Otology & Neurotology- Genomics of vestibular disorders

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Otology & Neurotology- Genomics of vestibular disorders

Dr. Jose Antonio Lopez-Escamez

Scientific interest areas

Proyecto de investigación de acúfenos

Estudio descriptivo del acufeno en España mediante dos cuestionarios:

1. Cuestionario THI
2. Cuestionario ESIT

Vertigo and imbalance are a major health problem caused by several disorders of the vestibular system involving the inner ear and the brain. The most common causes are benign paroxysmal positional vertigo, vestibular migraine and Menière’s disease. Among them, Menière’s disease (MD) is the most severe form of vertigo and tinnitus.

Meniere is a set of rare disorders of the inner ear causing sensorineural hearing loss, vertigo episodes and tinnitus with a prevalence of 75 cases/100.000 population in Spain. Familial Menière’s disease represents 8-9% of the cases and it has a genetic heterogeneity with an autosomal dominant inheritance pattern. There are several clinical subgroups, suggesting different mechanisms of disease including autoimmune, autoinflamatory and genetic factors. Our group has compiled the largest collection of human DNA samples from MD patients including >100 multicase families and > 2000 sporadic cases to define the genetic contribution associated with Md. For this purpose we have genotyped sporadic cases defining common variants in noncoding regions. Also, we have performed whole exome sequencing (WES) in multicase families in order to identify very rare or de novo coding variants with high penetrance.

We have identified a common variant rs4947296 in chromosome 6p21.33, in cases with involvement of both ears, that could define autoimmune inner ear disease. This regulatory variant is an eQTL that influence several genes in the the TWEAK/Fn14 pathway Furthermore, we have defined novel mutations for familial MD in FAM136A, PRKCB, DTNA, DPT and SEMA3D genes in 4 families with autosomal dominant inheritance. Currently, we are assessing the functional role of these genes in a stem cell and zebrafish model.

We are developing an integrated network of molecular pathways, the MDmap, which includes multi-omics data to define endophenotypes according to specific mechanisms of the disease http://disease-maps.org/menieres.

Research areas

  • Line 1. Genetic contribution to autoimmune Ménière’s disease (MD).
    The aim of the proposed research is to identify the major genes involved in autoimmune MD as well as the biochemical pathways associated with sporadic MD to decode the driving and modifiers genes of MD.For this purpose we genotyped by a microarray with 186 loci associated with autoimmune diseases (Inmunochip) in a cohort of patients from Spain and we identified a locus at chromosome 6p21.33 in patients with bilateral sensorineural hearing loss. These locus regulates the expression of HLA class II molecules, as well as several genes in the TWEAK / Fn14 pathway. The carriers of this variant have an NF-kB-mediated inflammatory response in monocytes and lymphocytes.
  • Line 2. Identification of driver genes in familial Ménière’s disease. Familial MD represents 8-9% of the cases and it has a genetic heterogeneity with autosomal dominant, autosomal recessive and mitochondrial inheritance patterns, being expected an interaction between multiple genes in each family, which would explain the incomplete penetrance or intermediate phenotypes.Bioinformatic analysis includes the selection of rare variants in our cases to identify candidate genes in each family, and gene-set enrichment analysis to find significant signaling pathways or biochemical common processes.Our group has sequenced > 100 familial cases and early onset MD to search for an enrichment of rare variants in familial MD. This work is conducted in a multicenter collaboration with the Baylor-Hopkins Center for Medelian Genomics and the Luxembourg Centre for System Biomedicine. We expect to generate a list of 25-50 candidate genes to define signaling pathways that determine the cochlear and vestibular phenotype of MD. We have identified novel mutations in DTNA, FAM136A, PRCKB, DPT and SEMA3D genes.In addition, our group has designed two panel of genes related with sensorineural hearing loss and cochlear and supporting cells to find rare variants associated with sporadic MD.
  • Line 3. Molecular mechanisms of the immune response to molds in MD. The autoimmune inner ear disease (AIED) is characterized by bilateral sensorineural hearing loss with periods of exacerbation caused by a–not-well-known allergic stimulus. This disease is characterized by an immune response in which pro-inflammatory cytokines such as TNFα and IL-1β are released. These cytokines can be released by macrophages or macrophage-like melanocytes of the cochlea that are located in the stria vascularis in the blood-fluid intraestrial barrier. A subset of patients with MD presents an abnormal elevated levels of IL-1β, IL-6 and TNFα. In addition, exposure of mononuclear cells of these patients to fungal extract from could lead to overexpression of IL-1β and IL-6, suggesting an abnormal response to molds.Our hypothesis is that a significant group of patients with MD have an altered immune response and this subgroup would be part of AIED. The objective is to characterize the cellular subpopulations associated with the proinflamatory response by mass cytometry and single cell RNAseq.
  • Line 4. Development of a cellular model in familial Meniere’s disease. The main goal of this project is to obtain induced pluripotent stem cells (iPSC) derived from mononuclear cells from individuals with familial MD with the mutations of interest, to prove the persistence of mutations in the iPSC. We have already developed an iPSC model with DTNA and FAM136A mutations. Subsequently, we want to generate otic progenitors to differentiate them into hair cells, auditory and vestibular neurons and epithelial cells with secretory activity.
  • Line 5. Molecular basis of hiperacusia and tinnitus in Meniere’s disease. Bilateral tinnitus has high heritability. Hyperacusia and tinnitus are constant symptoms in MD. Hypersensitivity and tinnitus poor tolerance reflect an altered brain excitability. The goal of the proposed research is to identify which individuals have a tinnitus problem and to develop a neuronal cell model from iPSC to define the molecular basis of abnormal neuronal excitability.Our group will select individuals with an extreme phenotype (MD with hyperacusis and unilateral tinnitus persistent without treatment and THI> percentile 90) to undertake a WES study to identify the responsible genes.Furthermore, our group collaborates with Prof. Christopher Cederroth of Karoliska Institutet in the identification of rare variants in multicase families with tinnitus and high frequency hearing loss.

Technology platforms

    • Illumina iSCAN: high performance genotyping
    • Real-time PCR (Applied Biosystem 7900 and 7500)
    • Illumina Nextseq high performance sequencing
    • Bioinformatic analysis, data sequencing and prioritization of variants
    • Gene networks analysis by IPA and MetaCore
    • Mass cytometry (Helios Cytof System, Fluidigm)
    • Cellular reprogramming and iPSCs generation by Sendai virus
    • Target mutagenesis and cell lines transduction by lentiviral vectors
    • Acoustic otoemissions, auditory and vestibular evoked potentials (Interacoustic)
    • Dynamic posturography (Synapsis)
    • Video-Head Impulse Test (vHIT, Otometrics)


Title: European School for Interdisciplinary tinnitus research. (Investigador colaborador)

Principal investigator: Winfried Schlee

Financing entity: EU-H2020. Code: MSCA-ITN-722046

Period: 2017-2020

Funding: 3.823.897€


Title: Validación de un marcador genético regulador de la inflamación para el diagnóstico de enfermedad de Meniere autoinmune (DIEMA).

Principal investigator: José Antonio López Escámez

Financing entity: Programa INNBIO-ADVANCE, FIBAO. Code: INB-007

Period: 2017-2019

Funding: 14.000€


Title: Papel de la variante reguladora rs4947296 y la respuesta proinflamatoria en la Enfermedad de Meniere (REM).

Principal investigator: José Antonio López Escámez

Financing entity: Instituto de Salud Carlos III Code: PI17/01644

Period: 2018-2020

Funding: 171.820€


Title: The combined role of genetic and environmental risk factors in the gender-specific development of severe tinnitus TIGER

Principal investigator: Christopher R. Cederroth, Jose Antonio Lopez-Escamez, Silvano Gallus, Jan Bulla.

Financing entity: GENDER-NET Plus ERA-NET Cofund

Period: 2019-2022

Funding: 1.000.000€


Title: In Vitro Clinical Trial with BIIB023 and monitoring of clinical response in Meniere

Disease (CLINMON-MD)

Principal investigator: José Antonio López Escámez

Financing entity: FIBAO / Meniere´s Society

Period: 2019-2023

Funding: 176.487€


Title: Unification of treatments and interventions for tinnitus patients UNITI

Principal investigator: Winfried Schlee

Financing entity: EU-H2020 Codigo: SC1-2019-RIA-SEP-210574924

Period: 2020-2022

Funding: 5.989.343€.

Perfil de citoquinas y analisis integrado multiomico para redefinir fenotipos clínicos en pacientes con enfermedad de Meniere, migraña y migraña vestibular (Cytomic-Phen)

Principal Investigator: Jose Antonio Lopez-Escamez.

Financing entity: Instituto de Salud Carlos III

Code: PI20/01126

Period: 2021-2023.

Funding: 165.770 €


Title: Pro-inflammatory cytokines and epigenetic signature to improve molecular diagnosis and personalized medicine in patients with episodic vertigo and migraine (EPIVERT)

Principal Investigator: Jose Antonio Lopez-Escamez/Estrella Martinez-Gomez

Financing entity: Consejeria de Salud y Familias

Code: PI-0027-2020

Period: 2021-2023.

Funding: 149522 €


Title: Papel de la regulación epigenómica en la penetrancia y expresividad en la enfermedad de Meniere (EPIMEN)

Principal Investigator: Jose Antonio Lopez-Escamez

Financing entity: Consejeria de Conocimiento, Investigacion y Universidad

Code: PI20.00303

Period: 2021-2023.

Funding: 153170 €


Research group patents

Application Number: P201930255 Priority date: 20/03/2019
Title: Panel de Citoquinas/Quimiocinas para el diagnostico diferencial en el Síndrome Vestibular Episódico
Authors: Lopez-Escamez JA, Flook M, Frejo L
Applicant: Servicio Andaluz de Salud
Application Number: P201630745 Priority date: 03/06/2016

Citoquinas proinflamatorias como marcador diagnóstico en el

síndrome vestibular episódico

Authors: Lopez-Escamez JA, Frejo Navarro L, Espinosa-Sanchez Juan Manuel, Requena T.
Applicant: Servicio Andaluz de Salud
Application Number: P201531458 Priority date: 09/10/2015

Uso de variantes alélicas en la región 6p21.33 para el diagnóstico

y pronóstico en la Enfermedad de Meniere

Authors: Lopez-Escamez JA, Cabrera S, Alarcon-Riquelme ME, Requena T.
Applicant: Fundación Progreso y Salud /Servicio Andaluz de Salud
Application Number: P201430716 Priority date: 16/05/2014

Uso de polimorfismos (SNPs) del gen NFKB1 para el pronóstico

auditivo en la enfermedad de Meniere

Authors: Lopez-Escamez JA, Cabrera S, Sanchez E, , Alarcon-Riquelme ME, Espinosa-Sanchez JM, Requena T.
Applicant: Fundación Progreso y Salud /Servicio Andaluz de Salud
Application Number: p2011132013 Priority date: 14/12/2011

Método de obtención de datos útiles para el diagnóstico y

pronóstico de la hipoacusia neurosensorial

Authors: Lopez-Escamez JA, Lopez-Nevot MA, Gazquez I, Moreno A, Aran I, Soto-Varela A, Santos S, Perez-Garrigues H, Lopez-Nevot A, Requena T.
Applicant: Fundación Progreso y Salud /Agencia Publica Hospital de Poniente

Additional information

Doctoral theses supervised

    • Monitorización de la función vestibular y calidad de vida relacionada con la salud en pacientes con vértigo posicional paroxístico benigno. María Isabel Molina Palma. 14/06/2007.
    • Bases inmunogenéticas de la enfermedad de Meniere: búsqueda de marcadores genéticos. Irene Gazquez Perez. 24/09/2012.
    • Identification and validation of mutations in familial Ménière’s disease. Teresa Requena Navarro. 02/10/2015.
    • Mecanismos de inflamación en la Enfermedad de Meniere. Lidia Frejo Navarro. 12/05/2017
    • Variantes alélicas raras en la enfermedad de Ménière: De los casos familiares a los casos esporádicos. Álvaro Gallego Martínez. 25/02/2019
    • Allelic variants of genes kcnq2 and kcnq3 and tinnitus extreme phenotype in patients with Meniere’s disease. Patricia Pérez Carpena. 2020
    • Análisis agregado de variantes en el genoma de pacientes con enfermedad de meniere familiar e inicio precoz. Pablo Román-Naranjo Varela. 2020

Scientific Societies:

    • Miembro del Comité para el Programa de la Association for Research in Otolaryngology. 2016-2019.
    • Presidente de la Comisión de Investigación de la Sociedad Española de Otorrinolaringología. 2016.
    • Miembro del Comité Internacional para la Clasificación de los Trastornos vestibulares de la Barany Society. 2008-17.
    • Académico de número de la Real Academia de Medicina de Andalucia Oriental ocupando la plaza de Otorrinolaringologia. 2013-17.
    • Miembro de la European Society of Human Genetics. 2017.

Research Networks:

    • Better Understanding the Heterogeneity of Tinnitus to Improve and Develop New Treatments (TINNET). Chair: Berthold Langguth. COST Action BM1306. 2014-2017
    • European School for Interdisciplinary Tinnitus Research (ESIT). Chair: Winfried Schlee. H2020-MSCA-ITN 722046. European School for Interdisciplinary Tinnitus Research (ESIT). 2017-2020.
    • Meniere’s disease Consortium (MediC): European Network for the study of the Meniere’s disease. 2016.

Continued scientific collaborations with:

    • University of Illinois, Chicago, USA
    • Luxembourg Centre for System Biomedicine- Centre Hospitalier Emile Mayrisch, Luxembourg
    • San Raffaele Hospital, Milano, Italy
    • Imperial College London, UK
    • Karolinska Institutet, Stockholm, Sweden
    • Baylor-Hopkins Center for Mendelian Genomics, Baltimore, USA

Organismos de evaluación en los que participo:

    • Fundacion progreso y salud
    • EU-FP7

Editorial Board Membership:

    • Acta Otorrinolaringológica Española. 2013
    • Audiology Research. 2014
    • Current Otorhinolaryngology Reports. 2013-2018
    • Frontiers in Neurology-Neurotology Section. 2016-2018
    • Hellenic Otorhinolaryngology. 2014
    • Scientific Reports. 2015-2018
    • International Journal of Otolaryngology. 2015

Reviewer of the following Journals:

    • Acta Otorrinolaringologica Española. 2007-2019
    • Biochimica and Biophysica Acta- Molecular Basis of Disease. 2013.
    • Brain. A Journal of Neurology. 2007-2009
    • British Medical Journal 2017-19
    • Canadian Medical Association Journal. 2006-11, Current Genomics. 2011, Ear and Hearing. 2012-2013, European Journal of Medical Genetics. 2012-13., Frontiers Neurology. 2016-198., Hearing Research. 2015-197, International Journal of Audiology. 2012, International Journal Otolaryngology. 2011
    • Journal Neurology Neurosurgery & Psychiatry. BMJ Group. 2007
    • Journal of Clinical Immunology. 2013.
    • Lancet. 2018-2019
    • Molecular Biology Reports. 2010.
    • Molecular Neurobiology. 2009.
    • Pharmacogenetics and genomics. 2012.
    • PloS ONE. 2011-20194
    • Scientific Reports. 2015-198
    • The Laryngoscope. Lippincott Williams & Wilkins. 2004-11

Selected publications

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