title: Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia.
abstract: We have previously shown that familial septo-optic dysplasia (SOD), a syndromic form of congenital hypopituitarism involving optic nerve hypoplasia and agenesis of midline brain structures, is associated with homozygosity for an inactivating mutation in the homeobox gene HESX1/Hesx1 in man and mouse. However, as most SOD/congenital hypopituitarism occurs sporadically, the possible contribution of HESX1 mutations to the aetiology of these cases is presently unclear. Interestingly, a small proportion of mice heterozygous for the Hesx1 null allele show a milder SOD phenocopy, implying that heterozygous mutations in human HESX1 could underlie some cases of congenital pituitary hypoplasia with or without midline defects. Accordingly, we have now scanned for HESX1 mutations in 228 patients with a broad spectrum of congenital pituitary defects, ranging in severity from isolated growth hormone deficiency to SOD with panhypopituitarism. Three different heterozygous missense mutations were detected in individuals with relatively mild pituitary hypoplasia or SOD, which display incomplete penetrance and variable phenotype amongst heterozygous family members. Gel shift analysis of the HESX1-S170L mutant protein, which is encoded by the C509T mutated allele, indicated that a significant reduction in relative DNA binding activity results from this mutation. Segregation analysis of a haplotype spanning 6.1 cM, which contains the HESX1 locus, indicated that only one HESX1 mutation was present in the families containing the C509T and A541G mutations. These results demonstrate that some sporadic cases of the more common mild forms of pituitary hypoplasia have a genetic basis, resulting from heterozygous mutation of the HESX1 gene.
authors.affiliation: Gene Discovery Unit, The Murdoch Children's Research Institute, Royal Children's Hospital, Flemington Road, Parkville, Melbourne, Vic. 3052, Australia. thomasp@cryptic.rch.unimelb.edu.au
authors.forename: P Q
authors.initials: PQ
authors.lastname: Thomas
authors.forename: M T
authors.initials: MT
authors.lastname: Dattani
authors.forename: J M
authors.initials: JM
authors.lastname: Brickman
authors.forename: D
authors.initials: D
authors.lastname: McNay
authors.forename: G
authors.initials: G
authors.lastname: Warne
authors.forename: M
authors.initials: M
authors.lastname: Zacharin
authors.forename: F
authors.initials: F
authors.lastname: Cameron
authors.forename: J
authors.initials: J
authors.lastname: Hurst
authors.forename: K
authors.initials: K
authors.lastname: Woods
authors.forename: D
authors.initials: D
authors.lastname: Dunger
authors.forename: R
authors.initials: R
authors.lastname: Stanhope
authors.forename: S
authors.initials: S
authors.lastname: Forrest
authors.forename: I C
authors.initials: IC
authors.lastname: Robinson
authors.forename: R S
authors.initials: RS
authors.lastname: Beddington
mesh_terms: D000483:Alleles; D051792:Basic Helix-Loop-Helix Proteins; D002648:Child; D018244:Chromosomes, Artificial, Yeast; D004247:DNA / Q000378:metabolism; D005192:Family Health; D005260:Female; D006239:Haplotypes; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D009900:Optic Nerve / Q000002:abnormalities*; D010375:Pedigree; D010641:Phenotype; D010902:Pituitary Gland / Q000002:abnormalities*; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA; 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