title: Novel GUCA1A mutations suggesting possible mechanisms of pathogenesis in cone, cone-rod, and macular dystrophy patients.
abstract: 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.
authors.affiliation: Department of Cellular Therapy and Regenerative Medicine, Andalusian Centre for Molecular Biology and Regenerative Medicine (CABIMER), 'Isla Cartuja', 41092 Seville, Spain.
authors.forename: Kunka
authors.initials: K
authors.lastname: Kamenarova
authors.forename: Marta
authors.initials: M
authors.lastname: Corton
authors.forename: Blanca
authors.initials: B
authors.lastname: García-Sandoval
authors.forename: Patricia
authors.initials: P
authors.lastname: Fernández-San Jose
authors.forename: Valentin
authors.initials: V
authors.lastname: Panchev
authors.forename: Almudena
authors.initials: A
authors.lastname: Avila-Fernández
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: López-Molina
authors.forename: Christina
authors.initials: C
authors.lastname: Chakarova
authors.forename: Carmen
authors.initials: C
authors.lastname: Ayuso
authors.forename: Shomi S
authors.initials: SS
authors.lastname: Bhattacharya
mesh_terms: D005260:Female; D008040:Genetic Linkage; D015894:Genome, Human; D051604:Guanylate Cyclase-Activating Proteins / Q000235:genetics*; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics* / Q000503:physiopathology; D017948:Retinal Rod Photoreceptor Cells / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000473:pathology
chemical_list: C496736:GUCA1A protein, human; D051604:Guanylate Cyclase-Activating Proteins
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