title: Idiopathic Hypogonadotropic Hypogonadism Caused by Inactivating Mutations in SRA1.
abstract: OBJECTIVE
  What initiates the pubertal process in humans and other mammals is still unknown. We hypothesized that gene(s) taking roles in triggering human puberty may be identified by studying a cohort of idiopathic hypogonadotropic hypogonadism (IHH).
  
  
  METHODS
  A cohort of IHH cases was studied based on autozygosity mapping coupled with whole exome sequencing.
  
  
  RESULTS
  Our studies revealed three independent families in which IHH/delayed puberty is associated with inactivating SRA1 variants. SRA1 was the first gene to be identified to function through its protein as well as noncoding functional ribonucleic acid products. These products act as co-regulators of nuclear receptors including sex steroid receptors as well as SF-1 and LRH-1, the master regulators of steroidogenesis. Functional studies with a mutant SRA1 construct showed a reduced co-activation of ligand-dependent activity of the estrogen receptor alpha, as assessed by luciferase reporter assay in HeLa cells.
  
  
  CONCLUSIONS
  Our findings strongly suggest that SRA1 gene function is required for initiation of puberty in humans. Furthermore, SRA1 with its alternative products and functionality may provide a potential explanation for the versatility and complexity of the pubertal process.
authors.forename: Leman Damla
authors.initials: LD
authors.lastname: Kotan
authors.forename: Charlton
authors.initials: C
authors.lastname: Cooper
authors.forename: Şükran
authors.initials: Ş
authors.lastname: Darcan
authors.forename: Ian M
authors.initials: IM
authors.lastname: Carr
authors.forename: Samim
authors.initials: S
authors.lastname: Özen
authors.forename: Yi
authors.initials: Y
authors.lastname: Yan
authors.forename: Mohammad K
authors.initials: MK
authors.lastname: Hamedani
authors.forename: Fatih
authors.initials: F
authors.lastname: Gürbüz
authors.forename: Eda
authors.initials: E
authors.lastname: Mengen
authors.forename: İhsan
authors.initials: İ
authors.lastname: Turan
authors.forename: Ayça
authors.initials: A
authors.lastname: Ulubay
authors.forename: Gamze
authors.initials: G
authors.lastname: Akkuş
authors.forename: Bilgin
authors.initials: B
authors.lastname: Yüksel
authors.affiliation: Çukurova University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Endocrinology, Adana, Turkey Phone: +90 322 338 60 60-3148 E-mail: ktopaloglu@cu.edu.tr.
authors.forename: A Kemal
authors.initials: AK
authors.lastname: Topaloğlu
authors.forename: Etienne
authors.initials: E
authors.lastname: Leygue
mesh_terms: D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D008297:Male; D008856:Microscopy, Fluorescence; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011628:Puberty, Delayed / Q000235:genetics*; D012741:Sexual Maturation / Q000235:genetics*; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; C548898:steroid receptor RNA activator, human