Mutation analysis identifies GUCY2D as the major gene responsible for autosomal dominant progressive cone degeneration

¹ Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University Tubingen, Tubingen, Germany
² Institute for Ophthalmic Research, Centre for Ophthalmology, University Tubingen, Tubingen, Germany
³ Department of Ophthalmology, Charite Campus Benjamin Franklin, Berlin, Germany
⁴ RetinaScience, Bonn, Germany
⁵ Dipartimento di Neuroscienze, Cliniche Oftalmologia Universita di Palermo, Palermo, Italy
⁶ Anderson Vision Research Center, Retina Foundation of the Southwest, Dallas, Texas, United States

^* To whom correspondence should be addressed. E-mail: veronique.kitiratschky{at}klinikum.uni-tuebingen.de.

	Abstract

Purpose. Heterozygous mutations in the GUCY2D gene which encodes the membrane bound retinal guanylyl cyclase-1 protein (RetGC-1) have been identified to cause autosomal dominant inherited cone degeneration and cone rod degeneration (adCD, adCRD). Here we report a comprehensive screening of the GUCY2D gene in 27 adCD and adCRD unrelated families of these rare disorders. Methods. Mutation analysis was performed by direct sequencing as well as PCR and subsequent restriction length polymorphism analysis (PCR/RFLP). Haplotype analysis was performed in selected patients using microsatellite markers. Results. We identified GUCY2D gene mutations in 11 of 27 patients (40%), and all mutations clustered to codon 838 including two known and one novel missense mutations: p.R838C, p.R838H, and p.R838G. Haplotype analysis showed that among the studied patients only two of the six analyzed p.R838C mutation carriers shared a common haplotype but none of the p.R838H mutation carriers. Conclusion. Our findings indicate that GUCY2D is a major gene responsible for progressive autosomal dominant cone degeneration. All identified mutations localize to codon 838. Haplotype analysis indicates that in most cases these mutations arose independently. Thus codon 838 is likely to be a mutation hotspot in the GUCY2D gene.

Key Words: retinal degeneration, mutation screening, haplotype analysis, GUCY2D gene

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