SUMMARY OF RESEARCH

Genetics and Molecular Bases of Multiple Sclerosis

Multiple sclerosis(MS) is a disease that affects the central nervous system. The prevalence of MS in Spain is 50-100 per 100,000 inhabitants. The symptoms of the disease are varied, mainly affecting the motor skills of the individual. It is caused by the destruction of the myelin sheath of neurons due to an autoimmune attack to the oligodendrocytes, the myelin producing cells. Another feature of the disease is the accelerated death of the neurons, possibly not only as a result of the demyelination process. The etiology of this disease is unknown but it is believed that is triggered by the interaction of genetic and environmental factors .
To understand the cascade of events leading to the onset of MS, our team is developing several projects to identify molecular pathways affected in MS. For them, we perform Genome wide association study (GWAS) in collaboration with national and international consortia as the Spanish Multiple Sclerosis Network (REEM) or MSBase.

In recent years we have focused on the study of the loci IL2RA, CYP27B1, and SP140 CLEC2D. To determine as the variants localized at these loci confer susceptibility to MS, we performed functional studies analyzing the effect of the polymorphisms in the expression and processing of the mRNA. To perform this studies we employ Microarray, RNAseq and real time PCR for quantification of expression in different cell types of healthy and sick individuals and correlate this data with genotypes associated with MS. We also use data from international projects as GTEX projects, 1000 Genomes and ENCODE to determine the functional effect of the variants.

FUNDING AGENCIES LAST 5 YEARS

- INTERACCIONES GENE X AMBIENTE EN LA HETEROGENEIDAD DE LA ESCLEROSIS MULTIPLE REVELADA POR POLYGENIC RISK SCORES (PRS). PROYECTO, PN2019 - Proyectos I+D+i «Retos Investigación», Ref: PID2019-110487RB-C21, (2020 - 2024).

- Biomarcadores de Esclerosis Múltiple: RNA-Seq de células únicas en líquido cefaloraquídeo e integración de datos de GWAS internacional. PROYECTO, J.A.- Retos de la sociedad andaluza, Ref: P18-RT-2623, (2020 - 2023).

- Red Española de Esclerosis Múltiple (REEM). PROYECTO, PN2016 - REDES TEMATICAS INV. COOPERATIVA, Ref: RD16/0015/0016, (2018 - 2020).

PUBLICATIONS LAST 5 YEARS

-Isabel de Rojas;  César Martin-Montero;  Maria Fedetz;  Adela González-Jiménez;  Fuencisla Matesanz;  Elena Urcelay; Laura Espino-Paisán, Polymorphisms in ARNTL/BMAL1 and CLOCK Are Not Associated with Multiple Sclerosis in Spanish Population, Biology, 2022, Vol. 11: 141710-1417, ARTÍCULO, Id:905272

-González-Jiménez, A.; López-Cotarelo, P.; Agudo-Jiménez, T.; Casanova, I.; Silanes, C.L.d.; Martín-Requero, Á.; Matesanz, F.; Urcelay, E.; Espino-Paisán, L., Impact of Multiple Sclerosis Risk Polymorphism rs7665090 on MANBA Activity, Lysosomal Endocytosis, and Lymphocyte Activation, International Journal of Molecular Sciences, 2022, Vol. 23: 15-8116, ARTÍCULO, Id:903391

-Antonio Alcina; Maria Fedetz; Isabel Vidal-Cobo; Eduardo Andrés-León; Maria-Isabel García-Sánchez; Alicia Barroso-Del-Jesus; Sara Eichau; Elia Gil-Varea; Luisa-Maria Villar; Albert Saiz; Laura Leyva; Koen Vandenbroeck; David Otaegui; Guillermo Izquierdo; Manuel Comabella; Elena Urcelay; Fuencisla Matesanz, Identification of the genetic mechanism that associates L3MBTL3 to multiple sclerosis, Human Molecular Genetics, 2022, Vol. 31: 2155-2163, ARTÍCULO, Id:887580

-Gil-Varea, E.; Spataro, N.; Villar, L.M.; Tejeda-Velarde, A.; Midaglia, L.; Matesanz, F.; Malhotra, S.; Eixarch, H.; Patsopoulos, N.; Fernández, Ó.; Fernández, Ó.; Oliver-Martos, B.; Saiz, A.; Llufriu, S.; Ramió-Torrentà, L.; Ramió-Torrentà, L.; Quintana, E.; Izquierdo, G.; Alcina, A.; Bosch, E.; Navarro, A.; Montalban, X.; Montalban, X.; Comabella, M.; Comabella, M., Targeted resequencing reveals rare variants enrichment in multiple sclerosis susceptibility genes, Human Mutation, 2020, Vol. 41: 1308-1320, ARTÍCULO, Id:822307

-Gil-Varea E; Fedetz M; Eixarch H; Spataro N; Villar LM; Urcelay E; Saiz A; Fernández Ó; Leyva L; Ramió-Torrentà L; Vandenbroeck K; Otaegui D; Castillo-Triviño T; Izquierdo G; Malhotra S; Bosch E; Navarro A; Alcina A; Montalban X; Matesanz F; Comabella M., A New Risk Variant for Multiple Sclerosis at 11q23.3 Locus Is Associated with Expansion of CXCR5+ Circulating Regulatory T Cells, Journal of Clinical Medicine, 2020, Vol. 9: 6253-625, ARTÍCULO, Id:819279

-Gómez-Fernández P; Lopez de Lapuente Portilla A; Astobiza I; Mena J; Urtasun A; Altmann V; Matesanz F; Otaegui D; Urcelay E; Antigüedad A; Malhotra S; Montalban X; Castillo-Triviño T; Espino-Paisán L; Aktas O; Buttmann M; Chan A; Fontaine B; Gourraud PA; Hecker M; Hoffjan S; Kubisch C; Kümpfel T; Luessi F; Zettl UK; Zipp F; Alloza I; Comabella M; Lill CM; Vandenbroeck K., The Rare IL22RA2 Signal Peptide Coding Variant rs28385692 Decreases Secretion of IL-22BP Isoform-1, -2 and -3 and Is Associated with Risk for Multiple Sclerosis., Cells, 2020, Vol. 9: 1751-175, ARTÍCULO, Id:819277

-Dominguez-Mozo, M.I.; Perez-Perez, S.; Villar, L.M.; Oliver-Martos, B.; Villarrubia, N.; Matesanz, F.; Costa-Frossard, L.; Pinto-Medel, M.J.; García-Sánchez, M.I.; Ortega-Madueño, I.; Lopez-Lozano, L.; Garcia-Martinez, A.; Izquierdo, G.; Fernández, Ó.; Álvarez-Cermeño, J.C.; Arroyo, R.; Alvarez-Lafuente, R., Predictive factors and early biomarkers of response in multiple sclerosis patients treated with natalizumab, Scientific Reports, 2020, Vol. 10: 1-14244, ARTÍCULO, Id:815823

-Malhotra, S.; Costa, C.; Eixarch, H.; Keller, C.W.; Amman, L.; Martínez-Banaclocha, H.; Midaglia, L.; Sarró, E.; Machín-Díaz, I.; Villar, L.M.; Triviño, J.C.; Oliver-Martos, B.; Parladé, L.N.; Calvo-Barreiro, L.; Matesanz, F.; Vandenbroeck, K.; Urcelay, E.; Martínez-Ginés, M.L.; Tejeda-Velarde, A.; Fissolo, N.; Castilló, J.; Sanchez, A.; Robertson, A.A.B.; Clemente, D.; Prinz, M.; Pelegrin, P.; Lünemann, J.D.; Espejo, C.; Montalban, X.; Comabella, M., NLRP3 inflammasome as prognostic factor and therapeutic target in primary progressive multiple sclerosis patients, Brain, a journal of neurology, 2020, Vol. 143: 1414-1430, ARTÍCULO, Id:807041

-Vilariño-Güell, C.; Zimprich, A.; Martinelli-Boneschi, F.; Herculano, B.; Wang, Z.; Matesanz, F.; Urcelay, E.; Vandenbroeck, K.; Leyva, L.; Gris, D.; Massaad, C.; Quandt, J.A.; Traboulsee, A.L.; Encarnacion, M.; Bernales, C.Q.; Follett, J.; Yee, I.M.; Criscuoli, M.G.; Deutschländer, A.; Reinthaler, E.M.; Zrzavy, T.; Mascia, E.; Zauli, A.; Esposito, F.; Alcina, A.; Izquierdo, G.; Espino-Paisán, L.; Mena, J.; Antigüedad, A.; Urbaneja-Romero, P.; Ortega-Pinazo, J.; Song, W.; Sadovnick, A.D., Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease, PLoS Genetics, 2019, Vol. 15: , ARTÍCULO, Id:766650

-Pérez-Núñez, I.; Karaky, M.; Fedetz, M.; Barrionuevo, C.; Izquierdo, G.; Matesanz, F.; Alcina, A., Splice-site variant in ACSL5: a marker promoting opposing effect on cell viability and protein expression, European Journal of Human Genetics, 2019, Vol. : , ARTÍCULO, Id:763391

-Karaky, M.; Fedetz, M.; Potenciano, V.; Andrés-León, E.; Codina, A.E.; Barrionuevo, C.; Alcina, A.; Matesanz, F., SP140 regulates the expression of immune-related genes associated with multiple sclerosis and other autoimmune diseases by NF-κB inhibition, Human Molecular Genetics, 2018, Vol. 27: 4012-4023, ARTÍCULO, Id:735380

-Gil-Varea, E.; Urcelay, E.; Vilariño-Güell, C.; Costa, C.; Midaglia, L.; Matesanz, F.; Rodríguez-Antigüedad, A.; Oksenberg, J.; Espino-Paisan, L.; Dessa Sadovnick, A.; Saiz, A.; Villar, L.M.; García-Merino, J.A.; Ramió-Torrentà, L.; Triviño, J.C.; Quintana, E.; Robles, R.; Sánchez-López, A.; Arroyo, R.; Alvarez-Cermeño, J.C.; Vidal-Jordana, A.; Malhotra, S.; Fissolo, N.; Montalban, X.; Comabella, M., Exome sequencing study in patients with multiple sclerosis reveals variants associated with disease course 06 Biological Sciences 0604 Genetics 11 Medical and Health Sciences 1109 Neurosciences, Journal of Neuroinflammation, 2018, Vol. 15: 1-265, ARTÍCULO, Id:734143

DOCTORAL THESES LAST 5 YEARS