%0 Journal Article %J PLoS One %D 2014 %T Exome sequencing reveals novel and recurrent mutations with clinical significance in inherited retinal dystrophies. %A González-del Pozo, María %A Méndez-Vidal, Cristina %A Bravo-Gil, Nereida %A Vela-Boza, Alicia %A Dopazo, Joaquin %A Borrego, Salud %A Antiňolo, Guillermo %K Adolescent %K Adult %K Amino Acid Sequence %K Base Sequence %K Child %K Chromosome Segregation %K DNA Mutational Analysis %K Exome %K Family %K Female %K Humans %K Inheritance Patterns %K Male %K Middle Aged %K Molecular Sequence Data %K mutation %K Pedigree %K Retinal Dystrophies %K Rhodopsin %X

This study aimed to identify the underlying molecular genetic cause in four Spanish families clinically diagnosed of Retinitis Pigmentosa (RP), comprising one autosomal dominant RP (adRP), two autosomal recessive RP (arRP) and one with two possible modes of inheritance: arRP or X-Linked RP (XLRP). We performed whole exome sequencing (WES) using NimbleGen SeqCap EZ Exome V3 sample preparation kit and SOLID 5500xl platform. All variants passing filter criteria were validated by Sanger sequencing to confirm familial segregation and the absence in local control population. This strategy allowed the detection of: (i) one novel heterozygous splice-site deletion in RHO, c.937-2_944del, (ii) one rare homozygous mutation in C2orf71, c.1795T>C; p.Cys599Arg, not previously associated with the disease, (iii) two heterozygous null mutations in ABCA4, c.2041C>T; p.R681* and c.6088C>T; p.R2030*, and (iv) one mutation, c.2405-2406delAG; p.Glu802Glyfs*31 in the ORF15 of RPGR. The molecular findings for RHO and C2orf71 confirmed the initial diagnosis of adRP and arRP, respectively, while patients with the two ABCA4 mutations, both previously associated with Stargardt disease, presented symptoms of RP with early macular involvement. Finally, the X-Linked inheritance was confirmed for the family with the RPGR mutation. This latter finding allowed the inclusion of carrier sisters in our preimplantational genetic diagnosis program.

%B PLoS One %V 9 %P e116176 %8 2014 %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/25544989?dopt=Abstract %R 10.1371/journal.pone.0116176 %0 Journal Article %J Hum Mutat %D 2010 %T Mutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa. %A Barragán, Isabel %A Borrego, Salud %A Pieras, Juan Ignacio %A González-del Pozo, María %A Santoyo, Javier %A Ayuso, Carmen %A Baiget, Montserrat %A Millán, José M %A Mena, Marcela %A Abd El-Aziz, Mai M %A Audo, Isabelle %A Zeitz, Christina %A Littink, Karin W %A Dopazo, Joaquin %A Bhattacharya, Shomi S %A Antiňolo, Guillermo %K Amino Acid Sequence %K Animals %K Case-Control Studies %K DNA Mutational Analysis %K Drosophila Proteins %K Evolution, Molecular %K Eye Proteins %K Female %K Genes, Recessive %K Genetic Variation %K Humans %K Male %K Molecular Sequence Data %K mutation %K Pedigree %K Polymorphism, Single Nucleotide %K Protein Structure, Tertiary %K Retinitis pigmentosa %K Spain %K Structural Homology, Protein %X

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. We have recently identified a new gene(EYS) encoding an ortholog of Drosophila space maker (spam) as a commonly mutated gene in autosomal recessive RP. In the present study, we report the identification of 73 sequence variations in EYS, of which 28 are novel. Of these, 42.9% (12/28) are very likely pathogenic, 17.9% (5/28)are possibly pathogenic, whereas 39.3% (11/28) are SNPs. In addition, we have detected 3 pathogenic changes previously reported in other populations. We are also presenting the characterisation of EYS homologues in different species, and a detailed analysis of the EYS domains, with the identification of an interesting novel feature: a putative coiled-coil domain.Majority of the mutations in the arRP patients have been found within the domain structures of EYS. The minimum observed prevalence of distinct EYS mutations in our group of patients is of 15.9% (15/94), confirming a major involvement of EYS in the pathogenesis of arRP in the Spanish population. Along with the detection of three recurrent mutations in Caucasian population, our hypothesis of EYS being the first prevalent gene in arRP has been reinforced in the present study.

%B Hum Mutat %V 31 %P E1772-800 %8 2010 Nov %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/21069908?dopt=Abstract %R 10.1002/humu.21334