Article

A novel nonsense mutation in the Pit-1 gene: evidence for a gene dosage effect.

Division of Endocrinology, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Journal of Clinical Endocrinology &amp Metabolism (impact factor: 6.5). 04/2003; 88(3):1241-7. pp.1241-7
Source: PubMed

ABSTRACT The POU transcription factor Pit-1 functions in the development of somatotrophs, lactotrophs, and thyrotrophs of the anterior pituitary gland. It also plays a role in cell-specific gene expression and regulation of the gene products from these cell types, GH, prolactin, and TSH, respectively. In the present report we studied a patient with severe growth failure. Provocative studies revealed undetectable GH, prolactin, and TSH levels, and her pituitary gland was hypoplastic on magnetic resonance imaging. She had a novel homozygous nonsense mutation in the 3' end of the first alpha-helix of the POU-specific domain of the Pit-1 gene. This mutation results in a truncated protein with loss of most of the Pit-1 DNA-binding domains. Interestingly, her parents, who each have one mutant allele, have evidence of mild endocrine dysfunction. Thus, two normal copies of the Pit-1 gene appear necessary for full Pit-1 gene function.

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    Article: The role of transcription factors implicated in anterior pituitary development in the aetiology of congenital hypopituitarism.
    Daniel Kelberman, Mehul T Dattani
    [show abstract] [hide abstract]
    ABSTRACT: The anterior pituitary gland is a central regulator of growth, reproduction and homeostasis, and is the end-product of a carefully orchestrated pattern of expression of signalling molecules and transcription factors leading to the development of this complex organ secreting six hormones from five different cell types. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of combined pituitary hormone deficiency (CPHD). These include the transcription factors HESX1, PROP1, POU1FI, LHX3, LHX4, TBX19 (TPIT), SOX3 and SOX2. The expression pattern of these transcription factors, their interaction with co-factors and their impact on target genes dictate the phenotype that results when the gene encoding the relevant transcription factor is mutated. The highly variable phenotype may consist of isolated hypopituitarism, or more complex disorders such as septo-optic dysplasia (SOD) and holoprosencephaly. Since mutations in any one transcription factor are uncommon, and since the overall incidence of mutations in known transcription factors is low in patients with CPHD, it is clear that many genes remain to be identified, and characterization of these will further elucidate the pathogenesis of these complex conditions, and also shed light on normal pituitary development.
    Annals of Medicine 02/2006; 38(8):560-77. · 3.52 Impact Factor
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Keywords

anterior pituitary gland
 
cell types
 
cell-specific gene expression
 
first alpha-helix
 
full Pit-1 gene function
 
magnetic resonance imaging
 
mild endocrine dysfunction
 
mutant allele
 
mutation results
 
novel homozygous nonsense mutation
 
parents
 
Pit-1 DNA-binding domains
 
Pit-1 gene
 
pituitary gland
 
POU transcription factor Pit-1 functions
 
POU-specific domain
 
present report
 
prolactin
 
Provocative studies
 
truncated protein