Best Practice & Research Clinical Endocrinology & Metabolism
4Pituitary transcription factors in the aetiology of combined pituitary hormone deficiency
Introduction
Growth is a multifactorial trait, in which about 80% are determined by genetic factors.1 Some of the genes directly involved in growth regulation have been identified during the last decades, many of them have been found to be mutated in various conditions of human growth retardation. The pituitary plays a central role in growth regulation, in that it executes instructions that it receives from the hypothalamus, which in turn coordinates the multitude of central and peripheral signals to maintain the body’s internal balance. Pituitary hormone secretion regulates metabolism, stress response, reproduction, puberty, and lactation, but also relays signals for the somatotropic axis, that controls proportionate longitudinal and organ growth.
Transcription factors orchestrate the ontogeny of the pituitary, maintain the differentiated state of the developed gland and mediate the coordinated expression of cell type specific pituitary hormones. Some of the transcription factors involved in pituitary organogenesis, particularly early-acting genes, are not pituitary specific, but are also required for the development of other organs and structures. Factors acting later in the specifications of pituitary cell lineages are rather specific for but not necessarily restricted to the developing or mature pituitary gland. For various pituitary transcription factors the expression pattern and mode of action have been studied in mammalian and non-mammalian animal models during the last decades. Impaired expression or function of these factors causes mal- or underdevelopment of the pituitary gland and eventually leads to the diminished or entirely missing secretion of pituitary hormones. Resequencing studies in patients presenting with hypopituitarism have confirmed the participation of some of the respective human orthologs in human pituitary function. However, the majority of patients with syndromic or isolated hypopituitarism have to be labelled idiopathic to date, even if a familial history of the condition suggests a genetic aetiology.
This review will summarize and compare clinical findings in patients with mutations of the genes encoding for the transcription factors PROP1, POU1F1 (PIT1), LHX3, and LHX4. Recent results from molecular research will be set into relation to clinical manifestations. An outlook will be given for future investigations.
Section snippets
Transcriptional regulation of pituitary development and function
Organogenesis of the pituitary is a highly organised cascade, in which endogenous programs and factors in concert with exogenous signals give rise to specialised cells of the anterior, intermediate (adenohypophysis) and posterior lobes (neurohypophysis) of the pituitary. Fate map analyses, reverse genetics approaches, and organ culture experiments performed in different vertebrate species (zebrafish, chicken, mice) revealed general principles of the molecular machinery that integrate extrinsic
CPHD – clinical manifestations of patients with transcription factor mutations
Hypopituitarism may manifest as insufficiency of one or more of the six hormones secreted by the anterior pituitary gland. Isolated hormone deficiency due to congenital functional failure of a single lineage has been reported for all pituitary cell types, i.e. the somatotropes (isolated GH deficiency, IGHD), thyrotropes (central or secondary hypothyroidism), lactotropes (isolated PRL deficiency; very rare anecdotal reports of patients with unknown aetiology;6 and citations therein),
Human mutations
Within the last two decades numerous mutations in the genes encoding for PROP1, POU1F1, LHX3 and LHX4 have been identified in children suffering from CPHD. However, most cases are still idiopathic. The high proportion of cases with unknown aetiology even with a familial history of CPHD suggests that other mutations in so far unidentified genes account for the majority of affected individuals. This assumption is further strengthened by the high phenotypic variability observed in the distinct
Summary
Development of the anterior pituitary gland is a complex process and mutations within genes encoding for transcription factors that orchestrate the maturation of the anterior lobe from the earliest primordium to the terminally differentiated cell lineages cause various combinations of pituitary hormone deficiencies. Profound health complications may arise due to insufficient instruction of peripheral target organs. A common feature of patients carrying mutations within the transcription factors
Acknowledgment
This work was supported in part by a grant from the Deutsche Forschungsgemeinschaft (Bonn, Germany, project PF 225/3-1 to R.P.). We thank Eleonore Bertko for providing information on POU1F1 and PROP1 deletion analysis.
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