PURPOSE: Keratoconus and cataract are common causes of visual morbidity. Both conditions show genetic predisposition. The purpose of this study was to map the disease locus in a large three-generation family affected by combined early-onset autosomal dominant anterior polar cataract and clinically severe keratoconus. Uniquely, in this family both disorders were present and fully penetrant in those affected. METHODS: Thirty members of the family were examined clinically on two occasions, at an interval of 5 years, to establish their phenotypes and determine the progression of the disease. Genomic DNA was extracted from blood samples of 16 affected and 14 unaffected individuals, and typed with more than 350 highly polymorphic microsatellite loci in a genome-wide linkage screen. Markers were amplified by PCR with fluorescently labeled primers and sized with an automated DNA analyser before calculation of lod scores. After linkage was established, several positional candidate genes were assessed by PCR-based DNA sequencing. RESULTS: The locus for keratoconus with cataract was mapped to a 6.5-Mb region of the long arm of chromosome 15, at 22.33-24.2 between CYP11A and D15S211. The positional and functional candidate genes CTSH, CRABP1, IREB2, and RASGRF1 were excluded as the cause of keratoconus with cataract in this family. CONCLUSIONS: This is the first report of a family with autosomal dominant inheritance of keratoconus in association with cataract. The causative gene maps to the long arm of chromosome 15 but has not yet been identified.
PURPOSE: Keratoconus and cataract are common causes of visual morbidity. Both conditions show genetic predisposition. The purpose of this study was to map the disease locus in a large three-generation family affected by combined early-onset autosomal dominant anterior polar cataract and clinically severe keratoconus. Uniquely, in this family both disorders were present and fully penetrant in those affected. METHODS: Thirty members of the family were examined clinically on two occasions, at an interval of 5 years, to establish their phenotypes and determine the progression of the disease. Genomic DNA was extracted from blood samples of 16 affected and 14 unaffected individuals, and typed with more than 350 highly polymorphic microsatellite loci in a genome-wide linkage screen. Markers were amplified by PCR with fluorescently labeled primers and sized with an automated DNA analyser before calculation of lod scores. After linkage was established, several positional candidate genes were assessed by PCR-based DNA sequencing. RESULTS: The locus for keratoconus with cataract was mapped to a 6.5-Mb region of the long arm of chromosome 15, at 22.33-24.2 between CYP11A and D15S211. The positional and functional candidate genes CTSH, CRABP1, IREB2, and RASGRF1 were excluded as the cause of keratoconus with cataract in this family. CONCLUSIONS: This is the first report of a family with autosomal dominant inheritance of keratoconus in association with cataract. The causative gene maps to the long arm of chromosome 15 but has not yet been identified.
Authors: Kathryn P Burdon; Stuart Macgregor; Yelena Bykhovskaya; Sharhbanou Javadiyan; Xiaohui Li; Kate J Laurie; Dorota Muszynska; Richard Lindsay; Judith Lechner; Talin Haritunians; Anjali K Henders; Durga Dash; David Siscovick; Seema Anand; Anthony Aldave; Douglas J Coster; Loretta Szczotka-Flynn; Richard A Mills; Sudha K Iyengar; Kent D Taylor; Tony Phillips; Grant W Montgomery; Jerome I Rotter; Alex W Hewitt; Shiwani Sharma; Yaron S Rabinowitz; Colin Willoughby; Jamie E Craig Journal: Invest Ophthalmol Vis Sci Date: 2011-10-31 Impact factor: 4.799
Authors: Kathryn P Burdon; Douglas J Coster; Jac C Charlesworth; Richard A Mills; Kate J Laurie; Cecilia Giunta; Alex W Hewitt; Paul Latimer; Jamie E Craig Journal: Hum Genet Date: 2008-09-05 Impact factor: 4.132
Authors: Justyna A Karolak; Karolina Kulinska; Dorota M Nowak; Jose A Pitarque; Andrea Molinari; Malgorzata Rydzanicz; Bassem A Bejjani; Marzena Gajecka Journal: Mol Vis Date: 2011-03-30 Impact factor: 2.367
Authors: Andrea L Vincent; David M Markie; Betina De Karolyi; Catherine E Wheeldon; Dipika V Patel; Christina N Grupcheva; Charles N J McGhee Journal: Mol Vis Date: 2009-08-26 Impact factor: 2.367