title: Variations in PROKR2, but not PROK2, are associated with hypopituitarism and septo-optic dysplasia.
abstract: BACKGROUND
  Loss-of-function mutations in PROK2 and PROKR2 have been implicated in Kallmann syndrome (KS), characterized by hypogonadotropic hypogonadism and anosmia. Recent data suggest overlapping phenotypes/genotypes between KS and congenital hypopituitarism (CH), including septo-optic dysplasia (SOD).
  
  
  OBJECTIVE
  We screened a cohort of patients with complex forms of CH (n = 422) for mutations in PROK2 and PROKR2.
  
  
  RESULTS
  We detected 5 PROKR2 variants in 11 patients with SOD/CH: novel p.G371R and previously reported p.A51T, p.R85L, p.L173R, and p.R268C-the latter 3 being known functionally deleterious variants. Surprisingly, 1 patient with SOD was heterozygous for the p.L173R variant, whereas his phenotypically unaffected mother was homozygous for the variant. We sought to clarify the role of PROKR2 in hypothalamopituitary development through analysis of Prokr2(-/-) mice. Interestingly, these revealed predominantly normal hypothalamopituitary development and terminal cell differentiation, with the exception of reduced LH; this was inconsistent with patient phenotypes and more analogous to the healthy mother, although she did not have KS, unlike the Prokr2(-/-) mice.
  
  
  CONCLUSIONS
  The role of PROKR2 in the etiology of CH, SOD, and KS is uncertain, as demonstrated by no clear phenotype-genotype correlation; loss-of-function variants in heterozygosity or homozygosity can be associated with these disorders. However, we report a phenotypically normal parent, homozygous for p.L173R. Our data suggest that the variants identified herein are unlikely to be implicated in isolation in these disorders; other genetic or environmental modifiers may also impact on the etiology. Given the phenotypic variability, genetic counseling may presently be inappropriate.
authors: Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, University College London (UCL)-Institute of Child Health, London WC1N 1EH, United Kingdom.
authors: Mark J
authors: MJ
authors: McCabe
authors: Carles
authors: C
authors: Gaston-Massuet
authors: Louise C
authors: LC
authors: Gregory
authors: Kyriaki S
authors: KS
authors: Alatzoglou
authors: Vaitsa
authors: V
authors: Tziaferi
authors: Oualid
authors: O
authors: Sbai
authors: Philippe
authors: P
authors: Rondard
authors: Koh-hei
authors: KH
authors: Masumoto
authors: Mamoru
authors: M
authors: Nagano
authors: Yasufumi
authors: Y
authors: Shigeyoshi
authors: Marija
authors: M
authors: Pfeifer
authors: Tony
authors: T
authors: Hulse
authors: Charles R
authors: CR
authors: Buchanan
authors: Nelly
authors: N
authors: Pitteloud
authors: Juan-Pedro
authors: JP
authors: Martinez-Barbera
authors: Mehul T
authors: MT
authors: Dattani
mesh_terms: D000818:Animals; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005768:Gastrointestinal Hormones / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D057809:HEK293 Cells; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007018:Hypopituitarism / Q000151:congenital / Q000235:genetics*; D007030:Hypothalamo-Hypophyseal System / Q000196:embryology / Q000502:physiology; D007223:Infant; D007231:Infant, Newborn; D017436:Kallmann Syndrome / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D018000:Receptors, Peptide / Q000235:genetics*; D025962:Septo-Optic Dysplasia / 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
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