Autosomal Dominant Hereditary Hearing Loss Research Articles

A novel PLS1 c.981+1G>A variant causes autosomal-dominant hereditary hearing loss in a family.

The fimbrin protein family contains a variety of proteins, among which Plastin1 (PLS1) is an important member. According to recent studies, variations in the coding region of the PLS1 gene are associated with the development of deafness. However, the molecular mechanism of deafness caused by PLS1 gene variants remains unknown. Whole-exome sequencing was performed on hearing-impaired family members and hearing family members to identify pathogenic variants, followed by Sanger sequencing. A minigene assay was conducted to investigate the effect of the variant on PLS1 mRNA splicing. The pathogenicity of the variant was further investigated in zebrafish. RNA-sequencing (RNA-seq) was performed to analyze the dysregulation of downstream signaling pathways caused by knockdown of PLS1 expression. We identified a novel variant, PLS1 c.981+1G>A, in a large Chinese family with hearing loss and showed that the variant is responsible for the occurrence of hearing loss by inducing exon 8 skipping. The variant caused abnormal inner ear phenotypes, characterized by decreases in the mean otolith distance, anterior otolith diameter, posterior otolith diameter, cochlear diameter, and swimming speed and distance in zebrafish. Furthermore, silencing PLS1 expression significantly upregulated the expression of genes in the PI3K-Akt signaling pathway, including Col6a3, Spp1, Itgb3 and hepatocyte growth factor (Hgf). PLS1 c.981+1G>A is a novel pathogenic variant causing hearing loss by inducing exon 8 skipping. Upregulation of the expression of genes in the PI3K-Akt signaling pathway plays an important role in the pathogenesis caused by variants in the PLS1 gene.

High Prevalence of MYO6 Variants in an Austrian Patient Cohort With Autosomal Dominant Hereditary Hearing Loss.

Genetic hearing loss (HL) is often monogenic. Whereas more than half of autosomal recessive (AR) cases in Austria are caused by mutations in a single gene, no disproportionately frequent contributing genetic factor has been identified in cases of autosomal dominant (AD) HL. The genetic characterization of HL continues to improve diagnosis, genetic counseling, and lays a foundation for the development of personalized medicine approaches. Diagnostic HL panel screening was performed in an Austrian multiplex family with AD HL, and segregation was tested with polymerase chain reaction and Sanger sequencing. In an independent approach, 18 unrelated patients with AD HL were screened for causative variants in all known HL genes to date and segregation was tested if additional family members were available. The pathogenicity of novel variants was assessed based on previous literature and bioinformatic tools such as prediction software and protein modeling. In six of the 19 families under study, candidate pathogenic variants were identified in MYO6, including three novel variants (p.Gln441Pro, p.Ser612Tyr, and p.Gln650ValfsTer7). Some patients carried more than one likely pathogenic variant in known deafness genes. These results suggest a potential high prevalence of MYO6 variants in Austrian cases of AD HL. The presence of multiple rare HL variants in some patients highlights the relevance of considering multiple-hit diagnoses for genetic counseling and targeted therapy design.

Clinical Profiles of DFNA11 at Diverse Stages of Development and Aging in a Large Family Identified by Linkage Analysis.

The phenotype of DFNA11 consists of specific features at diverse developmental and age stages. Only eight mutations have been identified for autosomal dominant non-syndromic hearing loss related to MYO7A (DFNA11), and the onset and progression of DFNA11 are poorly understood. After linkage analysis and following Sanger sequencing in a family suspected to have autosomal dominant hereditary hearing loss, we analyzed the audiometric and vestibular functions and their long-term changes in the subjects carrying the variant. A reported variant of uncertain significance, NP_000251.3:p.Arg853His, in MYO7A was detected and cosegregation data of this large family provided evidence that the variant was likely pathogenic for DFNA11. Family members with the variant had no other symptoms associated with hearing loss and were confirmed to have autosomal dominant non-syndromic sensorineural hearing loss. Audiograms tended to show gently sloping configuration in childhood and flat configuration after the age of 30 years. Hearing loss at high frequencies progressed slowly, while hearing at low frequencies started to deteriorate later but progressed more rapidly. Some subjects showed partly abnormal results in the distortion products of otoacoustic emissions before the elevation of hearing thresholds. Vestibular function was within the normal range in all the subjects tested. We revealed that hearing loss at high frequencies was mainly noted in early developmental stages and that thresholds increased more rapidly in the low frequency range, resulting in changes in audiometric configuration. Deterioration of distortion product otoacoustic emissions (DPOAE) before the elevation of hearing thresholds was considered as a clinical feature of DFNA11.

Mutations in TOP2B cause autosomal-dominant hereditary hearing loss via inhibition of the PI3K-Akt signalling pathway.

Hereditary hearing impairment is a clinically and genetically heterogeneous disease. Whole-exome sequencing was performed on seven affected and six unaffected members in a large Chinese family with autosomal-dominant nonsyndromic hearing loss. The pathogenic variant of the gene encoding human topoisomerase IIβ TOP2B (c.G4837C:p.D1613H) was cosegregated with hearing loss in this pedigree and another two variants of TOP2B were detected in 66 sporadic patients with hearing loss. top2b knockdown led to significant defects in zebrafish inner ears and caused downregulation of akt which resulted in inactivation of PI3K-Akt signalling. As a result, supporting cell and hair cell numbers were reduced through inhibition of the PI3K-Akt pathway. Therefore, we hypothesized that mutations in TOP2B can cause autosomal-dominant nonsyndromic hearing impairment through inhibition of the PI3K-Akt signalling pathway. DATABASE: The whole-exome sequence data in the study are available at the Sequence Read Archive database (NCBI) under the accession numbers SRR9050868, SRR9050867, SRR90508676, SRR90508675, SRR90508674, SRR90508673, SRR90508672, SRR90508671, SRR90508679, SRR90508670, SRR9050859. SRR9050858 and SRR9050857, respectively.

C.G2114A MYH9 mutation (DFNA17) causes non-syndromic autosomal dominant hearing loss in a Brazilian family.

We studied a family presenting 10 individuals affected by autosomal dominant deafness in all frequencies and three individuals affected by high frequency hearing loss. Genomic scanning using the 50k Affymetrix microarray technology yielded a Lod Score of 2.1 in chromosome 14 and a Lod Score of 1.9 in chromosome 22. Mapping refinement using microsatellites placed the chromosome 14 candidate region between markers D14S288 and D14S276 (8.85 cM) and the chromosome 22 near marker D22S283. Exome sequencing identified two candidate variants to explain hearing loss in chromosome 14 [PTGDR – c.G894A:p.R298R and PTGER2 – c.T247G:p.C83G], and one in chromosome 22 [MYH9, c.G2114A:p.R705H]. Pedigree segregation analysis allowed exclusion of the PTGDR and PTGER2 variants as the cause of deafness. However, the MYH9 variant segregated with the phenotype in all affected members, except the three individuals with different phenotype. This gene has been previously described as mutated in autosomal dominant hereditary hearing loss and corresponds to DFNA17. The mutation identified in our study is the same described in the prior report. Thus, although linkage studies suggested a candidate gene in chromosome 14, we concluded that the mutation in chromosome 22 better explains the hearing loss phenotype in the Brazilian family.

Cloning and developmental expression of nonmuscle myosin IIA (Myh9) in the mammalian inner ear.

MYH9 encoding a nonmuscle myosin heavy chain has been linked to nonsyndromic and syndromic forms of autosomal dominant hereditary hearing loss, suggesting a critical biological role of this motor protein in the auditory organ. While Myh9 expression has been described in the adult mouse, critical parameters pertaining to its developmental expression remain to be characterized. The current study describes cloning of the mouse Myh9 cDNA and the temporal onset and spatial distribution of Myh9 expression in the inner ear of the developing fetus, the neonate, and the adult. The cloned Myh9 cDNA contained two single-base-pair differences from the published genomic sequence: T990C (G330G) and T5198A (L1733Q). Immunoblotting of embryonic (E15.5) and adult tissues from several organs, including the cochlea, identified a single 250-kDa anti-Myh9-immunoreactive band, supporting an absence of Myh9 splice variants in the fetus and the adult. In situ expression analysis identified Myh9 distributed within the epithelial layer of the otic vesicle at E10.5. Myh9 expression was found to persist within the epithelia surrounding the cochlear duct at E13.5 and E16.5. The sensory cells of the developing cochlea were positive for Myh9 expression at E16.5. Within the neonate and the adult cochlea, Myh9 expression was observed within the sensory hair cells and the supporting hair cells of the organ of Corti, the spiral ligament, and the spiral limbus, but not in the stria vascularis. Identification of Myh9 in the developing and mature inner ear suggests a role for this protein in the development and maintenance of auditory function.