Johanna Känsäkoski1, Rainer Fagerholm2, Eeva-Maria Laitinen3, Kirsi Vaaralahti1, Peter Hackman4, Nelly Pitteloud5, Taneli Raivio1, Johanna Tommiska1. 1. 1] Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland [2] Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland. 2. 1] Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland [2] Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland. 3. Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland. 4. Department of Medical Genetics, Folkhälsan Institute of Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland. 5. Service of Endocrinology, Diabetes and Metabolism, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
Abstract
BACKGROUND: Congenital hypogonadotropic hypogonadism (HH), a rare disorder characterized by absent, partial, or delayed puberty, can be caused by the lack or deficient number of hypothalamic gonadotropin-releasing hormone (GnRH) neurons. SEMA3A was recently implicated in the etiology of the disorder, and Sema7A-deficient mice have a reduced number of GnRH neurons in their brains. METHODS: SEMA3A and SEMA7A were screened by Sanger sequencing in altogether 50 Finnish HH patients (34 with Kallmann syndrome (KS; HH with hyposmia/anosmia) and 16 with normosmic HH (nHH)). In 20 patients, mutation(s) had already been found in genes known to be implicated in congenital HH. RESULTS: Three heterozygous variants (c.458A>G (p.Asn153Ser), c.1253A>G (p.Asn418Ser), and c.1303G>A (p.Val435Ile)) were found in SEMA3A in three KS patients, two of which also had a mutation in FGFR1. Two rare heterozygous variants (c.442C>T (p.Arg148Trp) and c.1421G>A (p.Arg474Gln)) in SEMA7A were found in one male nHH patient with a previously identified KISS1R nonsense variant and one male KS patient with a previously identified mutation in KAL1, respectively. CONCLUSION: Our results suggest that heterozygous missense variants in SEMA3A and SEMA7A may modify the phenotype of KS but most likely are not alone sufficient to cause the disorder.
BACKGROUND:Congenital hypogonadotropic hypogonadism (HH), a rare disorder characterized by absent, partial, or delayed puberty, can be caused by the lack or deficient number of hypothalamic gonadotropin-releasing hormone (GnRH) neurons. SEMA3A was recently implicated in the etiology of the disorder, and Sema7A-deficientmice have a reduced number of GnRH neurons in their brains. METHODS:SEMA3A and SEMA7A were screened by Sanger sequencing in altogether 50 Finnish HHpatients (34 with Kallmann syndrome (KS; HH with hyposmia/anosmia) and 16 with normosmic HH (nHH)). In 20 patients, mutation(s) had already been found in genes known to be implicated in congenital HH. RESULTS: Three heterozygous variants (c.458A>G (p.Asn153Ser), c.1253A>G (p.Asn418Ser), and c.1303G>A (p.Val435Ile)) were found in SEMA3A in three KS patients, two of which also had a mutation in FGFR1. Two rare heterozygous variants (c.442C>T (p.Arg148Trp) and c.1421G>A (p.Arg474Gln)) in SEMA7A were found in one male nHH patient with a previously identified KISS1R nonsense variant and one male KS patient with a previously identified mutation in KAL1, respectively. CONCLUSION: Our results suggest that heterozygous missense variants in SEMA3A and SEMA7A may modify the phenotype of KS but most likely are not alone sufficient to cause the disorder.
Authors: Ulrich Boehm; Pierre-Marc Bouloux; Mehul T Dattani; Nicolas de Roux; Catherine Dodé; Leo Dunkel; Andrew A Dwyer; Paolo Giacobini; Jean-Pierre Hardelin; Anders Juul; Mohamad Maghnie; Nelly Pitteloud; Vincent Prevot; Taneli Raivio; Manuel Tena-Sempere; Richard Quinton; Jacques Young Journal: Nat Rev Endocrinol Date: 2015-07-21 Impact factor: 43.330
Authors: Kim L Keen; Andrew J Petersen; Alexander G Figueroa; Benjamin I Fordyce; Jaeweon Shin; Rachita Yadav; Serkan Erdin; Robert A Pearce; Michael E Talkowski; Anita Bhattacharyya; Ei Terasawa Journal: Endocrinology Date: 2021-09-01 Impact factor: 4.736