McNay, David Euan Graham; (2003) The role of HESX1 in septo-optic dysplasia and its variants. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Septo-Optic Dysplasia (SOD) is a highly variable developmental abnormality of the midline structures of the brain, classically resulting in hypoplasia of the optic nerves, absence of the septum pellucidum and dysgenesis of the pituitary gland. The homeobox gene Hesx1 is a transcriptional repressor expressed at gastrulation within the anterior midline visceral endoderm, with subsequent expression in the prosencephalon and Rathke's pouch. Hesx1 null mutant mice manifest a phenotype similar to SOD in man and this led to the successful characterisation of a recessive HESX1 mutation within two familial cases (Dattani et al., 1998). However, the cohort sample size was too small to draw general conclusion about the role of HESX1 in SOD. This thesis investigated the role of HESX1 in SOD, particularly sporadic cases, and involved the collection of the largest cohort of SOD and SOD-like phenotypes to date (n=670). Mutation screening of HESX1 was carried out using both SSCP detection and d-HPLC heteroduplex detection. The mutation screen identified a number of heterozygous sequence variants of which two appear to be mutations (S170L and E149K). An S170L mutation was identified in a sporadic case of growth hormone deficiency and an ectopic posterior pituitary. This mutation had been previously described in a sib pair and functional analysis carried out (Thomas et al., 2001 and Brickman et al, 2002). An E149K variant was identified in a child demonstrating growth hormone deficiency, hypoplasia of the anterior pituitary and an ectopic posterior pituitary. The E149K variant lies at position 42 of the homeodomain, at the first position of the third helix. This change is highly conserved and has not been found in 140 control chromosomes. Functional studies were undertaken to investigate the function of this variant, including in-vitro DNA binding assays and in-vitro transfection studies.

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