title: Molecular genetics of septo-optic dysplasia.
abstract: Septo-optic dysplasia (SOD) is a highly variable condition characterized by midline neurological abnormalities associated with pituitary hypoplasia and optic nerve hypoplasia. The aetiology is unknown. Mutant mice, in which a novel homeobox gene, Hesx1, has been disrupted, exhibit a phenotype that resembles the phenotype of SOD. We therefore wished to explore the possibility that this gene is implicated in SOD. We cloned and sequenced the human homologue HESX1 and screened for mutations in affected individuals using single-stranded conformational polymorphism analysis, followed by cloning and sequencing of any exons which showed a band shift. Two siblings with SOD were homozygous for an Arg53Cys missense mutation within the HESX1 homeodomain, leading to a loss of in vitro DNA binding. Subsequently, we have identified heterozygous mutations in HESX1 that are associated with milder pituitary phenotypes. Our studies indicate a vital role for Hesx1/HESX1 in forebrain and pituitary development in mouse and man, and hence in some cases of SOD.
authors.affiliation: London Centre for Paediatric Endocrinology and Metabolism, Institute of Child Health, London, UK. M.Dattani@ich.ucl.ac.uk
authors.forename: M L
authors.initials: ML
authors.lastname: Dattani
authors.forename: J
authors.initials: J
authors.lastname: Martinez-Barbera
authors.forename: P Q
authors.initials: PQ
authors.lastname: Thomas
authors.forename: J M
authors.initials: JM
authors.lastname: Brickman
authors.forename: R
authors.initials: R
authors.lastname: Gupta
authors.forename: J K
authors.initials: JK
authors.lastname: Wales
authors.forename: P C
authors.initials: PC
authors.lastname: Hindmarsh
authors.forename: R S
authors.initials: RS
authors.lastname: Beddington
authors.forename: I C
authors.initials: IC
authors.lastname: Robinson
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D005801:Genes, Homeobox; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D008967:Molecular Biology; D009154:Mutation; D009900:Optic Nerve / Q000002:abnormalities*; D010375:Pedigree; D010903:Pituitary Gland, Anterior / Q000196:embryology; D012097:Repressor Proteins; D012688:Septum Pellucidum / Q000002:abnormalities*; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; C489736:HESX1 protein, human; C489734:Hes1 protein, mouse; C489733:Hesx1 protein, mouse; C078493:HES1 protein, human