title: Identification of Novel PROP1 and POU1F1 Mutations in Patients with Combined Pituitary Hormone Deficiency.
abstract: Growth hormone deficiency (GHD) results from variations affecting the production and release of growth hormone (GH) and is of 2 types: isolated growth hormone deficiency (IGHD) and combined pituitary hormone deficiency (CPHD). IGHD results from mutations inGH1andGHRHRwhile CPHD is associated with defects in transcription factor genesPROP1,POU1F1, andHESX1.The present study reports on screening ofPOU1F1,PROP1, andHESX1in CPHD patients and the novel variations identified. Fifty-one CPHD patients from 49 unrelated families clinically diagnosed on the basis of biochemical and imaging investigations along with 100 controls were enrolled. Detailed family history was noted from all participants and 5 ml blood samples drawn were processed for DNA isolation followed by direct sequencing ofPOU1F1,PROP1, andHESX1genes. Of the 51 patients, 8 were females and 43 were males. Mean height standard deviation score (SDS) and weight SDS were -5.50 and -2.76, respectively. Thirty-six of the 51 patients underwent MRI of which 9 (25%) had normal pituitary structure and morphology while 27 (75%) showed abnormalities. Molecular analysis revealed 10 (20%) patients to havePOU1F1andPROP1mutations/variations of which 5 were novel and 2 previously reported. No mutations were identified inHESX1.The novel variations identified were absent in the 100 healthy individuals screened and the control database Exome Aggregation Consortium (ExAC). ReportedPOU1F1andPROP1mutation hotspots were absent in our patients. Instead, novelPOU1F1changes were identified suggesting existence of a distinct mutation spectrum in our population.
authors.affiliation: Laboratory of Cyto-Molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: S
authors.initials: S
authors.lastname: Birla
authors.affiliation: Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: R
authors.initials: R
authors.lastname: Khadgawat
authors.affiliation: Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: V P
authors.initials: VP
authors.lastname: Jyotsna
authors.affiliation: Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: V
authors.initials: V
authors.lastname: Jain
authors.affiliation: Department of Endocrinology and Metabolism, Army Hospital (Referral & Research), Delhi Cantonment, India.
authors.forename: M K
authors.initials: MK
authors.lastname: Garg
authors.affiliation: Department of Radio-Diagnosis, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: A S
authors.initials: AS
authors.lastname: Bhalla
authors.affiliation: Laboratory of Cyto-Molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: A
authors.initials: A
authors.lastname: Sharma
mesh_terms: D001483:Base Sequence; D002648:Child; D003062:Codon / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007018:Hypopituitarism / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D050817:Transcription Factor Pit-1 / Q000235:genetics*
chemical_list: D003062:Codon; C489736:HESX1 protein, human; D018398:Homeodomain Proteins; C494187:POU1F1 protein, human; C102134:Prophet of Pit-1 protein; D050817:Transcription Factor Pit-1