone receptor signal peptide causing 46, XY disorder of sex development. Eur J Endocrinol 181:K11–K20

Article  CAS  PubMed  Google Scholar 

Qiao J, Han B (2019) Diseases caused by mutations in luteinizing hormone/chorionic gonadotropin receptor. Prog Mol Biol Transl Sci 161:69–89

Article  CAS  PubMed  Google Scholar 

Quigley CA, De Bellis A, Marschke KB, el-Awady MK, Wilson EM, French FS (1995) Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr Rev 16:271–321

CAS  PubMed  Google Scholar 

Richter-Unruh A, Martens J, Verhoef‐Post M, Wessels H, Kors W, Sinnecker G, Boehmer A, Drop S, Toledo S, Brunner H (2002) Leydig cell hypoplasia: cases with new mutations, new polymorphisms and cases without mutations in the luteinizing hormone receptor gene. Clin Endocrinol 56:103–112

Article  CAS  Google Scholar 

Rivero-Muller A, Huhtaniemi I (2022) Genetic variants of gonadotrophins and their receptors: impact on the diagnosis and management of the infertile patient. Best Pract Res Clin Endocrinol Metab 36:101596

Article  CAS  PubMed  Google Scholar 

Rodien P, Cetani F, Costagliola S, Tonacchera M, Duprez L, Minegishi T, Govaerts C, Vassart G (1998) Evidences for an allelic variant of the human LC/CG receptor rather than a gene duplication: functional comparison of wild-type and variant receptors. J Clin Endocrinol Metab 83:4431–4434

CAS  PubMed  Google Scholar 

Rutkowski DT, Ott CM, Polansky JR, Lingappa VR (2003) Signal sequences initiate the pathway of maturation in the endoplasmic reticulum lumen. J Biol Chem 278:30365–30372

Article  CAS  PubMed  Google Scholar 

Sinha SK, Bhangoo A, Ten S, Gromoll J (2011) Leydig cell hypoplasia due to inactivating luteinizing hormone/chorionic gonadotropin receptor gene mutation presenting as a 46, XY DSD. In: Hormonal and Genetic Basis of Sexual Differentiation Disorders and Hot Topics in Endocrinology: Proceedings of the 2nd World Conference. Springer, pp 147–148

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

Article  CAS  Google Scholar 

Toledo SP, Arnhold IJ, Luthold W, Russo EM, Saldanha PH (1985) Leydig cell hypoplasia determining familial hypergonadotropic hypogonadism. Prog Clin Biol Res 200:311–314

CAS  PubMed  Google Scholar 

Troppmann B, Kleinau G, Krause G, Gromoll J (2013) Structural and functional plasticity of the luteinizing hormone/choriogonadotrophin receptor. Hum Reprod Update 19:583–602

Article  CAS  PubMed  Google Scholar 

Ulloa-Aguirre A, Zarinan T, Dias JA, Conn PM (2014) Mutations in G protein-coupled receptors that impact receptor trafficking and reproductive function. Mol Cell Endocrinol 382:411–423

Article  CAS  PubMed  Google Scholar 

Venselaar H, Te Beek TA, Kuipers RK, Hekkelman ML, Vriend G (2010) Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinformatics 11:548

Article  PubMed  PubMed Central  Google Scholar 

Vezzoli V, Duminuco P, Vottero A, Kleinau G, Schulein R, Minari R, Bassi I, Bernasconi S, Persani L, Bonomi M (2015) A new variant in signal peptide of the human luteinizing hormone receptor (LHCGR) affects receptor biogenesis causing leydig cell hypoplasia. Hum Mol Genet 24:6003–6012

Article  CAS  PubMed  Google Scholar 

Wang W, Guo DY, Tao YX (2019) Therapeutic strategies for diseases caused by loss-of-function mutations in G protein-coupled receptors. Prog Mol Biol Transl Sci 161:181–210

Article  CAS  PubMed  Google Scholar 

Wu S-M, Hallermeier KM, Laue L, Brain C, Berry AC, Grant DB, Griffin JE, Wilson JD, Cutler GB Jr, Chan W-Y (1998) Inactivation of the luteinizing hormone/chorionic gonadotropin receptor by an insertional mutation in Leydig cell hypoplasia. Mol Endocrinol 12:1651–1660

Article  CAS  PubMed  Google Scholar 

Yuan P, He Z, Zheng L, Wang W, Li Y, Zhao H, Zhang VW, Zhang Q, Yang D (2017) Genetic evidence of ‘genuine’ empty follicle syndrome: a novel effective mutation in the LHCGR gene and review of the literature. Hum Reprod 32:944–953

Article