Scientific Background

Over the last 20 years, the DBGen team has been deeply involved in the study of the genetic basis of visual disorders, with emphasis on retinal degenerative diseases. To increase patients’ quality of life, we have been deeply involved in optimizing genetic testing and increasing the understanding of the pathogenic basis of retinal disorders.

The diagnosis of retinal disorders has been greatly hampered by the extreme genetic heterogeneity of this group of diseases. In the last twenty five years we have witnessed an enormous increase in the number of pathogenic genes, reaching over 270 in today estimates. The costs and time involved in the screening of all the candidate genes by conventional Sanger sequencing were just unattainable.

Stemming from an academic background, which facilitates the incorporation of conceptual, methodological and bioinformatic improvements, we initially developed SNP genotyping approaches for genetic testing of retinitis pigmentosa. Lately, NGS-based approaches have revolutionized genetic testing and reduced considerably the cost and time involved in DNA sequencing by capillary electrophoresis. In line with our aim for continuous innovation and improvement, we have incorporated massive sequencing approaches to our routine genetic test portfolio, among them customized gene panels, WES and WGS.

We aim to contribute to the understanding of the molecular basis of visual disorders and inspire novel therapeutic approaches. Therefore, our research is also focused on the generation of animal models and cell lines that mimic the effects associated to the pathogenic variants identified in retinal degeneration-causing genes.

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Image: Confocal images of photoreceptors, the key cells for visual signal processing, from retinal cryosections of mouse and bovine eyes. Rods and cones have been stained with specific markers: nuclei of cones and rods appear in blue, internal and external segment of cones in magenta, external segment of cones in red, and internal segment of cones and rods in green.

 

Relevant publications concerning this area of research:

DE CASTRO-MIRÓ, M.; TONDA, R.; ESCUDERO-FERRUZ, P.; ANDRÉS, R.; MAYOR-LORENZO, A.; CASTRO, J.; CICCIOLI, M.; HIDALGO, D.A.; RODRÍGUEZ-EZCURRA, J.J.; FARRANDO, J.; PÉREZ-SANTONJA, J.J.; CORMAND, B.; MARFANY, G.; GONZÀLEZ-DUARTE, R. Novel Candidate Genes and a Wide Spectrum of Structural and Point Mutations Responsible for Inherited Retinal Dystrophies Revealed by Exome Sequencing. PLoS One 11(12), 2016.

MASOUMI, K.C.; MARFANY, G.; WU, Y.; MASOUMI, R. Putative role of SUMOylation in controlling the activity of deubiquitinating enzymes in cancer. Future Oncology. 12(4): 565 – 574, 2016.

ESQUERDO, M.; GRAU-BOVÉ, X., GARANTO, A.; TOULIS, V.; GARCIA-MONCLÚS, S.; MILLO, E.; LÓPEZ-INIESTA, Mª J.; ABAD-MORALES, V.; RUIZ-TRILLO, I; MARFANY, G. Expression atlas of the deubiquitinating enzymes in the adult mouse retina, their evolutionary diversification and phenotypic roles. PLoS One 11(3): e0150364, 2016.

ABAD-MORALES, V.; DOMÈNECH, E.B.; GARANTO, A.; MARFANY, G. mRNA expression analysis of the SUMO pathway genes in the adult mouse retina. Biology Open 4(2):224-32, 2015.

BOLOC D., CASTILLO-LARA S., MARFANY M., GONZALEZ-DUARTE R. & ABRIL JF. Distilling a visual network of Retinitis Pigmentosa gene-protein interactions to uncover new disease candidates. PLoS One 10(8):e0135307, 2015.

MARFANY G. & GONZÀLEZ-DUARTE R. Clinical applications of high-throughput genetic diagnosis in retinal dystrophies: present challenges and future directions. World J Med Genet 5(2):14-22, 2015. Review.

DE CASTRO-MIRÓ M., POMARES E., LORÉS L, MARFANY G. & GONZÀLEZ-DUARTE R. Combined Genetic and High-Throughput Strategies for Molecular Diagnosis of Inherited Retinal Dystrophies. . PLoS One 9(2):e88410, 2014.

FATHINAJAFABADI A., PÉREZ-JIMÉNEZ E., RIERA M., KNECHT E & GONZÀLEZ-DUARTE R. CERKL, a Retinal Disease Gene, Encodes an mRNA-Binding Protein that Localizes in Compact and Untranslated mRNPs Associated to Microtubules. PLoS One 9(2):e87898, 2014.

RIERA M., BURGUERA D., GARCIA-FERNÀNDEZ J. & GONZÀLEZ-DUARTE R. Cerkl knockdown causes retinal degeneration in zebrafish. PLoS One 8(5):e64048, 2013.

GARANTO A., MANDAL N.M., EGIDO-GABÁS M., MARFANY G, FABRIÀS G, ANDERSON R.E., CASAS J. & GONZÀLEZ-DUARTE R. Cerkl knockdown mouse retinas show consistent sphingolipid content decrease. Exp Eye Res. 110:96-106, 2013.

GARANTO A., VICENTE-TEJEDOR J, RIERA M., DE LA VILLA-POLO P., GONZÀLEZ-DUARTE R., BLANCO-VELASCO R. & MARFANY G. The use of alternative promoters turns a targeted knockout of the Retinitis Pigmentosa gene Cerkl into a knockdown with mild affectation of the retinal ganglion cell layer. BBA – Molecular Basis of Disease. 1822: 1258–1269, 2012.

POMARES E., BURÉS-JELSTRUP A., RUIZ-NOGALES S., CORCÓSTEGUI B., GONZÁLEZ-DUARTE R. & NAVARRO R. Nonsense-mediated decay as the molecular cause for autosomal recessive bestrophinopathy in two unrelated families. Invest Ophthalmol Vis Sci. 53(1): 532-7, 2012.

OUNT, J. R.; BURR, A.A; DENUC, A.; MARFANY, G. & TODI, S.V. Ubiquitin-specific protease 25 functions in endoplasmic reticulum-associated degradation. Plos ONE 7: e36542, 2012.

POMARES E., MARFANY G. & GONZÀLEZ-DUARTE R. High-throughput approaches for the genetic diagnosis of retinal dystrophi. Adv Exp Med Biol.:329-35, 2012. Review.

GARANTO A., RIERA M., POMARES E., PERMANYER J., DE CASTRO-MIRÓ M., SAVA F., ABRIL J., MARFANY G. & GONZALEZ-DUARTE, R. High transcriptional complexity of the retinitis pigmentosa CERKL gene in human and mouse. Invest Ophthalmol Vis Sci. 52: 5202-5214, 2011.

PERMANYER, J., NAVARRO, R., FRIEDMAN, J., POMARES, E., CASTRO-NAVARRO, J., MARFANY, G., SWAROOP, A. & GONZÀLEZ-DUARTE, R. Autosomal Recessive Retinitis Pigmentosa with Early Macular Affectation Caused by Premature Trucation in PROM1. Invest Ophthalmol Vis Sci. 51:2656-63, 2010

POMARES, E.; RIERA, M.; PERMANYER, J.; MENDEZ, P.; CASTRO-NAVARRO, J.; ANDRÉS-GUTIÉRREZ, A.; MARFANY, G. & GONZÀLEZ-DUARTE, R. Comprehensive SNP-chip for Retinitis Pigmentosa-Leber Congenital Amaurosis diagnosis: new mutations and detection of mutational founder effects. Eur J Hum Genet. 18(1):118-24, 2010

POMARES E., MARFANY G., BRION M., CARRACEDO A. & GONZÀLEZ-DUARTE R. Novel high-throughput SNP genotyping cosegregation analysis for genetic diagnosis of autosomal recessive Retinitis Pigmentosa and Leber Congenital Amaurosis. Human Mutation 28(5): 511-6, 2007

USÓN M., MARFANY G. & Gonzàlez-Duarte R. Mutation of CERKL, a novel human ceramide kinase gene, causes autosomal recessive retinitis pigmentosa (RP26). American J. Human Genetics 74: 128-138, 2004

MARTINEZ MIR A., PALOMA E, ALLIKMETS R., DEAN M., AYUSO C., DEL RIO T., VILAGELIU LL., GONZÀLEZ-DUARTE R.& BALCELLS S. Retinitis pigmentosa caused by homozygous mutation in the Stargardt disease gene ABCR. Nature Genetics 18: 11-12, 1998