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Mutations in KERA, encoding keratocan, cause cornea plana

Nature Genetics volume 25, pages 91–95 (2000)Cite this article

Abstract

Specialized collagens and small leucine-rich proteoglycans (SLRPs) interact to produce the transparent corneal structure1. In cornea plana, the forward convex curvature is flattened, leading to a decrease in refraction2. A more severe, recessively inherited form (CNA2; MIM 217300) and a milder, dominantly inherited form (CNA1; MIM 121400) exist. CNA2 is a rare disorder with a worldwide distribution, but a high prevalence in the Finnish population3. The gene mutated in CNA2 was assigned by linkage analysis to 12q (refs 4,5), where there is a cluster of several SLRP genes6,7,8,9. We cloned two additional SLRP genes highly expressed in cornea: KERA (encoding keratocan) in 12q and OGN (encoding osteoglycin) in 9q. Here we report mutations in KERA in 47 CNA2 patients: 46 Finnish patients are homozygous for a founder missense mutation, leading to the substitution of a highly conserved amino acid; and one American patient is homozygous for a mutation leading to a premature stop codon that truncates the KERA protein. Our data establish that mutations in KERA cause CNA2. CNA1 patients had no mutations in these proteoglycan genes.

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Figure 1: Haplotype sharing among CNA2 patients.
Figure 2: Physical map of the CNA2 region with relevant BAC clones.
Figure 3: Gene and protein structure of human keratocan.
Figure 4: Expression of human keratocan.
Figure 5: Identification of the two mutations in KERA associated with CNA2.

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Acknowledgements

We thank the patients and their families for cooperation; R. Chadwick, C. Johnson and B. Yuan for sequencing and data assembly assistance; Y. Huang and J. Lockman for technical assistance; I. Maumenee, J. Hecht, A. Sigler-Villanueva and E.-M. Sankila for providing materials; and P. Kaumaya, K. Mrozek, S. Tanner and P. Peltomäki for helpful discussions. N.S.P. was supported in part by a fellowship from the ACSBI-UICC. This work was supported by grants from the National Institutes of Health (NG1763 and P30 CA16058) and the Academy of Finland.

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Authors and Affiliations

  1. Division of Human Cancer Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA

    Natalia S. Pellegata, Ralf Krahe & Albert de la Chapelle

  2. Folkhälsan Institute of Genetics, Helsinki, Finland

    Jose L. Dieguez-Lucena, Tarja Joensuu, Henrik Forsius & Albert de la Chapelle

  3. Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York, USA

    Stephanie Lau, Kate T. Montgomery & Raju Kucherlapati

  4. Department of Ophthalmology, University Hospital of Helsinki, Helsinki, Finland

    Tero Kivelä

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  1. Natalia S. Pellegata
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Correspondence to Albert de la Chapelle.

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Pellegata, N., Dieguez-Lucena, J., Joensuu, T. et al. Mutations in KERA, encoding keratocan, cause cornea plana. Nat Genet 25, 91–95 (2000). https://doi.org/10.1038/75664

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