Replication of Missense OTOG Gene Variants in a Brazilian Patient with Menière's Disease

Abstract

Ménière's Disease (MD) is a chronic inner ear disorder defined by recurring episodes of vertigo, fluctuating sensorineural hearing loss, tinnitus, and/or fullness in the ear. Its prevalence varies by region and ethnicity, with scarce epidemiological data in the Brazilian population. Although most MD cases are sporadic, familial MD (FMD) is observed in 5% to 20% of European cases. Through exome sequencing, we have found a rare missense variant in the OTOG gene in a Brazilian individual with MD with probable European ancestry (chr11:17599671C>T), which was previously reported in a Spanish cohort. Two additional rare missense heterozygous OTOG variants were found in the same proband. Splice Site analysis showed that chr11:17599671C>T may lead to substantial changes generating exonic cis regulatory elements, and protein modelling revealed structural changes in the presence of chr11:17599671C>T, chr11:17576581G>C, and chr11:17594108C>T, predicted to highly destabilize the protein structure. The manuscript aims to replicate genes previously reported in a Spanish cohort, and the main finding is that a Brazilian patient with MD also has variants previously reported in familial MD, supporting OTOG as the most frequently mutated gene in MD.

Keywords: Meniere disease; OTOG gene; hearing loss; molecular bioinformatics.

Figure 1

Variant density profile along the OTOG CDS in the NFE, AFR, SAS, EAS, and AMR populations calculated with a 201 bp sliding window. The threshold density for each population based on the anticipated number of variants within CDS is indicated by the red dashed line.

Figure 2

(a) Otogelin protein domains: EGF-like (epidermal growth factor), VWFD (von Willebrand factor type D), TIL (trypsin inhibitor-like, cysteine-rich domain) and CTCK (C-terminal cystine knot) (created with IBS v.1.0.3 software). (b) Modelled Otogelin protein showing the three selected variants. (c–e) Structural differences between wild-type (WT, in blue) and mutated (in cyan) Otogelin residues at positions p.850, p.1129, and p.1240. Interactions between amino acids are represented by yellow (polar contacts) and green (hydrophobic) dotted lines, with respective distances measured in Ängstrom. It is possible to observe that all mutated amino acids create new bonds with neighbouring residues (in grey).