MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency

Over the last 5 years, new actors involved in the pathogenesis of combined pituitary hormone deficiency in humans have been reported: they included a member of the immunoglobulin superfamily glycoprotein and ciliary G protein-coupled receptors, as well as new transcription factors and signalling molecules. New modes of inheritance for alterations of genes encoding transcription factors have also been described. Finally, actors known to be involved in a very specific phenotype (hypogonadotroph hypogonadism for instance) have been identified in a wider range of phenotypes. These data thus suggest that new mechanisms could explain the low rate of aetiological identification in this heterogeneous group of diseases. Taking into account the fact that several reviews have been published in recent years on classical aetiologies of CPHD such as mutations ofPOU1F1orPROP1, we focused the present overview on the data published in the last 5 years, to provide the reader with an updated review on this rapidly evolving field of knowledge.

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Pituitary transcription factors in the aetiology of combined pituitary hormone deficiency

Best Practice & Research Clinical Endocrinology & Metabolism ◽

10.1016/j.beem.2010.10.014 ◽

2011 ◽

Vol 25 (1) ◽

pp. 43-60 ◽

Cited By ~ 69

Author(s):

R. Pfäffle ◽

J. Klammt

Keyword(s):

Transcription Factors ◽

Hormone Deficiency ◽

Pituitary Hormone ◽

Pituitary Hormone Deficiency ◽

Combined Pituitary Hormone Deficiency ◽

Pituitary Transcription Factors

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Identification and Analysis of Prophet of Pit-1-Binding Sites in Human Pit-1 Gene

Endocrinology ◽

10.1210/en.2008-0030 ◽

2008 ◽

Vol 149 (11) ◽

pp. 5491-5499 ◽

Cited By ~ 7

Author(s):

Nobuko Ikeshita ◽

Mayuko Kawagishi ◽

Hiromi Shibahara ◽

Keizo Toda ◽

Tomoe Yamashita ◽

...

Keyword(s):

Transcription Factors ◽

Binding Sites ◽

Consensus Sequence ◽

Hormone Deficiency ◽

Pituitary Hormone ◽

Pituitary Cells ◽

Reporter Plasmid ◽

Pituitary Hormone Deficiency ◽

Combined Pituitary Hormone Deficiency ◽

Huh7 Cells

Prophet of Pit-1 (Prop1) is a transcription factor that regulates Pit-1 gene expression. Because Pit-1 regulates the differentiation of pituitary cells and the expressions of GH, prolactin and TSHβ genes, Prop1 mutation results in combined pituitary hormone deficiency in humans. However, Prop1-binding sites in human Pit-1 gene and the mechanism leading to combined pituitary hormone deficiency have remained unclear. In this study, we identified and analyzed Prop1-binding elements of the human Pit-1 gene. Prop1 stimulated the expression of the reporter plasmid containing Pit-1 gene from translation start site to −1340 dose dependently in GH3 cells. The activation by Prop1 was observed in GH3 and TtT/GF cells but not COS7, HeLa, JEG3, and HuH7 cells. Deletion analysis of Pit-1 gene showed that the Prop1-responsive elements were present within the −257-bp region. Within the −257-bp region, there are four elements similar to consensus sequence of paired-like transcription factors. Because Prop1 is a member of paired-like transcription factors, we assessed the elements. EMSA and transient transfection assay using the mutation of the elements revealed that the element from −63 to −53 (the proximal Prop1 binding element) was essential to Prop1-binding and Prop1-induced activation of Pit-1 reporter plasmid. A region at −8kb of human Pit-1 gene is similar to the distal region containing Prop1-binding elements in mouse Pit-1 gene. We showed the region functioned as an enhancer. Furthermore, chromatin immunoprecipitation assay showed that the proximal element could bind Prop1 in vivo cultured cells. Taken together, these findings indicated the novel functioning binding elements of Prop1 in human Pit-1 gene.

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