title: A new variant in signal peptide of the human luteinizing hormone receptor (LHCGR) affects receptor biogenesis causing leydig cell hypoplasia.
abstract: The human luteinizing hormone/chorionic gonadotropin receptor (LHCGR) plays a fundamental role in male and female reproduction. In males, loss-of-function mutations in LHCGR have been associated with distinct degrees of impairment in pre- and postnatal testosterone secretion resulting in a variable phenotypic spectrum, classified as Leydig cell hypoplasia (LCH) type 1 (complete LH resistance and disorder of sex differentiation) and type 2 (partial LH resistance with impaired masculinization and fertility). Here, we report the case of an adolescent who came to the pediatric endocrinologist at the age of 12 years old for micropenis and cryptorchidism. Testis biopsy showed profound LCH and absent germinal line elements (Sertoli-only syndrome). The sequence analysis of the LHCGR gene showed the presence of a compound heterozygosity, being one variation, c.1847C>A p.S616Y, already described in association to Hypergonadotropic Hypogonadism, and the other, c.29 C>T p.L10P, a new identified variant in the putative signal peptide (SP) of LHCGR. Functional and structural studies provide first evidence that LHCGR have a functional and cleavable SP required for receptor biogenesis. Moreover, we demonstrate the pathogenic role of the novel p.L10P allelic variant, which has to be considered a loss-of-function mutation significantly contributing, in compound heterozygosity with p.S616Y, to the LCH type 2 observed in our patient.
authors.affiliation: Dipartimento di Scienze Cliniche e di Comunità and Divisione di Medicina Generale ad Indirizzo Endocrino-Metabolico e Laboratorio di Ricerche Endocrino-Metaboliche, Istituto Auxologico Italiano IRCCS, Cusano Milanino, MI, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Vezzoli
authors.affiliation: Divisione di Medicina Generale ad Indirizzo Endocrino-Metabolico e Laboratorio di Ricerche Endocrino-Metaboliche, Istituto Auxologico Italiano IRCCS, Cusano Milanino, MI, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Duminuco
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Università Degli Studi di Parma, Parma, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Vottero
authors.affiliation: Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin, Berlin, Germany and.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Kleinau
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Schülein
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Università Degli Studi di Parma, Parma, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Minari
authors.affiliation: Dipartimento di Scienze Della Salute, Università di Milano, Milan, MI, Italy, Divisione di Medicina Generale ad Indirizzo Endocrino-Metabolico e Laboratorio di Ricerche Endocrino-Metaboliche, Istituto Auxologico Italiano IRCCS, Cusano Milanino, MI, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bassi
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Università Degli Studi di Parma, Parma, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Bernasconi
authors.affiliation: Dipartimento di Scienze Cliniche e di Comunità and Divisione di Medicina Generale ad Indirizzo Endocrino-Metabolico e Laboratorio di Ricerche Endocrino-Metaboliche, Istituto Auxologico Italiano IRCCS, Cusano Milanino, MI, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Persani
authors.affiliation: Dipartimento di Scienze Cliniche e di Comunità and Divisione di Medicina Generale ad Indirizzo Endocrino-Metabolico e Laboratorio di Ricerche Endocrino-Metaboliche, Istituto Auxologico Italiano IRCCS, Cusano Milanino, MI, Italy, marco.bonomi@unimi.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Bonomi
mesh_terms: D000818:Animals; D002648:Child; D003456:Cryptorchidism / Q000235:genetics; D004252:DNA Mutational Analysis; D058490:Disorder of Sex Development, 46,XY / Q000235:genetics*; D005832:Genital Diseases, Male / Q000235:genetics; D006801:Humans; D007021:Hypospadias / Q000235:genetics; D008297:Male; D009154:Mutation; D010413:Penis / Q000002:abnormalities; D021382:Protein Sorting Signals / Q000235:genetics*; D011974:Receptors, LH / Q000096:biosynthesis / Q000235:genetics*; D013737:Testis / Q000002:abnormalities*
chemical_list: D021382:Protein Sorting Signals; D011974:Receptors, LH