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BioMed Research International
Volume 2013, Article ID 517570, 15 pages
Clinical Study

Novel GUCA1A Mutations Suggesting Possible Mechanisms of Pathogenesis in Cone, Cone-Rod, and Macular Dystrophy Patients

1Department of Cellular Therapy and Regenerative Medicine, Andalusian Centre for Molecular Biology and Regenerative Medicine (CABIMER), ‘Isla Cartuja’, 41092 Seville, Spain
2Department of Genetics, IIS-Jiménez Díaz Foundation, 28040 Madrid, Spain
3Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, 46010 Valencia, Spain
4Department of Ophthalmology, Hospital ‘Fundación Jiménez Díaz’, 28040 Madrid, Spain
5Department of Genetics, UCL-Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK

Received 18 April 2013; Accepted 19 June 2013

Academic Editor: Claudia Gragnoli

Copyright © 2013 Kunka Kamenarova et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Here, we report two novel GUCA1A (the gene for guanylate cyclase activating protein 1) mutations identified in unrelated Spanish families affected by autosomal dominant retinal degeneration (adRD) with cone and rod involvement. All patients from a three-generation adRD pedigree underwent detailed ophthalmic evaluation. Total genome scan using single-nucleotide polymorphisms and then the linkage analysis were undertaken on the pedigree. Haplotype analysis revealed a 55.37 Mb genomic interval cosegregating with the disease phenotype on chromosome 6p21.31-q15. Mutation screening of positional candidate genes found a heterozygous transition c.250C>T in exon 4 of GUCA1A, corresponding to a novel mutation p.L84F. A second missense mutation, c.320T>C (p.I107T), was detected by screening of the gene in a Spanish patients cohort. Using bioinformatics approach, we predicted that either haploinsufficiency or dominant-negative effect accompanied by creation of a novel function for the mutant protein is a possible mechanism of the disease due to c.250C>T and c.320T>C. Although additional functional studies are required, our data in relation to the c.250C>T mutation open the possibility that transacting factors binding to de novo created recognition site resulting in formation of aberrant splicing variant is a disease model which may be more widespread than previously recognized as a mechanism causing inherited RD.