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1 From the Department of Molecular Genetics, Institute of Ophthalmology, London, United Kingdom; and 3 Moorfields Eye Hospital, London, United Kingdom.
PURPOSE. Mutations in keratocan (KERA), a small leucine-rich proteoglycan, have recently been shown to be responsible for cases of autosomal recessive cornea plana (CNA2). A consanguineous pedigree in which cornea plana cosegregated with microphthalmia was investigated by linkage analysis and direct sequencing.
METHODS. Linkage was sought to polymorphic microsatellite markers distributed around the CNA2 and microphthalmia loci (arCMIC, adCMIC, NNO1, and CHX10) using PCR and nondenaturing polyacrylamide gel electrophoresis before KERA was directly sequenced for mutations.
RESULTS. Positive lod scores were obtained with markers encompassing the
CNA2 locus, the maximum two-point lod scores of 2.18 at
recombination fraction 
= 0 was obtained with markers D12S95
and D12S327. Mutation screening of KERA revealed a novel
single-nucleotide substitution at codon 215, which results in the
substitution of lysine for threonine at the start of a highly conserved
leucine-rich repeat motif. Structural modeling predicts that the motifs
are stacked into an arched ß-sheet array and that the effect of the
mutation is to alter the length and position of one of these motifs.
CONCLUSIONS. This report describes a novel mutation in KERA that alters a highly conserved motif and is predicted to affect the tertiary structure of the molecule. Normal corneal function is dependent on the regular spacing of collagen fibrils, and the predicted alteration of the tertiary structure of KERA is the probable mechanism of the cornea plana phenotype.
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