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Heterozygous mutations of OTX2 cause severe ocular malformations

Lookup NU author(s): Dr Ross Henderson, Michael Clarke


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Major malformations of the human eye, including microphthalmia and anophthalmia, are examples of phenotypes that recur in families yet often show no clear Mendelian inheritance pattern. Defining loci by mapping is therefore rarely feasible. Using a candidate-gene approach, we have identified heterozygous coding-region changes in the homeobox gene OTX2 in eight families with ocular malformations. The expression pattern of OTX2 in human embryos is consistent with the eye phenotypes observed in the patients, which range from bilateral anophthalmia to retinal defects resembling Leber congenital amaurosis and pigmentary retinopathy. Magnetic resonance imaging scans revealed defects of the optic nerve, optic chiasm, and, in some cases, brain. In two families, the mutations appear to have occurred de novo in severely affected offspring, and, in two other families, the mutations have been inherited from a gonosomal mosaic parent. Data from these four families support a simple model in which OTX2 heterozygous loss-of-function mutations cause ocular malformations. Four additional families display complex inheritance patterns, suggesting that OTX2 mutations alone may not lead to consistent phenotypes. The high incidence of mosaicism and the reduced penetrance have implications for genetic counseling.

Publication metadata

Author(s): Ragge NK, Brown AG, Poloschek CM, Lorenz B, Henderson RA, Clarke MP, Russell-Eggitt I, Fielder A, Gerrelli D, Martinez-Barbera JP, Ruddle P, Hurst J, Collin JRO, Salt A, Cooper ST, Thompson PJ, Sisodiya SM, Williamson KA, FitzPatrick DR, van Heyningen V, Hanson IM

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2005

Volume: 76

Issue: 6

Pages: 1008-1022

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1086/430721


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Funder referenceFunder name
Wellcome Trust
G9826762Medical Research Council
MC_U127527199Medical Research Council