Rare diseases: what are they and who do they affect?


A Rare Disease is one with a prevalence of less than 1 case per 2000 inhabitants. It is estimated that there are between 5,000 and 7,000 different rare diseases, some of which affect a small number of people around the world. However, taking into account the different pathologies, it is calculated that between 6 and 8% of the world population would be afflicted by any of these diseases. Therefore, an estimated 30 million Europeans suffer from various rare diseases.


In the laboratory we are interested in understanding the mechanisms subjacent to Townes-Brocks Syndrome ad other diseases related to the Ubiquitin-like family, i.e. Angelman Syndrome.


Spalt-like (SALL) Family of Transcription Factors


Mutations in this important family of zinc finger transcription factors are related to hereditary syndromes, such as the Townes-Brocks or the Okihiro (Duane-Radial Ray) Syndromes. These are considered as Rare Diseases and characterized by hearing loss, renal and limb malformations, among other symptoms.

In Drosophila we studied the role of Sall factors in neurodegeneration, limb and nervous system formation. We also studied the modification of these proteins by SUMO and how this affects their role.

In humans and mouse models we study the mechanis by which these factors are involved in Townes-Brocks Syndrome. We discovered that primary cilia are altered in cells from affected individuals.


Click here if you are a person affected by Townes-Brocks Syndrome.



> Cells derived from Townes-Brocks individuals show longer primary cilia. Publication: Bozal-Basterra et al. Truncated SALL1 impedes primary cilia function in Townes-Brocks Syndrome. The American Journal of Human Genetics (2018), 102, 249–265. PMID: 29395072








Publications on SALL & Rare Diseases

Other Laboratory Publications




Orhi Barroso-Gomila, Fredrik Trulsson, Veronica Muratore, Iñigo Canosa, Laura Merino-Cacho, Ana Rosa Cortazar, Coralia Perez, Mikel Azkargorta, Ibon Iloro, Arkaitz Carracedo, Ana M Aransay, Felix Elortza, Ugo Mayor, Alfred C. O. Vertegaal, Rosa Barrio*, James D. Sutherland*

Nat Commun. 2021 Nov 18;12(1):6671. doi: 10.1038/s41467-021-26807-6.

PMID: 34795231










SALL1 Modulates CBX4 Stability, Nuclear Bodies, and Regulation of Target Genes.

Giordano I, Pirone L, Muratore V, Landaluze E, Pérez C, Lang V, Garde-Lapido E, Gonzalez-Lopez M, Barroso-Gomila O, Vertegaal ACO, Aransay AM, Rodriguez JA, Rodriguez MS, Sutherland JD*, Barrio R.*

Front Cell Dev Biol. 2021 Sep 21;9:715868. doi: 10.3389/fcell.2021.715868. eCollection 2021.

PMID: 34153521










LUZP1 controls cell division, migration and invasion through regulation of the actin cytoskeleton

Bozal-Basterra L, Gonzalez-Santamarta M, Muratore V, Martín-Martín N, Ercilla A, Rodríguez JA, Carracedo A, Sutherland JD*, Barrio R.*

Front Cell Dev Biol. 2021 Apr 1;9:624089. doi: 10.3389/fcell.2021.624089.

PMID: 33869174










Role of Sumoylation in Neurodegenerative Diseases and Inflammation

Esmeralda Parra-Peralbo, Veronica Muratore, Orhi Barroso-Gomila, Ana Talamillo, James D. Sutherland, Rosa Barrio*

Oxidative Stress and Disease book series edited by Enrique Cadenas and Helmut Sies on Proteostasis, CRC Press, Taylor & Francis Group. doi: 10.1201/9781003048138-8.

ISBN: 9781003048138










Proteostasis and Disease: From Basic Mechanisms to Clinics

Editors: Rosa Barrio, James D. Sutherland, Manuel S. Rodriguez

Advances in Experimental Medicine and Biology (AEMB, volume 1233), 2020, Springer. doi: 10.1007/978-3-030-38266-7.

ISBN: 9783030382650; ISBN: 9783030382667









LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is a contributing factor in Townes-Brocks Syndrome.

Bozal-Basterra L, Gonzalez-Santamarta M, Muratore V, Bermejo-Arteagabeitia A, Da Fonseca C, Barroso-Gomila O, Azkargorta M, Iloro I, Pampliega O, Andrade R, Martín-Martín N, Branon TC, Ting AY, Rodríguez JA, Carracedo A, Elortza F, Sutherland JD*, Barrio R.*

Elife. 2020 Jun 18;9:e55957. doi: 10.7554/eLife.55957.

PMID: 32553112









The role of SUMOylation during development

Talamillo A*, Barroso-Gomila O, Giordano I, Ajuria L, Grillo M, Mayor U, Barrio R.*

Biochem Soc Trans. 2020 Apr 29;48(2):463-478. doi: 10.1042/BST20190390.

PMID: 32311032












Proteostasis

Semin Cell Dev Biol. 2019 Sep;93 special issue



Proteostasis: The network behind the networks.

Barrio R, Sutherland JD.

Semin Cell Dev Biol. 2019 Sep;93:97-99. doi: 10.1016/j.semcdb.2019.04.011. Epub 2019 Apr 21.

PMID: 31004754



Impaired proteostasis in rare neurological diseases.

Osinalde N, Duarri A, Ramirez J, Barrio R, de Nanclares GP, Mayor U.*

Semin Cell Dev Biol. (2018) pii: S1084-9521(18)30161-7. doi: 10.1016/j.semcdb.2018.10.007.

PMID: 30355526







Putting the Stress on UFM1 (Ubiquitin-Fold Modifier 1).

Sutherland JD*, Barrio R*.

Circ Heart Fail. (2018) 11(10):e005455. doi: 10.1161/CIRCHEARTFAILURE.118.005455.

PMID: 30354403







Quantitative proteomics reveals neuronal ubiquitination of Rngo/Ddi1 and several proteasomal subunits by Ube3a, accounting for the complexity of Angelman syndrome.

Ramirez J, Lectez B, Osinalde N, Sivá M, Elu N, Aloria K, Procházková M, Perez C, Martínez-Hernández J, Barrio R, Grantz Šašková K, Arizmendi JM and Mayor U*

Human Molecular Genetics (2018) 27(11):1955-1971. doi: 10.1093/hmg/ddy103.

PMID: 29788202



Truncated SALL1 impedes primary cilia function in Townes-Brocks Syndrome.

Bozal-Basterra L, Martín-Ruíz I, Pirone L, Liang Y, Sigurdsson JO, Gonzalez-Santamarta M, Giordano I, Gabicagogeascoa E, de Luca A, Rodríguez JA, Wilkie AOM, Kohlhase J, Eastwood D, Yale C, Olsen JV, Rauchman M, Anderson KV, Sutherland JD*, Barrio R*

The American Journal of Human Genetics (2018), 102, 249–265. doi: 10.1016/j.ajhg.2017.12.017.

PMID: 29395072






Drosophila melanogaster White Mutant w1118 undergo retinal degeneration

Ferreiro MJ*, Pérez C, Ruiz S, Marchesano M, Ruiz S, Caputi A, Aguilera P, Barrio R, Cantera R.

Frontiers in Neuroscience (2018) 11:732. doi: 10.3389/fnins.2017.00732.

PMID: 29354028


Quantitative proteomic analysis of Parkin substrates in Drosophila neurons.

Martinez A, Lectez B, Ramirez J, Popp O, Sutherland JD, Urbé S, Dittmar G, Clague MJ, Mayor U.*

Mol Neurodegener. 2017 Apr 11;12(1):29. doi: 10.1186/s13024-017-0170-3

PMID: 28399880



A comprehensive platform for the analysis of ubiquitin-like protein modifications using in vivo biotinylation

Pirone L, Xolalpa W, Sigurðsson JO, Ramirez J, Pérez C, González M, de Sabando AR, Elortza F, Rodriguez MS, Mayor U, Olsen JV, Barrio R*, Sutherland JD.*

Scientific Reports (2017) 7:40756. doi: 10.1038/srep40756

PMID: 28098257




SALL1 and the Townes-Brocks syndrome.

Kohlhase J*, Barrio R and Sutherland JD

Epstein's Inborn Errors of Development (2016) Oxford University Press USA Chapter 33. doi: 10.1093/med/9780199934522.003.0033

ISBN: 9780199934522


SALL4 and the Duane Radial-Ray/ Okihiro and Acro-renal-ocular syndromes.

Kohlhase J*, Barrio R and Sutherland JD

Epstein's Inborn Errors of Development (2016) Oxford University Press USA Chapter 135. doi: 10.1093/med/9780199934522.003.0135

ISBN: 9780199934522



The Spalt Transcription Factors Generate the Transcriptional Landscape of the Drosophila melanogaster Wing Pouch Central Region

Organista MF, Martín M, de Celis JM, Barrio R, López-Varea A, Esteban N, Casado M, de Celis JF.*

PLoS Genetics (2015) 11(8):e1005370. doi: 10.1371/journal.pgen.1005370

PMID: 26241320


Cantera R*, Barrio R.

Journal of Innate Immunity (2015) 7(1):3-10s. doi: 10.1159/000365195

PMID: 25115549



Global gene expression shift during the transition from early neural development to late neuronal differentiation in Drosophila melanogaster.

Cantera R*, Ferreiro MJ, Aransay AM, Barrio R.*

PLoS One (2014) 9(5):e97703. doi: 10.1371/journal.pone.0097703

PMID: 24830291


Ube3a, the E3 ubiquitin ligase causing Angelman syndrome and linked to autism, regulates protein homeostasis through the proteasomal shuttle Rpn10.

Lee SY, Ramirez J, Franco M, Lectez B, Gonzalez M, Barrio R, Mayor U.*

Cell Mol Life Sci. 2014, 71(14):2747-58. doi: 10.1007/s00018-013-1526-7.

PMID: 24292889


Whole transcriptome analysis of a reversible neurodegenerative process in Drosophila reveals potential neuroprotective genes.

Ferreiro MJ, Rodríguez-Ezpeleta N, Pérez C, Hackenberg M, Aransay AM, Barrio R*, Cantera R.*

BMC Genomics. 2012 Sep 15;13(1):483. doi: 10.1186/1471-2164-13-483

PMID: 22978642


Efficient allele-specific targeting of LRRK2 R1441 mutations mediated by RNAi.

de Yñigo-Mojado L, Martín-Ruíz I, Sutherland JD.*

PLoS One. 2011;6(6):e21352. Epub 2011 Jun 21. doi: 10.1371/journal.pone.0021352

PMID: 21712955


Drosophila Sal and Salr are transcriptional repressors.

Sánchez J, Talamillo A, González M, Sánchez-Pulido L, Jiménez S, Pirone L, Sutherland JD, Barrio R.*

Biochem J. 2011 Sep 15;438(3):437-45. doi: 10.1042/BJ20110229

PMID: 21689070





J Biol Chem. 2010 Aug 13;285(33):25841-9. Epub 2010 Jun 18.

Sumoylation modulates the activity of Spalt-like proteins during wing development in Drosophila.

Sánchez J, Talamillo A, Lopitz-Otsoa F, Pérez C, Hjerpe R, Sutherland JD, Herboso L, Rodríguez MS, Barrio R.

PMID: 20562097





Int J Dev Biol. 2009;53(8-10):1385-98.

Regulation and function of Spalt proteins during animal development.

de Celis JF, Barrio R.

PMID: 19247946


Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6021-6. Epub 2004 Apr 12.

Regulation of spalt expression in the Drosophila wing blade in response to the Decapentaplegic signaling pathway.

Barrio R, de Celis JF.

PMID: 15079076


Dev Biol. 2004 Sep 1;273(1):121-33.

Regulation of R7 and R8 differentiation by the spalt genes.

Domingos PM, Brown S, Barrio R, Ratnakumar K, Frankfort BJ, Mardon G, Steller H, Mollereau B.

PMID: 15302602


Development. 2002 Dec;129(24):5577-86.

Mutations in spalt cause a severe but reversible neurodegenerative phenotype in the embryonic central nervous system of Drosophila melanogaster.

Cantera R, Lüer K, Rusten TE, Barrio R, Kafatos FC, Technau GM.

PMID: 12421699



Development. 2001 Mar;128(5):711-22.

Spalt modifies EGFR-mediated induction of chordotonal precursors in the embryonic PNS of Drosophila promoting the development of oenocytes.

Rusten TE, Cantera R, Urban J, Technau G, Kafatos FC, Barrio R.

PMID: 11171396



Mech Dev. 2000 Mar 1;91(1-2):31-41.

Function of the spalt/spalt-related gene complex in positioning the veins in the Drosophila wing.

de Celis JF, Barrio R.

PMID: 10704828


Dev Biol. 1999 Nov 1;215(1):33-47.

Identification of regulatory regions driving the expression of the Drosophila spalt complex at different developmental stages.

Barrio R, de Celis JF, Bolshakov S, Kafatos FC.

PMID: 10525348


Development. 1999 Jun;126(12):2653-62.

Regulation of the spalt/spalt-related gene complex and its function during sensory organ development in the Drosophila thorax.

de Celis JF, Barrio R, Kafatos FC.

PMID: 10331977



Development, Genes and Evolution. 1996;206(5):315-325.

The spalt-related gene of Drosophila melanogaster is a member of an ancient gene family, defined by the adjacent, region-specific homeotic gene spalt.

R. Barrio, Martin J. Shea, John Carulli, Karen Lipkow, Ulrike Gaul, Götz Frommer, Reinhard Schuh, Herbert Jäckle, F. C. Kafatos

PMID: 24173589




Chromosoma. 1996 Mar;104(6):445-54.

Regulation, function and potential origin of the Drosophila gene spalt adjacent, which encodes a secreted protein expressed in the early embryo.

Reuter D, Kühnlein RP, Frommer G, Barrio R, Kafatos FC, Jäckle H, Schuh R.

PMID: 8601339


Nature. 1996 May 30;381(6581):421-4.

A gene complex acting downstream of dpp in Drosophila wing morphogenesis.

de Celis JF, Barrio R, Kafatos FC.

PMID: 8632798



Other Laboratory Publications