We also found combinations of de novo (SLC20A1/SLC15A4) and transmitted variants (GLI2/LHX3) in the same individuals, leading to the full-blown CPHD phenotype.
To test the role of wtPIT-1 (PITWT) or PIT-1 (R271W) (PIT271) in somatolactotroph cells, we established, using inducible lentiviral vectors, sublines of GH4C1 somatotroph cells that allow the blockade of the expression of endogenous PIT-1 and/or the expression of PITWT or PIT271, a dominant negative mutant of PIT-1 responsible for Combined Pituitary Hormone Deficiency in patients.
Anti-PIT-1 (pituitary-specific transcription factor 1) antibody syndrome is a novel clinical entity that presents an acquired combined pituitary hormone deficiency characterized by a specific defect in growth hormone, prolactin, and thyroid-stimulating hormone.
The genetic form of CPHD may originate from mutations in pituitary transcription factor (PTF) genes and the pituitary image in these cases may give a clue of what PTF is most probably mutated: defects in LHX4 are usually associated with ectopic posterior pituitary (EPP); defects in LHX3, PIT1, and PROP1, with normally placed posterior pituitary (NPPP); HESX1 mutations are associated with both.
PROP1 and POU1F: Recessive mutations within the pituitary-specific transcription factor Prophet of Pit1, or PROP1, are associated with CPHD (GH, prolactin [PRL] and TSH deficiency with additional LH and FSH deficiency).
It was found to be a major developmental regulator, because natural Pit-1 gene mutations cause a dwarf phenotype in mice and cause combined pituitary hormone deficiency associated with pituitary hypoplasia in humans.
From these studies, we suggest that CBP/p300 recruitment and Pit-1 dimerization are necessary for Pit-1 target gene activation and are important in the pathogenesis of CPHD.
Mutations in the genes encoding the transcription factors PROP1 and POUF-1 (Pit-1) have been reported as common causes of combined pituitary hormone deficiency (CPHD), and HESX1 mutations have been identified in children with septo-optic dysplasia (SOD).There are few data on UK children.
MR evidence of normal or small anterior pituitary gland, enlarged empty sella, pituitary hyperplasia and/or intrasellar or suprasellar mass when associated with combined pituitary hormone deficiency call for molecular analysis of Pit-1, Prop-1, Hesx-1, or Lhx-3.
A number of developmental genes known to be important for organ commitment and cell differentiation and proliferation (HESX1, LHX3, LHX4, PROP1 and PIT1) have been implicated in CPHD with or without other syndromic features.
Familial combined pituitary hormone deficiency due to a novel mutation R99Q in the hot spot region of Prophet of Pit-1 presenting as constitutional growth delay.
The pituitary transcription factor Pit-1 is expressed during the later differentiation stages of anterior pituitary development and Pit-1 mutations have been identified as the cause of a combined pituitary hormone deficiency (CPHD) for GH, prolactin and TSH.
In the present report, we provide in vivo evidence that retinoic acid induction of the Pit-1 gene can be impaired by a Pit-1 gene mutation, suggesting a new molecular mechanism for combined pituitary hormone deficiency in man.
Pit-1 gene mutations result in complete growth hormone (GH) and PRL deficiencies and variable degrees of TSH deficiency, producing the clinical syndrome of combined pituitary hormone deficiency (CPHD).
My laboratory and others have recently described several patients with combined pituitary hormone deficiency (CPHD) due to point mutations in the pit-1 gene.
This case is the first demonstration of CPHD due to compound heterozygous Pit-1 point mutations, as most reported cases of the CPHD phenotype involve either the dominant negative R271W allele or homozygosity for recessive Pit-1 mutations.
Mutations in the Pit-1 gene result in insufficient expression of this factor, accounting for a form of combined pituitary hormone deficiency for growth hormone (GH), prolactin, and thyroid-stimulating hormone.