T-box and isolated ACTH deficiency

The organogenesis of the pituitary gland has provided several insights into molecular mechanisms and regulatory factors controlling both differentiation and gene transcription. Different pituitary transcription factors are involved in the commitment, development and cell differentiation of the gland. The control of pituitary cell differentiation has been shown to depend on a limited set of lineage-restricted transcription factors. In particular, Prop1-dependent (1) and Pit1/growth-hormone factor 1 (GHF1)-dependent (2, 3) lineages give rise to thyroid-stimulating hormone (TSH)-positive thyrotrophs around embryonic day (E) 14.5, to growth hormone (GH)-positive somatotrophs around E15.5, and to prolactin-expressing lactotrophs on E16.5 (Fig. 1) (4). (See Fig. 1 legend for definition of abbreviations not defined in the text.) The GATA-2and SF-1-dependent gonadotrophs appear around E16.5 (Fig. 1) (5 –7). The mechanisms for corticotroph differentiation remain to be clarified. Only one transcription factor has been so far demonstrated to be restricted to this lineage, i.e. NeuroD1 (8), but it does not seem to be sufficient for corticotroph differentiation. The corticotrophs are the first hormone-producing pituitary cells to reach terminal differentiation. Indeed, the expression of pro-opiomelanocortin (POMC) starts in corticotrophs at E12.5 during mouse development (4). Two POMC-expressing cell lineages are present in the pituitary gland: the adrenocorticotrophin (ACTH)-producing corticotrophs in the anterior lobe and the a-melanocyte-stimulating hormoneproducing melanotrophs in the intermediate lobe. Recently, Lamolet et al. (9) have identified in the mouse a novel cell-restricted transcription factor (Tpit) only present in the two pituitary POMC-expressing lineages and apparently in no other tissue, including hypothalamic POMC neurons. In pituitary cells, Tpit activation of POMC gene transcription requires cooperation with a tissue-restricted homeodomain transcription factor, Pitx1, the two factors binding to contiguous sites within the same regulatory element. In gain-of-function experiments, Tpit induced POMC expression in undifferentiated pituitary cells, indicating that it can initiate differentiation into POMC-expressing lineages (9). The human homologue of Tpit appears to be TBX19, a T-box gene of unknown function that shares 94% amino acid homology. TBX19 was first identified by Yi et al. (10). It belongs to the family of the T-box genes, i.e. a novel family of transcription factors that play a critical role in embryonic development (Fig. 1) (11). Different paralogues of the T-box gene family are expressed in different spatial and temporal patterns during embryogenesis, especially in mesodermally derived tissues (12). The defining feature of the T-box gene family is a region of conserved DNA sequence, the T-box, which encodes a DNA-binding domain (13). Outside the T-box region, polypeptides encoded by T-box genes are widely divergent. The prototypic member of this family, Brachyury (T ), was positionally cloned in 1990 (14), 70 years after the locus was first identified in the mouse. Mutation of this gene causes defects in mesoderm formation in mice. Comparison within the T-box revealed that TBX19 is a member of the Brachyury (T ) subfamily. It was mapped to human chromosome 1q23-q24 and encodes a 448-amino acid protein (10). The exclusive expression of Tpit in pituitary POMC cells suggests that the human homologue TBX19 could also be restricted to the same pituitary cells, and, thus, loss of TBX19 function might produce an isolated deficiency of pituitary POMC (ACTH). To test this hypothesis, Lamolet et al. (9) analysed the TBX19 gene in three children born with adrenal insufficiency due to an isolated ACTH deficiency. These authors have identified TBX19 gene mutations in two patients who presented with very similar symptoms, including a sister of the patient previously described by Malpuech et al. in 1988 (15) and a boy born to consanguineous parents. The boy had very low basal plasma cortical, no ACTH response to corticotrophin-releasing hormone, but maintained cortisol response to exogenous ACTH. This patient was found homozygous for a nonsense mutation in exon 6 of the TBX19 gene (R286X), which leads to a truncation of most TBX19 C-terminal sequences. His parents and one grandparent, who showed normal adrenal function, were found to be heterozygous for the mutation, suggesting a recessive inheritance of ACTH deficiency. A different TBX19 gene mutation has been identified in the sister of the patient described by Malpuech et al. (15). This patient was found to be heterozygous for a missense mutation (S128F) in exon 2 of the TBX19 H IG H L IG H T European Journal of Endocrinology (2002) 146 463–465 ISSN 0804-4643