Biology subjects

Lopez-Escamez, J. A.

Publications and source records attributed to Lopez-Escamez, J. A..

3 recordsLinked to original sources

bioRxiv2025

An updated inventory of genes essential for oxidative phosphorylation identifies a mitochondrial origin in familial Meniere disease

Mitochondrial disorders (MDs) are among the most common inborn errors of metabolism and primarily arise from defects in oxidative phosphorylation (OXPHOS). Their complex mode of inheritance and diverse clinical presentations render the diagnosis of MDs challenging and, to date, most lack a cure. Here, we build on previous efforts to discover genes necessary for OXPHOS and report a highly complementary galactose-sensitized CRISPR-Cas9 "growth" screen, presenting an updated inventory now with 481 OXPHOS genes, including 157 linked to MDs. We further focus on FAM136A, a gene associated with Menieres disease, and show that it supports inter-membrane space protein homeostasis and OXPHOS in cell lines, mice, and patients. Our study identifies a mitochondrial basis in a familial form of Menieres disease (fMD), provides a comprehensive resource of OXPHOS-related genes, and sheds light on the pathways involved in mitochondrial disorders, with the potential to guide future diagnostics and treatments for MDs. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/635272v1_ufig1.gif" ALT="Figure 1"> View larger version (79K): org.highwire.dtl.DTLVardef@1841a8forg.highwire.dtl.DTLVardef@1ebbaa8org.highwire.dtl.DTLVardef@12b70aeorg.highwire.dtl.DTLVardef@f2da2a_HPS_FORMAT_FIGEXP M_FIG C_FIG Bullet pointsO_LIGenome-wide CRISPR-Cas9 growth screening complements death screening C_LIO_LI481 genes essential for OXPHOS, including 157 mitochondrial disease genes C_LIO_LIFAM136A supports mitochondrial intermembrane space protein homeostasis C_LIO_LIDepletion of FAM136A in Menieres disease models causes OXPHOS defects C_LI

cell biology↗

bioRxiv2019

Rare Variants in the OTOG Gene Are a Frequent Cause of Familial Meniere’s Disease

ObjectivesMenieres disease (MD) is a rare inner ear disorder characterized by sensorineural hearing loss, episodic vertigo and tinnitus. Familial MD has been reported in 6-9% of sporadic cases, and few genes including FAM136A, DTNA, PRKCB, SEMA3D and DPT have been involved in single families, suggesting genetic heterogeneity. In this study, the authors recruited 46 families with MD to search for relevant candidate genes for hearing loss in familial MD.\n\nDesignExome sequencing data from MD patients were analyzed to search for rare variants in hearing loss genes in a case-control study. A total of 109 patients with MD (73 familial cases and 36 early-onset sporadic patients) diagnosed according to the diagnostic criteria defined by the Barany Society were recruited in 11 hospitals. The allelic frequencies of rare variants in hearing loss genes were calculated in individuals with familial MD. A single rare variant analysis (SRVA) and a gene burden analysis (GBA) were conducted in the dataset selecting one patient from each family. Allelic frequencies from European and Spanish reference datasets were used as controls.\n\nResultsA total of 5136 single nucleotide variants in hearing loss genes were considered for SRVA in familial MD cases, but only one heterozygous variant in the OTOG gene (rs552304627) was found in two unrelated families. The GBA found an enrichment of rare missense variants in the OTOG gene in familial MD. So, 15/46 families (33%) showed at least one rare missense variant in the OTOG gene, suggesting a key role in familial MD.\n\nConclusionsThe authors found an enrichment of multiplex rare missense variants in the OTOG gene in familial MD. This finding supports OTOG as a relevant gene in familial MD and set the groundwork for genetic testing in MD.

genetics↗

bioRxiv2018

Excess of rare missense variants in hearing loss genes in sporadic Meniere disease

Menieres disease (MD) is a clinical spectrum of rare disorders characterized by vertigo attacks, associated with sensorineural hearing loss (SNHL) and tinnitus involving low to medium frequencies. Although it shows familial aggregation with incomplete phenotypic forms and variable expressivity, most cases are considered sporadic. The aim of this study was to investigate the burden for rare variation in SNHL genes in patients with sporadic MD.\n\nWe conducted a targeted-sequencing study including SNHL and familial MD genes in 890 MD patients to compare the frequency of rare variants in cases using three independent public datasets as controls.\n\nPatients with sporadic MD showed a significant enrichment of missense variants in SNHL genes that was not found in the controls. The list of genes includes GJB2, USH1G, SLC26A4, ESRRB and CLDN14. A rare synonymous variant with unknown significance was found in the MARVELD2 gene in several unrelated patients with MD.\n\nThere is a burden of rare variation in certain SNHL genes in sporadic MD. Furthermore, the physical interaction of specific gene variants at protein level can explain the additive effect of rare variants in different genes in MD. This study will contribute to design a gene panel for the genetic diagnosis of MD.

genomics↗