Human microphthalmia associated with mutations in the retinal homeobox gene CHX10 (original) (raw)

• Letter
• Published: August 2000
• Lynda A. Ploder3 na1,
• Jessica J. Yu3,
• Kemal Arici2,
• D. Jonathan Horsford3,5,
• Adam Rutherford6,
• Bharati Bapat7,
• Diane W. Cox8,
• Alessandra M.V. Duncan9,
• Vitauts I. Kalnins10,
• Aysegul Kocak-Altintas11,
• Jane C. Sowden6,
• Elias Traboulsi12,
• Mansoor Sarfarazi1 &
• …
• Roderick R. McInnes3,4,5

Nature Genetics volume 25, pages 397–401 (2000)Cite this article

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Abstract

Isolated human microphthalmia/anophthalmia, a cause of congenital blindness, is a clinically and genetically heterogeneous developmental disorder characterized by a small eye and other ocular abnormalities. Three microphthalmia/anophthalmia loci have been identified1,2,3, and two others have been inferred by the co-segregation of translocations with the phenotype4,5. We previously found that mice with ocular retardation (the or-J allele), a microphthalmia phenotype6, have a null mutation in the retinal homeobox gene Chx10 (refs 7,8). We report here the mapping of a human microphthalmia locus on chromosome 14q24.3, the cloning of CHX10 at this locus and the identification of recessive CHX10 mutations in two families with non-syndromic microphthalmia (MIM 251600), cataracts and severe abnormalities of the iris. In affected individuals, a highly conserved arginine residue in the DNA-recognition helix of the homeodomain is replaced by glutamine or proline (R200Q and R200P, respectively). Identification of the CHX10 consensus DNA-binding sequence (TAATTAGC) allowed us to demonstrate that both mutations severely disrupt CHX10 function. Human CHX10 is expressed in progenitor cells of the developing neuroretina and in the inner nuclear layer of the mature retina. The strong conservation in vertebrates of the CHX10 sequence, pattern of expression and loss-of-function phenotypes demonstrates the evolutionary importance of the genetic network through which this gene regulates eye development.

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Acknowledgements

We thank the participating members of the families; M. Hankin for the description of the iris of Chx10or-J/or-J mice; J. Nathans for the adult human retina λgt10 cDNA library; D. Zarkower for the PT7tagN vector and advice; M. Ozguc for facilitating DNA extraction; W. Shih and L. Collins for technical assistance; and L. Wong. This study was supported by grants from the TUBITAK, Ankara, Turkey to E.F.P., the MRC UK to J.C.S., and from The Medical Research Council of Canada, The Canadian Genetic Disease Network and The RP Eye Research Foundation of Canada to R.R.M. D.J.H. is the recipient of a FFB Canada/MRC doctoral research award, and A.R. is a Fight for Sight Research Student. R.R.M. is an International Research Scholar of the Howard Hughes Medical Institute.

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Author notes

1. E. Ferda Percin and Lynda A. Ploder: These authors contributed equally to this work.

Authors and Affiliations

1. Department of Surgery, Molecular Ophthalmic Genetics Laboratory, Surgical Research Center, University of Connecticut Health Center, Farmington, Connecticut, USA
   E. Ferda Percin & Mansoor Sarfarazi
2. Departments of Medical Biology, Genetics and Ophthalmology, Cumhuriyet University, Sivas, Turkey
   E. Ferda Percin & Kemal Arici
3. Programs in Developmental Biology and Genetics, The Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada
   Lynda A. Ploder, Jessica J. Yu, D. Jonathan Horsford & Roderick R. McInnes
4. Department of Pediatrics, University of Toronto, Toronto, Ontario, USA
   Roderick R. McInnes
5. Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, USA
   D. Jonathan Horsford & Roderick R. McInnes
6. Developmental Biology Unit, Institute of Child Health, University College London, London, UK
   Adam Rutherford & Jane C. Sowden
7. Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada
   Bharati Bapat
8. Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada
   Diane W. Cox
9. Departments of Pathology and Human Genetics, McGill University Hospital Centre, Montreal Children's Hospital, Montreal, Canada
   Alessandra M.V. Duncan
10. The Department of Anatomy and Cell Biology, University of Toronto, Toronto, Ontario, Canada
    Vitauts I. Kalnins
11. Ophthalmology Clinics, Ankara Hospital, Ankara, Turkey
    Aysegul Kocak-Altintas
12. Department of Pediatrics, Division of Ophthalmology, The Center for Genetic Eye Diseases, The Cleveland Clinic Foundation, Cleveland, Ohio, USA
    Elias Traboulsi

Authors

1. E. Ferda Percin
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2. Lynda A. Ploder
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3. Jessica J. Yu
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4. Kemal Arici
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5. D. Jonathan Horsford
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6. Adam Rutherford
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7. Bharati Bapat
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8. Diane W. Cox
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9. Alessandra M.V. Duncan
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10. Vitauts I. Kalnins
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11. Aysegul Kocak-Altintas
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12. Jane C. Sowden
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13. Elias Traboulsi
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14. Mansoor Sarfarazi
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15. Roderick R. McInnes
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Corresponding authors

Correspondence toMansoor Sarfarazi or Roderick R. McInnes.

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Ferda Percin, E., Ploder, L., Yu, J. et al. Human microphthalmia associated with mutations in the retinal homeobox gene CHX10.Nat Genet 25, 397–401 (2000). https://doi.org/10.1038/78071

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• Received: 29 February 2000
• Accepted: 15 May 2000
• Issue Date: August 2000
• DOI: https://doi.org/10.1038/78071

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