Mutation screening of SEMA3A and SEMA7A in patients with congenital hypogonadotropic hypogonadism.
- Känsäkoski J 1] Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland [2] Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.
- Fagerholm R 1] Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland [2] Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland.
- Laitinen EM Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.
- Vaaralahti K 1] Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland [2] Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.
- Hackman P Department of Medical Genetics, Folkhälsan Institute of Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
- Pitteloud N Service of Endocrinology, Diabetes and Metabolism, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
- Raivio T 1] Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland [2] Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.
- Tommiska J 1] Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland [2] Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.
- 2014-02-14
Published in:
- Pediatric research. - 2014
Antigens, CD
DNA Mutational Analysis
Female
Finland
GPI-Linked Proteins
Genetic Variation
Gonadotropin-Releasing Hormone
Heterozygote
Humans
Hypogonadism
Kallmann Syndrome
Male
Mutation
Mutation, Missense
Neurons
Phenotype
Semaphorin-3A
Semaphorins
English
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.
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.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1038/pr.2014.23
- PMID 24522099
- Persistent URL
- https://sonar.ch/global/documents/122950
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