Heterozygous mutations of OTX2 cause severe ocular malformations

Nicola K Ragge, Alison G Brown, Charlotte M Poloschek, Birgit Lorenz, R Alex Henderson, Michael P Clarke, Isabelle Russell-Eggitt, Alistair Fielder, Dianne Gerrelli, Juan Pedro Martinez-Barbera, Piers Ruddle, Jane Hurst, J Richard O Collin, Alison Salt, Simon T Cooper, Pamela J Thompson, Sanjay M Sisodiya, Kathleen A Williamson, David R Fitzpatrick, Veronica van HeyningenIsabel M Hanson

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)1008-22
Number of pages15
JournalAmerican Journal of Human Genetics
Issue number6
Publication statusPublished - Jun 2005

Keywords / Materials (for Non-textual outputs)

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Anophthalmos
  • Brain
  • Chromosome Mapping
  • DNA Mutational Analysis
  • Eye Abnormalities
  • Female
  • Gene Expression Regulation, Developmental
  • Genes, Homeobox
  • Genetic Variation
  • Heterozygote
  • Homeodomain Proteins
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Models, Genetic
  • Mosaicism
  • Mutation
  • Open Reading Frames
  • Otx Transcription Factors
  • Pedigree
  • Penetrance
  • Protein Structure, Tertiary
  • Sequence Analysis, DNA


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