title: Phenotypic spectrum of POLR3B mutations: isolated hypogonadotropic hypogonadism without neurological or dental anomalies.
abstract: A constellation of neurodegenerative disorders exists (Gordon Holmes syndrome, 4H leucodystrophy, Boucher-Neuhauser syndrome) in which patients suffer from both neurological disease (typically manifested by ataxia) and reproductive failure (idiopathic hypogonadotropic hypogonadism (IHH)). POLR3B, which encodes the second largest subunit of RNA polymerase III (pol III), and POLR3A, which forms the pol III catalytic centre, are associated with 4H leucodystrophy.
  
  
  
  Whole exome sequencing was performed on a large cohort of subjects with IHH (n=565). Detailed neuroendocrine studies were performed in some individuals within this cohort.
  
  
  
  Four individuals (two of them siblings) were identified with two rare nucleotide variants in POLR3B. On initial evaluation, all subjects were free of neurological disease. One patient underwent treatment with exogenous pulsatile gonadotropin-releasing hormone for 8 weeks which failed to result in normalisation of his sex steroid milieu due to pituitary resistance.
  
  
  
  These findings suggest that the spectrum of phenotypes resulting from POLR3B mutations is wider than previously believed and that POLR3B can be associated exclusively with disorders characterised by abnormal gonadotropin secretion.
authors: Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors: Mary R
authors: MR
authors: Richards
authors: Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors: Lacey
authors: L
authors: Plummer
authors: Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.|Division of Endocrinology, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
authors: Yee-Ming
authors: YM
authors: Chan
authors: Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors: Margaret F
authors: MF
authors: Lippincott
authors: Institute for Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
authors: Richard
authors: R
authors: Quinton
authors: Clinical Center of Endocrinology and Gerontology, Medical University of Sofia, Sofia, Bulgaria.
authors: Philip
authors: P
authors: Kumanov
authors: Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors: Stephanie B
authors: SB
authors: Seminara
mesh_terms: D000293:Adolescent; D059472:Exome / Q000235:genetics; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000627:therapeutic use; D006801:Humans; D007006:Hypogonadism / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D055099:Neuroendocrine Cells / Q000187:drug effects; D012320:RNA Polymerase III / Q000235:genetics*; D055815:Young Adult
chemical_list: D007987:Gonadotropin-Releasing Hormone; C468558:POLR3B protein, human; D012320:RNA Polymerase III
keywords: 4H Leukodystrophy; Ataxia; Idiopathic Hypogonadotropic Hypogonadism; POLR3B; whole exome sequencing