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Apparent autosomal dominant keratoconus in a large Australian pedigree accounted for by digenic inheritance of two novel loci


Burdon, KP and Coster, DJ and Charlesworth, JC and Mills, RA and Laurie, KJ and Giunta, C and Hewitt, AW and Latimer, P and Craig, JE, Apparent autosomal dominant keratoconus in a large Australian pedigree accounted for by digenic inheritance of two novel loci, Human Genetics, 124, (4) pp. 379-386 . ISSN 0340-6717 (2008) [Refereed Article]

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Copyright Statement

Copyright 2008 Springer-Verlag

DOI: doi:10.1007/s00439-008-0555-z


Keratoconus is a debilitating ocular disease characterised by progressive asymmetrical thinning of the cornea, the clear covering at the front of the eye. The resulting protrusion of the cornea results in severe refractive error, in the most severe cases requiring corneal grafting. It is a complex disease with a genetic component. Despite several reports of linked loci, major gene identification has been elusive. A genome-wide linkage scan in a large Australian pedigree with apparent autosomal dominant keratoconus was conducted using the Affymetrix 10K SNP chip and two regions of linkage identified. Functional candidate genes from within both linkage peaks were assessed for corneal expression and screened for mutations in affected family members. Equal evidence of linkage was detected to both 1p36.23-36.21 and 8q13.1-q21.11 with LOD scores of 1.9. Analysis of both loci concurrently suggests digenic linkage with two-locus LOD score of 3.4. All affected individuals carry identical haplotypes at both loci. Carriers of either linked haplotype without the other do not have keratoconus. No mutations were identified in the following candidate genes expressed in the cornea: ENO1, CTNNBIP1, PLOD1, UBIAD1, SPSB1 or TCEB1. Although the pedigree appears to demonstrate simple autosomal dominant inheritance, the disorder is actually genetically complex. This pedigree may provide a link between inherited forms of keratoconus and sporadic cases.

Item Details

Item Type:Refereed Article
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Gene mapping
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Burdon, KP (Professor Kathryn Burdon)
UTAS Author:Charlesworth, JC (Dr Jac Charlesworth)
UTAS Author:Hewitt, AW (Professor Alex Hewitt)
ID Code:73575
Year Published:2008
Web of Science® Times Cited:52
Deposited By:Research Division
Deposited On:2011-10-17
Last Modified:2014-12-17

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