title: PROP1 gene analysis in Portuguese patients with combined pituitary hormone deficiency.
abstract: OBJECTIVE
  Mutations of the PROP1 gene lead to combined pituitary hormone deficiency (CPHD), which is characterized by a deficiency of GH, TSH, LH/FSH, PRL and, less frequently, ACTH. This study was undertaken to investigate the molecular defect in a cohort of patients with CPHD.
  
  
  METHODS
  A multicentric study involving 46 cases of CPHD (17 familial cases belonging to seven kindreds and 29 sporadic cases) selected on the basis of clinical and hormonal evidence of GH deficiency, central hypothyroidism and hypogonadotrophic hypogonadism, in the absence of an identified cause of hypopituitarism. Mutations of PROP1 were investigated by DNA sequencing. Clinical, hormonal and neuroradiological data were collected at each centre.
  
  
  RESULTS
  PROP1 mutations were identified in all familial cases: five kindreds presented a c. 301-302delAG mutation, one kindred presented a c. 358C --> T (R120C) mutation and one presented a previously unreported initiation codon mutation, c. 2T --> C. Of the 29 sporadic cases, only two (6.9%) presented PROP1 germline mutations (c. 301-302delAG, in both). Phenotypic variability was observed among patients with the same mutations, particularly the presence and age of onset of hypocortisolism, the levels of PRL and the results of pituitary imaging. One patient presented a sellar mass that persisted into adulthood.
  
  
  CONCLUSIONS
  This is the first report of a mutation in the initiation codon of the PROP1 gene and this further expands the spectrum of known mutations responsible for CPHD. The low mutation frequency observed in sporadic cases may be due to the involvement of other unidentified acquired or genetic causes.
authors.affiliation: Serviço de Genética Médica, Faculdade de Medicina da Universidade de Coimbra, Coimbra, Portugal. mlemos@ci.uc.pt
authors.forename: Manuel C
authors.initials: MC
authors.lastname: Lemos
authors.forename: Leonor
authors.initials: L
authors.lastname: Gomes
authors.forename: Margarida
authors.initials: M
authors.lastname: Bastos
authors.forename: Valeriano
authors.initials: V
authors.lastname: Leite
authors.forename: Edward
authors.initials: E
authors.lastname: Limbert
authors.forename: Davide
authors.initials: D
authors.lastname: Carvalho
authors.forename: Conceição
authors.initials: C
authors.lastname: Bacelar
authors.forename: Mariana
authors.initials: M
authors.lastname: Monteiro
authors.forename: Fernando
authors.initials: F
authors.lastname: Fonseca
authors.forename: Ana
authors.initials: A
authors.lastname: Agapito
authors.forename: João J
authors.initials: JJ
authors.lastname: Castro
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Regateiro
authors.forename: Manuela
authors.initials: M
authors.lastname: Carvalheiro
mesh_terms: D000293:Adolescent; D000324:Adrenocorticotropic Hormone / Q000172:deficiency; D000328:Adult; D017668:Age of Onset; D000368:Aged; D003062:Codon; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D006854:Hydrocortisone / Q000172:deficiency; D007018:Hypopituitarism / Q000235:genetics* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D010902:Pituitary Gland / Q000473:pathology; D010907:Pituitary Hormones / Q000172:deficiency*; D011174:Portugal; D011388:Prolactin / Q000172:deficiency
chemical_list: D003062:Codon; D018398:Homeodomain Proteins; D010907:Pituitary Hormones; C102134:Prophet of Pit-1 protein; D000324:Adrenocorticotropic Hormone; D011388:Prolactin; D006854:Hydrocortisone