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

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Abstract

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.

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References

  • Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2002) Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97–101

    Article  PubMed  CAS  Google Scholar 

  • Aldave AJ, Yellore VS, Salem AK, Yoo GL, Rayner SA, Yang H, Tang GY, Piconell Y, Rabinowitz YS (2006) No VSX1 gene mutations associated with keratoconus. Invest Ophthalmol Vis Sci 47:2820–2822

    Article  PubMed  Google Scholar 

  • Aso T, Lane WS, Conaway JW, Conaway RC (1995) Elongin (SIII): a multisubunit regulator of elongation by RNA polymerase II. Science 269:1439–1443

    Article  PubMed  CAS  Google Scholar 

  • Bisceglia L, Ciaschetti M, De Bonis P, Campo PA, Pizzicoli C, Scala C, Grifa M, Ciavarella P, Delle Noci N, Vaira F, Macaluso C, Zelante L (2005) VSX1 mutational analysis in a series of Italian patients affected by keratoconus: detection of a novel mutation. Invest Ophthalmol Vis Sci 46:39–45

    Article  PubMed  Google Scholar 

  • Brancati F, Valente EM, Sarkozy A, Feher J, Castori M, Del Duca P, Mingarelli R, Pizzuti A, Dallapiccola B (2004) A locus for autosomal dominant keratoconus maps to human chromosome 3p14-q13. J Med Genet 41:188–192

    Article  PubMed  CAS  Google Scholar 

  • Evereklioglu C, Madenci E, Bayazit YA, Yilmaz K, Balat A, Bekir NA (2002) Central corneal thickness is lower in osteogenesis imperfecta and negatively correlates with the presence of blue sclera. Ophthalmic Physiol Opt 22:511–515

    Article  PubMed  Google Scholar 

  • Fullerton J, Paprocki P, Foote S, Mackey DA, Williamson R, Forrest S (2002) Identity-by-descent approach to gene localisation in eight individuals affected by keratoconus from north-west Tasmania, Australia. Hum Genet 110:462–470

    Article  PubMed  CAS  Google Scholar 

  • Giunta C, Randolph A, Steinmann B (2005) Mutation analysis of the PLOD1 gene: an efficient multistep approach to the molecular diagnosis of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA). Mol Genet Metab 86:269–276

    Article  PubMed  CAS  Google Scholar 

  • Heon E, Greenberg A, Kopp KK, Rootman D, Vincent AL, Billingsley G, Priston M, Dorval KM, Chow RL, McInnes RR, Heathcote G, Westall C, Sutphin JE, Semina E, Bremner R, Stone EM (2002) VSX1: a gene for posterior polymorphous dystrophy and keratoconus. Hum Mol Genet 11:1029–1036

    Article  PubMed  CAS  Google Scholar 

  • Hughes AE, Dash DP, Jackson AJ, Frazer DG, Silvestri G (2003) Familial keratoconus with cataract: linkage to the long arm of chromosome 15 and exclusion of candidate genes. Invest Ophthalmol Vis Sci 44:5063–5066

    Article  PubMed  Google Scholar 

  • Hutchings H, Ginisty H, Le Gallo M, Levy D, Stoesser F, Rouland JF, Arne JL, Lalaux MH, Calvas P, Roth MP, Hovnanian A, Malecaze F (2005) Identification of a new locus for isolated familial keratoconus at 2p24. J Med Genet 42:88–94

    Article  PubMed  CAS  Google Scholar 

  • Li X, Rabinowitz YS, Tang YG, Picornell Y, Taylor KD, Hu M, Yang H (2006) Two-stage genome-wide linkage scan in keratoconus sib pair families. Invest Ophthalmol Vis Sci 47:3791–3795

    Article  PubMed  Google Scholar 

  • Orr A, Dube MP, Marcadier J, Jiang H, Federico A, George S, Seamone C, Andrews D, Dubord P, Holland S, Provost S, Mongrain V, Evans S, Higgins B, Bowman S, Guernsey D, Samuels M (2007) Mutations in the UBIAD1 gene, encoding a potential prenyltransferase, are causal for Schnyder crystalline corneal dystrophy. PLoS ONE 2:e685

    Article  PubMed  CAS  Google Scholar 

  • Pedersen U, Bramsen T (1984) Central corneal thickness in osteogenesis imperfecta and otosclerosis. ORL J Otorhinolaryngol Relat Spec 46:38–41

    PubMed  CAS  Google Scholar 

  • Rabinowitz YS (1998) Keratoconus. Surv Ophthalmol 42:297–319

    Article  PubMed  CAS  Google Scholar 

  • Rabinowitz YS (2003) The genetics of keratoconus. Ophthalmol Clin North Am 16:607–620 vii

    Article  PubMed  Google Scholar 

  • Rabinowitz YS, Dong L, Wistow G (2005) Gene expression profile studies of human keratoconus cornea for NEIBank: a novel cornea-expressed gene and the absence of transcripts for aquaporin 5. Invest Ophthalmol Vis Sci 46:1239–1246

    Article  PubMed  Google Scholar 

  • Strauch K, Fimmers R, Kurz T, Deichmann KA, Wienker TF, Baur MP (2000) Parametric and nonparametric multipoint linkage analysis with imprinting and two-locus-trait models: application to mite sensitization. Am J Hum Genet 66:1945–1957

    Article  PubMed  CAS  Google Scholar 

  • Tago K, Nakamura T, Nishita M, Hyodo J, Nagai S, Murata Y, Adachi S, Ohwada S, Morishita Y, Shibuya H, Akiyama T (2000) Inhibition of Wnt signaling by ICAT, a novel beta-catenin-interacting protein. Genes Dev 14:1741–1749

    PubMed  CAS  Google Scholar 

  • Tang YG, Rabinowitz YS, Taylor KD, Li X, Hu M, Picornell Y, Yang H (2005) Genomewide linkage scan in a multigeneration Caucasian pedigree identifies a novel locus for keratoconus on chromosome 5q14.3-q21.1. Genet Med 7:397–405

    Article  PubMed  CAS  Google Scholar 

  • Tyynismaa H, Sistonen P, Tuupanen S, Tervo T, Dammert A, Latvala T, Alitalo T (2002) A locus for autosomal dominant keratoconus: linkage to 16q22.3-q23.1 in Finnish families. Invest Ophthalmol Vis Sci 43:3160–3164

    PubMed  Google Scholar 

  • Wang D, Li Z, Messing EM, Wu G (2005) The SPRY domain-containing SOCS box protein 1 (SSB-1) interacts with MET and enhances the hepatocyte growth factor-induced Erk-Elk-1-serum response element pathway. J Biol Chem 280:16393–16401

    Article  PubMed  CAS  Google Scholar 

  • Weeks DE, Ott J, Lathrop GM (1990) SLINK: a general simulation program for linkage analysis. Am J Hum Genet 47:A204 Supplement

    Google Scholar 

  • Weiss JS, Kruth HS, Kuivaniemi H, Tromp G, White PS, Winters RS, Lisch W, Henn W, Denninger E, Krause M, Wasson P, Ebenezer N, Mahurkar S, Nickerson ML (2007) Mutations in the UBIAD1 gene on chromosome short arm 1, region 36, cause Schnyder crystalline corneal dystrophy. Invest Ophthalmol Vis Sci 48:5007–5012

    Article  PubMed  Google Scholar 

  • Williams K, Hornsby N, Bartlett C, Holland H, Esterman A, Coster D (2004) The Australian Corneal Graft Registry 2004 Report. Snap Printing, Adelaide

    Google Scholar 

  • Wistow GJ, Lietman T, Williams LA, Stapel SO, de Jong WW, Horwitz J, Piatigorsky J (1988) T-crystallin/a-enolase: one gene encodes both an enzyme and a lens structural protein. J Cell Biol 107:2729–2736

    Article  PubMed  CAS  Google Scholar 

  • Yellore VS, Khan MA, Bourla N, Rayner SA, Chen MC, Sonmez B, Momi RS, Sampat KM, Gorin MB, Aldave AJ (2007) Identification of mutations in UBIAD1 following exclusion of coding mutations in the chromosome 1p36 locus for Schnyder crystalline corneal dystrophy. Mol Vis 13:1777–1782

    PubMed  CAS  Google Scholar 

  • Zhang JG, Farley A, Nicholson SE, Willson TA, Zugaro LM, Simpson RJ, Moritz RL, Cary D, Richardson R, Hausmann G, Kile BJ, Kent SB, Alexander WS, Metcalf D, Hilton DJ, Nicola NA, Baca M (1999) The conserved SOCS box motif in suppressors of cytokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation. Proc Natl Acad Sci USA 96:2071–2076

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by a grant from the Ophthalmic Research Institute of Australia. KPB is a Peter Doherty Research Fellow of the National Health and Medical Research Council of Australia (NHMRC) and JEC is supported by a Practitioner Fellowship from NHMRC.

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Correspondence to Kathryn P. Burdon.

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Burdon, K.P., Coster, D.J., Charlesworth, J.C. et al. Apparent autosomal dominant keratoconus in a large Australian pedigree accounted for by digenic inheritance of two novel loci. Hum Genet 124, 379–386 (2008). https://doi.org/10.1007/s00439-008-0555-z

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  • DOI: https://doi.org/10.1007/s00439-008-0555-z

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