title: Contribution of human growth hormone-releasing hormone receptor (GHRHR) gene sequence variation to isolated severe growth hormone deficiency (ISGHD) and normal adult height.
abstract: OBJECTIVE
  Molecular causes of isolated severe growth hormone deficiency (ISGHD) in several genes have been established. The aim of this study was to analyse the contribution of growth hormone-releasing hormone receptor (GHRHR) gene sequence variation to GH deficiency in a series of prepubertal ISGHD patients and to normal adult height.
  
  
  METHODS
  A systematic GHRHR gene sequence analysis was performed in 69 ISGHD patients and 60 normal adult height controls (NAHC). Four GHRHR single-nucleotide polymorphisms (SNPs) were genotyped in 248 additional NAHC. An analysis was performed on individual SNPs and combined genotype associations with diagnosis in ISGHD patients and with height-SDS in NAHC.
  
  
  RESULTS
  Twenty-one SNPs were found. P3, P13, P15 and P20 had not been previously described. Patients and controls shared 12 SNPs (P1, P2, P4-P11, P16 and P21). Significantly different frequencies of the heterozygous genotype and alternate allele were detected in P9 (exon 4, rs4988498) and P12 (intron 6, rs35609199); P9 heterozygous genotype frequencies were similar in patients and the shortest control group (heights between -2 and -1 SDS) and significantly different in controls (heights between -1 and +2 SDS). GHRHR P9 together with 4 GH1 SNP genotypes contributed to 6·2% of height-SDS variation in the entire 308 NAHC.
  
  
  CONCLUSIONS
  This study established the GHRHR gene sequence variation map in ISGHD patients and NAHC. No evidence of GHRHR mutation contribution to ISGHD was found in this population, although P9 and P12 SNP frequencies were significantly different between ISGHD and NAHC. Thus, the gene sequence may contribute to normal adult height, as demonstrated in NAHC.
authors.affiliation: Departments of Paediatrics and Paediatric Endocrinology Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Hospital Vall d'Hebron, Autonomous University of Barcelona, CIBERER (Centre for Biomedical Research on Rare Diseases), Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Camats
authors.forename: Mónica
authors.initials: M
authors.lastname: Fernández-Cancio
authors.forename: Antonio
authors.initials: A
authors.lastname: Carrascosa
authors.forename: Pilar
authors.initials: P
authors.lastname: Andaluz
authors.forename: M Ángeles
authors.initials: MÁ
authors.lastname: Albisu
authors.forename: María
authors.initials: M
authors.lastname: Clemente
authors.forename: Miquel
authors.initials: M
authors.lastname: Gussinyé
authors.forename: Diego
authors.initials: D
authors.lastname: Yeste
authors.forename: Laura
authors.initials: L
authors.lastname: Audí
mesh_terms: D001827:Body Height / Q000235:genetics / Q000502:physiology; D002648:Child; D004393:Dwarfism, Pituitary / Q000097:blood / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018013:Receptors, Neuropeptide / Q000235:genetics*; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics*
chemical_list: D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D019382:Human Growth Hormone; C048250:somatotropin releasing hormone receptor