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Human Molecular Genetics, 2001, Vol. 10, No. 1 39-45
© 2001 Oxford University Press

Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia

Paul Q. Thomas1,+, Mehul T. Dattani2,3,4, Joshua M. Brickman2, David McNay4, Garry Warne5, Margaret Zacharin5, Fergus Cameron5, Jane Hurst6, Katie Woods7, David Dunger7, Richard Stanhope4, Susan Forrest1, Iain C.A.F. Robinson3 and Rosa S.P. Beddington2

1Gene Discovery Unit, The Murdoch Children’s Research Institute and 5Department of Endocrinology, Royal Children’s Hospital, Flemington Road, Parkville, Melbourne, Victoria 3052, Australia, 2Division of Mammalian Development and 3Division of Neurophysiology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK, 4London Centre for Paediatric Endocrinology and Metabolism, Institute of Child Health, London WC1N 1EH, UK, 6Department of Clinical Genetics, Oxford Radcliffe Hospital Trust, The Churchill, Oxford OX3 7LJ, UK and 7John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK.

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.

+ To whom correspondence should be addressed. Tel: +61 3 8341 6285; Fax: +61 3 9348 1391; Email: thomasp@cryptic.rch.unimelb.edu.au


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