OTOGL, a gelforming mucin protein, is nonessential for male germ cell development and spermatogenesis in mice.

Otogelin-like protein (encoded by Otogl) was highly structural similar to the gelforming mucin proteins. Although human OTOG mutations have been linked to deafness, the biological function of OTOGL in male germ cell development remains enigmatic. In screening 336 patients with non-obstructive azoospermia (NOA), OTOGL displays the high mutant ratio (13.99 %). Then, we examined the expression of OTOGL in developing mouse testes. Otogl mRNA and protein are continually expressed in postnatal developing testes from postnatal day 0 (P0) testes to P21 testes exhibiting a decreased trend with the age growth. We thus generated a global Otogl knockout mouse (KO) model using the CRISPR/Cas9 technology; however, Otogl KO mice displayed normal development and fertility. Further histological analysis of Otogl knockout mouse testes revealed that all types of spermatogenic cells are present in Otogl KO seminiferous tubules. Together, our study suggested that OTOGL is nonessential for male germ cell development and spermatogenesis.

[Phenotype and genotype analysis of recessive hereditary moderate sensorineural hearing loss caused by new mutations in OTOGL gene].

Objective: To perform the phenotype and genetic analysis on two families with moderate sensorineural hearing impairment and determine the cause of deafness. Methods: The phenotype and genetic analysis was performed on the two hearing impairment pedigrees coming to Chinese PLA General Hospital from January 2014 to August 2020. DNA samples of the proband from family 1 and the parents from family 2 were collected and tested through next generation sequencing on all deafness genes, and Sanger sequencing was performed to verify the mutation sites. The reported pathogenic variants of the otogelin-like (OTOGL) gene, the autosomal recessive inherited deafness genes that cause moderate sensorineural hearing loss and the clinical manifestations of the deafness genes that have the similar expression location as the OTOGL gene were summarized and analyzed. Results: The pathogenic variants in the families were compound heterozygous variants in the OTOGL gene c.2773C>T/c.2826C>G (p.Arg925*/p.Tyr942*) and c.4455G>A/c.875C>G (Trp1485*/p.Ser292*), respectively. c.2773C>T was an already reported pathogenic variant causing hearing impairment in the literature, while c.2826C>G, c.4455G>A and c.875C>G were novel reported variant sites. The above four variants were classified as pathogenic variants according to the variant interpretation standards and guideline of the Amercian College of Medical Genetics and Genomics. Conclusions: Pathogenic variants in OTOGL gene is an important genetic factor leading to moderate sensorineural hearing loss. The newly discovered variant sites c.2826C>G, c.4455G>A and c.875C>G enrich the variant spectrum of OTOGL gene. The results of the current study provide a basis for genetic counseling of the related families and a new target for the treatment of hereditary hearing loss in the future.

Novel heterozygous mutations in the otogelin-like (OTOGL) gene in a child with bilateral mild nonsyndromic sensorineural hearing loss.

Hearing loss is a common disease, of which genetic factors are the main cause. The incidence of mild or moderate postlingual deafness in children is not high, and the impact on life and learning is not as severe as that of prelingual deafness. This leads to insufficient attention to the disorder in the clinic. To date, only a few disease-causing genes have been reported. This report describe a case of novel heterozygous mutations in OTOGL that causes nonsyndromic mild sensorineural hearing loss. Basic information, imaging examinations, audiological examination, and vestibular function tests of the proband were collected. Blood samples of the proband's family were collected and analyzed by whole exome sequencing and Sanger sequencing. A pedigree diagram was drawn and the genetic patterns were analyzed. The proband is a 16-year-old female student with mild sensorineural hearing loss. High-resolution CT of the inner ear and vestibular function tests showed no abnormalities. The age of onset was approximately 4 years old. Except for hearing loss, no lesions were seen in other organs. The parents of the proband were not close relatives and had normal hearing. Two novel heterozygous mutations were found in the OTOGL gene. The c.5038del (p.D1680Ifs*6) variant was inherited from the father, and the c.2770C > T (p.R924X) variant from the mother. They enriched the mutation spectrum of OTOGL, which provides the basis for gene function research and genetic consultation.

Transcriptomic Profile Reveals Deregulation of Hearing-Loss Related Genes in Vestibular Schwannoma Cells Following Electromagnetic Field Exposure.

Hearing loss (HL) is the most common sensory disorder in the world population. One common cause of HL is the presence of vestibular schwannoma (VS), a benign tumor of the VIII cranial nerve, arising from Schwann cell (SC) transformation. In the last decade, the increasing incidence of VS has been correlated to electromagnetic field (EMF) exposure, which might be considered a pathogenic cause of VS development and HL. Here, we explore the molecular mechanisms underlying the biologic changes of human SCs and/or their oncogenic transformation following EMF exposure. Through NGS technology and RNA-Seq transcriptomic analysis, we investigated the genomic profile and the differential display of HL-related genes after chronic EMF. We found that chronic EMF exposure modified the cell proliferation, in parallel with intracellular signaling and metabolic pathways changes, mostly related to translation and mitochondrial activities. Importantly, the expression of HL-related genes such as NEFL, TPRN, OTOGL, GJB2, and REST appeared to be deregulated in chronic EMF exposure. In conclusion, we suggest that, at a preclinical stage, EMF exposure might promote the transformation of VS cells and contribute to HL.

The OTOGL p.Arg925* Variant is Associated with Moderate Hearing Loss in a Syrian Nonconsanguineous Family.

AIM: To screen for the genetic basis of congenital hearing loss in a Syrian family. METHODS: A Syrian patient living in Lebanon presented with moderate congenital hearing loss. The patient's large nonconsanguineous family was recruited. DNA was extracted from blood samples and sent for whole-exome sequencing. A detailed clinical examination along with audiograms was obtained for all subjects. RESULTS: Hearing loss was noted to be mild to moderate in the low and mid frequencies, sloping to moderate to severe in the high frequencies for all affected members. Results of DNA analysis showed the presence of a previously described p.Arg925* mutation in the OTOGL gene on both alleles in affected family members, whereas nonaffected members either had the wild type or one copy of the mutated allele. DISCUSSION: Mutations affecting the OTOGL gene have been recently connected with nonsyndromic sensorineural hearing loss. Seven such mutations have already been described. The p.Arg925* reported in this study has been found once in a French family. The current report is the first to describe this mutation in a Middle Eastern family.

Novel biallelic OTOGL mutations in a Chinese family with moderate non-syndromic sensorineural hearing loss.

OBJECTIVE: Autosomal recessive non-syndromic hearing loss (DFNB) is a genetically heterogeneous disorder. So far, 55 pathogenic genes have been identified. In this study, we aim to characterize the clinical feature and the genetic cause of a Chinese DFNB family. METHODS: Whole exome sequencing was performed on the proband. Co-segregation between the hearing loss phenotype and the potential causative mutations was verified in all family members by Sanger sequencing. RESULTS: Audiologic profiles of the affected family members revealed a moderate hearing loss mainly affecting higher frequencies. Novel biallelic OTOGL mutations, c.6467C>A (p.Ser2156*) and c.6474dupA (p.Ser2159Metfs*2), were identified in this family segregating with the childhood onset DFNB. Both mutations were predicted to cause either nonsense mediated mRNA decay or premature terminations of protein synthesis. CONCLUSIONS: We identified novel biallelic OTOGL mutations in a Chinese DFNB family. To the best of our knowledge, this is the first report of OTOGL mutations causing hearing loss in the East Asian population. Our finding enriched the mutation spectrum of OTOGL associated hearing loss.

Biallelic nonsense mutations in the otogelin-like gene (OTOGL) in a child affected by mild to moderate hearing impairment.

Hearing impairment is characterized by great genetic heterogeneity. We report the identification, by whole exome sequencing, of two different nonsense mutations (c.1558C>T; p.Gln520 and c.2773C>T; p.Arg925) in the otogelin-like gene (OTOGL), in a child affected by mild to moderate isolated deafness. Parental genotypes allowed us to conclude that these mutations are present in the compound heterozygous state in the patient. In addition, our clinical data establish that the tectorial membrane and/or the outer hair cells are defective in this form of deafness.