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W. Ferrini, C. Willoughby, M.A. Walter, E. Heon; Identification of a Potential Keratoconus/PPCD Locus on 6p25 . Invest. Ophthalmol. Vis. Sci. 2005;46(13):4935.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Familial cases of Keratoconus (KC) associated with Posterior polymorphous dystrophy (PPCD) have been documented in several reports. We investigated a three–generation UK family with 5 individuals affected with PPCD and KC. Methods:All patients underwent a full eye examination. Genotyping was performed using STRP markers covering the candidate loci on chromosomes 20 (VSX1: KC and PPCD), 1 (COL8A2: Fuchs endothelial dystrophy and PPCD), 15 (KC and cataract), 16 (KC) and 6p25 (FOXC1). Data was analyzed using haplotype analysis. Karyotyping was performed using standard cytogenetic procedures in one affected patient. Mutation analysis of candidate genes and putative regulatory elements were performed using direct sequencing. Results:Clinical examination revealed both KC and PPCD in all affected individuals, with autosomal dominant inheritance pattern and full penetrance. Haplotype and linkage analysis excluded candidate loci on chromosome 20, 1, 15 and 16. Haplotype analysis over 14 cM suggested linkage to the FOXC1 locus on 6p25. Sequencing of FOXC1, FOXF2 and FOXQ1 in this mapped interval failed to show any significant sequence change in the coding sequence and flanking regions. Sequence analysis of a highly conserved CpG island upstream of FOXC1 (putative regulatory element) failed to show any changes. Karyotyping using GTG banding showed no gross structural rearrangements (46, XY). We excluded the possibility of a duplication/deletion using polymorphic markers. Conclusions:The clinical spectrum of KC/PPD is overlapping and complex. The genetic analysis of this family suggests the presence of an additional KC/PPD gene on chromosome 6p25.
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