title: Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome.
abstract: BACKGROUND
  Physiological activation of the prokineticin pathway has a critical role in olfactory bulb morphogenesis and GnRH secretion in mice.
  
  
  OBJECTIVE
  To investigate PROK2 and PROKR2 mutations in patients with hypogonadotropic hypogonadism (HH) associated or not with olfactory abnormalities.
  
  
  METHODS
  We studied 107 Brazilian patients with HH (63 with Kallmann syndrome and 44 with normosmic HH) and 100 control individuals. The coding regions of PROK2 and PROKR2 were amplified by PCR followed by direct automatic sequencing.
  
  
  RESULTS
  In PROK2, two known frameshift mutations were identified. Two brothers with Kallmann syndrome harbored the homozygous p.G100fsX121 mutation, whereas one male with normosmic HH harbored the heterozygous p.I55fsX56 mutation. In PROKR2, four distinct mutations (p.R80C, p.Y140X, p.L173R, and p.R268C) were identified in five patients with Kallmann syndrome and in one patient with normosmic HH. These mutations were not found in the control group. The p.R80C, p.L173R, and p.R268C missense mutations were identified in the heterozygous state in the HH patients and in their asymptomatic first-degree relatives. In addition, no mutations of FGFR1, KAL1, GnRHR, KiSS-1, or GPR54 were identified in these patients. Notably, the new nonsense mutation (p.Y140X) was identified in the homozygous state in an anosmic boy with micropenis, bilateral cryptorchidism, and high-arched palate. His asymptomatic parents were heterozygous for this severe defect.
  
  
  CONCLUSIONS
  We expanded the repertoire of PROK2 and PROKR2 mutations in patients with HH. In addition, we show that PROKR2 haploinsufficiency is not sufficient to cause Kallmann syndrome or normosmic HH, whereas homozygous loss-of-function mutations either in PROKR2 or PROK2 are sufficient to cause disease phenotype, in accordance with the Prokr2 and Prok2 knockout mouse models.
authors.affiliation: Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Disciplina de Endocrinologia e Metabologia, 05403-900 Sao Paulo, Brasil.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Abreu
authors.forename: Ericka Barbosa
authors.initials: EB
authors.lastname: Trarbach
authors.forename: Margaret
authors.initials: M
authors.lastname: de Castro
authors.forename: Elaine Maria
authors.initials: EM
authors.lastname: Frade Costa
authors.forename: Beatriz
authors.initials: B
authors.lastname: Versiani
authors.forename: Maria Tereza
authors.initials: MT
authors.lastname: Matias Baptista
authors.forename: Heraldo Mendes
authors.initials: HM
authors.lastname: Garmes
authors.forename: Berenice Bilharinho
authors.initials: BB
authors.lastname: Mendonca
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Latronico
mesh_terms: D000293:Adolescent; D000328:Adult; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005768:Gastrointestinal Hormones / Q000235:genetics*; D005808:Genes, Recessive; D006801:Humans; D007006:Hypogonadism / Q000235:genetics; D040582:Inheritance Patterns; D017436:Kallmann Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000502:physiology; D009479:Neuropeptides / Q000235:genetics*; D010375:Pedigree; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D018000:Receptors, Peptide / Q000235:genetics*
chemical_list: D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C423608:PROK2 protein, human; C470838:PROKR2 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide