HESX1: a novel gene implicated in a familial form of septo‐optic dysplasia

Abstract

PC, Beddington RSP, Robinson ICAF. HESXI: a novel gene implicated in a familial form of septo-optic dysplasia. Acta Pzediatr 1999; Suppl 433: 49-54. Stockholm. ISSN 0803-5326The homeobox gene Hesxl, which encodes a pituitary transcription factor, is first expressed at gastrulation in the mouse embryo. Hesxl expression begins in prospective forebrain tissue but later becomes restricted to Rathke's pouch, the primordium of the anterior pituitary gland. Transgenic mice lacking Hesxl exhibit a phenotype comprising variable anterior CNS defects, such as a reduced prosencephalon, abnormalities in the corpus callosum and septum pellucidum, anophthalmia or microphthalmia, defective olfactory development and bifurcations in Rathke's pouch with pituitary dysplasia. A comparable and highly variable phenotype in humans is septo-optic dysplasia. We have cloned and sequenced the human homologue HESXI and screened for mutations in affected individuals using single-stranded conformational polymorphism analysis. Two siblings with septo-optic dysplasia were homozygous for a missense mutation within the HESXl homeobox. This mutation resulted in the substitution of a highly conserved arginine residue (Arg53) by cysteine and led to a loss of in vitro DNA binding. Hence, a vital role for Hesxl/HESXI in forebrain and pituitary development in mice and humans is suggested. 0 HESXl gene, homeobox, horneodomain, missense mutation, pituitary, Rathke 's pouch, septo-optic dysplasia MT Dattani,

The presence of Anf/Hesx1 homeobox gene in lampreys suggests that it could play an important role in emergence of telencephalon

“…3a–c, the expression of Lanf in the neural tissue at this stage was localized just above the expression domain of Shh in the prechordal mesoderm, in the territory corresponding to the forebrain and, thus, to the presumptive telencephalon and rostral diencephalon20. This expression pattern is similar to the patterns of Anf expression in other studied vertebrate embryos91013. As development proceeds, the expression of Lanf progressively ceases in the presumptive di- and telencephalic cells, persisting until stage 23 only in the oral ectoderm and the pituitary placode (Fig.…”

“…As shown previously, down-regulation of Anf in frog embryos results in anterior expansion of Otx2 domain, accompanied by a reduction of FoxG1 expression, whereas overexpression of Anf elicits opposite effects1113. To determine whether this result is also true for Lanf , we injected antisense morpholino oligonucleotides targeting Lanf (Lanf MO) or Lanf synthetic mRNA into lamprey embryos.…”

“…Importantly, this distribution correlates with the presence of the telencephalon in vertebrates, which is a unique region of the forebrain that is apparently absent in all other animals and is derived from the anterior neural fold, where Anf is expressed. Accordingly, gain- and loss-of-function experiments performed in Xenopus and mouse models have confirmed an essential role of Anf homeodomain proteins in the development of the telencephalon101113. Thus, in mouse Anf/Hesx1 −/− mutants telencephalic vesicles and eyes are reduced or absent at early somite stages15.…”

“…Thus, a novel monogenic class of homeoboxes, designated Anf , was described9. Moreover, an Anf orthologue was identified in mice by two other research groups and was designated Hesx1 or Rpx , after its expression in mouse ES cells and in the Rathke pouch121314.…”

The Role of the Pituitary-Growth Hormone-IGF Axis in Glucose Homeostasis

“…Both dominant and recessive mutations have been reported. A mutation in the gene HESX1 is associated with hypopituitarism as part of a De Morsier syndrome, also known as Septo-optic Dysplasia (Dattani, Martinez-Barbera et al 1999). Septo-optic Dysplasia includes optic nerve hypoplasia, midline anomolies (especially absence of the septum pellucidum and occasionally the corpus collosum), and varying degrees of hypopituitarism (usually of the anterior pituitary, but may also include the posterior pituitary) (Brickman, Clements et al 2001).…”