Genes and Mutations in Autosomal Dominant Cone and Cone-Rod Dystrophy

  • Susanne KohlEmail author
  • Veronique Kitiratschky
  • Monika Papke
  • Simone Schaich
  • Alexandra Sauer
  • Bernd Wissinger
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 723)


To date, mutations in ten genes have been described to cause autosomal dominant cone or cone-rod dystrophies; sometimes only a single report. Since a systematic investigation for these genes in patients with adCD and adCRD are lacking, we undertook a study to determine the prevalence and mutation spectrum of PRPH2, CRX, GUCA1A, GUCY2D, AIPL1, UNC119, PROM1 and PITPNM3 mutations in 52 unrelated patients and families with this rare diagnosis. We identified 15 different mutations in 25 families with adCD and adCRD: one patient carried a mutation in PROM1 (2%), 2 in CRX (4%), 4 in GUCA1A (8%), 6 in PRPH2 (11%) and 12 in GUCY2D (23%). Our analyses show that mutations in these genes account for ∼50% of all adCD and adCRD cases, while the other half still remains unsolved. No pathogenic variants were identified in AIPL1, UNC119 and PITPNM3 indicating that these only play a minor role in adCD and adCRD.


Cone dystrophy Cone-rod dystrophy Retinal degeneration PRPH2 CRX GUCA1A GUCY2D AIPL1 UNC119 PROM1 PITPNM3 



We thank all patients participating and all clinicians contributing patients to this study, and Britta Baumann for excellent technical assistance. This study was supported by the German Research Council DFG (KFO134:Ko2176/2-1).


  1. Boon CJ, den Hollander AI, Hoyng CB et al (2008) The spectrum of retinal dystrophies caused by mutations in the peripherin/RDS gene. Prog Retin Eye Res 27:213–35PubMedCrossRefGoogle Scholar
  2. Corbeil D, Röper K, Fargeas CA et al (2001) Prominin: a story of cholesterol, plasma membrane protrusions and human pathology. Traffic 2:82–91PubMedCrossRefGoogle Scholar
  3. Corbeil D, Röper K, Hellwig A et al (2000) The human AC133 hematopoietic stem cell antigen is also expressed in epithelial cells and targeted to plasma membrane protrusions. J Biol Chem 275:5512–20PubMedCrossRefGoogle Scholar
  4. Ding XQ, Stricker HM, Naash MI (2005) Role of the second intradiscal loop of peripherin/rds in homo and hetero associations. Biochemistry 44:4897–904PubMedCrossRefGoogle Scholar
  5. Grüning G, Millan JM, Meins M et al (1994) Mutations in the human peripherin/RDS gene associated with autosomal dominant retinitis pigmentosa. Hum Mutat 3:321–3PubMedCrossRefGoogle Scholar
  6. Hamel CP (2007) Cone rod dystrophies. Orphanet J Rare Dis. 2:1–7CrossRefGoogle Scholar
  7. Hunt DM, Buch P, Michaelides M (2010) Guanylate cyclases and associated activator proteins in retinal disease. Mol Cell Biochem 334:157–68PubMedCrossRefGoogle Scholar
  8. Kelsell RE, Gregory-Evans K, Payne AM et al (1998) Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant cone-rod dystrophy. Hum Mol Genet 7:1179–84PubMedCrossRefGoogle Scholar
  9. Kitiratschky VB, Behnen P, Kellner U et al (2009) Mutations in the GUCA1A gene involved in hereditary cone dystrophies impair calcium-mediated regulation of guanylate cyclase. Hum Mutat 30:E782–96PubMedCrossRefGoogle Scholar
  10. Kitiratschky VB, Nagy D, Zabel T et al (2008a) Cone and cone-rod dystrophy segregating in the same pedigree due to the same novel CRX gene mutation. Br J Ophthalmol 92:1086–91PubMedCrossRefGoogle Scholar
  11. Kitiratschky VB, Wilke R, Renner AB et al (2008b) Mutation analysis identifies GUCY2D as the major gene responsible for autosomal dominant progressive cone degeneration. Invest Ophthalmol Vis Sci 49:5015–23PubMedCrossRefGoogle Scholar
  12. Kobayashi A, Higashide T, Hamasaki D et al (2000) HRG4 (UNC119) mutation found in cone-rod dystrophy causes retinal degeneration in a transgenic model. Invest Ophthalmol Vis Sci 41:3268–77PubMedGoogle Scholar
  13. Kohl S, Christ-Adler M, Apfelstedt-Sylla E et al (1997) RDS/peripherin gene mutations are frequent causes of central retinal dystrophies. J Med Genet 34:620–6PubMedCrossRefGoogle Scholar
  14. Köhn L, Kadzhaev K, Burstedt MS et al (2007) Mutation in the PYK2-binding domain of PITPNM3 causes autosomal dominant cone dystrophy (CORD5) in two Swedish families. Eur J Hum Genet 15:664–71PubMedCrossRefGoogle Scholar
  15. Köhn L, Kohl S, Bowne SJ et al (2010) PITPNM3 is an uncommon cause of cone and cone-rod dystrophies. Ophthalmic Genet 31:139–40PubMedCrossRefGoogle Scholar
  16. Lamb TD, Pugh EN Jr (2006) Phototransduction, dark adaptation, and rhodopsin regeneration the proctor lecture. Invest Ophthalmol Vis Sci 47:5137–52PubMedCrossRefGoogle Scholar
  17. Maw MA, Corbeil D, Koch J et al (2000) A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration. Hum Mol Genet 9:27–34PubMedCrossRefGoogle Scholar
  18. Michaelides M, Gaillard MC, Escher P et al (2010) The PROM1 mutation p.R373C causes an autosomal dominant bull’s eye maculopathy associated with rod, rod-cone, and macular ­dystrophy. Invest Ophthalmol Vis Sci 51:4771–80PubMedCrossRefGoogle Scholar
  19. Payne AM, Morris AG, Downes SM et al (2001) Clustering and frequency of mutations in the retinal guanylate cyclase (GUCY2D) gene in patients with dominant cone-rod dystrophies. J Med Genet 38:611–4PubMedCrossRefGoogle Scholar
  20. Sohocki MM, Perrault I, Leroy BP et al (2000) Prevalence of AIPL1 mutations in inherited retinal degenerative disease. Mol Genet Metab 70:142–50PubMedCrossRefGoogle Scholar
  21. Sokal I, Dupps WJ, Grassi MA et al (2005) A novel GCAP1 missense mutation (L151F) in a large family with autosomal dominant cone-rod dystrophy (adCORD). Invest Ophthalmol Vis Sci 46:1124–32PubMedCrossRefGoogle Scholar
  22. Swaroop A, Kim D, Forrest D (2010) Transcriptional regulation of photoreceptor development and homeostasis in the mammalian retina. Nat Rev Neurosci 11:563–76PubMedCrossRefGoogle Scholar
  23. Wells J, Wroblewski J, Keen J et al (1993) Mutations in the human retinal degeneration slow (RDS) gene can cause either retinitis pigmentosa or macular dystrophy. Nat Genet 3:213–8PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Susanne Kohl
    • 1
    Email author
  • Veronique Kitiratschky
    • 1
  • Monika Papke
    • 1
  • Simone Schaich
    • 1
  • Alexandra Sauer
    • 1
  • Bernd Wissinger
    • 1
  1. 1.Department for Ophthalmology, Molecular Genetics Laboratory, Institute for Ophthalmic ResearchUniversity TuebingenS TuebingenGermany

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