Hearing impairment not etiologically associated with clinical signs in other organs (non-syndromic) is genetically heterogeneous, so that over 120 genes are currently known to be involved. The ...frequency of mutations in each gene and the most frequent mutations vary throughout populations. Here we review the genetic etiology of non-syndromic hearing impairment (NSHI) in Europe. Over the years, epidemiological data were scarce because of the large number of involved genes, whose screening was not cost-effective until implementation of massively parallel DNA sequencing. In Europe, the most common form of autosomal recessive NSHI is DFNB1, which accounts for 11–57% of the cases. Mutations in
STRC
account for 16% of the recessive cases, and only a few more (
MYO15A
,
MYO7A
,
LOXHD1
,
USH2A
,
TMPRSS3
,
CDH23
,
TMC1
,
OTOF
,
OTOA
,
SLC26A4
,
ADGRV1
and
TECTA
) have contributions higher than 2%. As regards autosomal-dominant NSHI, DFNA22 (
MYO6
) and DFNA8/12 (
TECTA
) represent the most common forms, accounting for 21% and 18% of elucidated cases, respectively. The contribution of
ACTG1
and
WFS1
drops to 9% in both cases, followed by
POU4F3
(6.5%),
MYO7A
(5%),
MYH14
and
COL11A2
(4% each). Four additional genes contribute 2.5% each one (
MITF, KCNQ4, EYA4, SOX10
) and the remaining are residually represented. X-linked hearing loss and maternally-inherited NSHI have minor contributions in most countries. Further knowledge on the genetic epidemiology of NSHI in Europe needs a standardization of the experimental approaches and a stratification of the results according to clinical features, familial history and patterns of inheritance, to facilitate comparison between studies.
The inner ear is a very complex sensory organ whose development and function depend on finely balanced interactions among diverse cell types. The many different kinds of inner ear supporting cells ...play the essential roles of providing physical and physiological support to sensory hair cells and of maintaining cochlear homeostasis. Appropriately enough, the gene most commonly mutated among subjects with hereditary hearing impairment (HI),
, encodes the connexin-26 (Cx26) gap-junction channel protein that underlies both intercellular communication among supporting cells and homeostasis of the cochlear fluids, endolymph and perilymph.
lies at the DFNB1 locus on 13q12. The specific kind of HI associated with this locus is caused by recessively-inherited mutations that inactivate the two alleles of the
gene, either in homozygous or compound heterozygous states. We describe the many diverse classes of genetic alterations that result in DFNB1 HI, such as large deletions that either destroy the
gene or remove a regulatory element essential for
expression, point mutations that interfere with promoter function or splicing, and small insertions or deletions and nucleotide substitutions that target the
coding sequence. We focus on how these alterations disrupt
and Cx26 functions and on their different effects on cochlear development and physiology. We finally discuss the diversity of clinical features of DFNB1 HI as regards severity, age of onset, inner ear malformations and vestibular dysfunction, highlighting the areas where future research should be concentrated.
Up to half of patients with congenital autosomal recessive nonsyndromic deafness have mutations in the gene encoding the gap-junction protein connexin 26 (
GJB2
); the rest have had no identifiable ...mutations. In this study, patients with this form of deafness who had one mutant
GJB2
allele were found to have a novel 342-kb deletion that truncates the gene encoding another gap-junction protein, connexin 30 (
GJB6
). Twenty-two of the 33 subjects studied were heterozygous for both mutations and 2 were homozygous for the
GJB6
mutation.
Homozygous mutations in either
GJB2
or
GJB6
or heterozygous mutations in both genes can result in prelingual deafness.
Hearing impairment affects about 1 in 1000 newborns.
1
Cases that are present before the development of speech (prelingual onset) hamper speech acquisition and, therefore, normal communication and social integration. Early detection is essential for the application of palliative treatments and special education. Since about 50 percent of the cases of hearing impairment have genetic causes,
1
molecular diagnosis and genetic counseling are needed. However, the main obstacle to molecular diagnosis is the extreme genetic heterogeneity of nonsyndromic hearing impairment. Most cases of genetic deafness are autosomal recessive. So far, 28 loci for autosomal recessive nonsyndromic hearing impairment have been identified, which . . .
Already 40 genes have been identified for autosomal-recessive nonsyndromic hearing impairment (arNSHI); however, many more genes are still to be identified. In a Dutch family segregating arNSHI, ...homozygosity mapping revealed a 2.4 Mb homozygous region on chromosome 11 in p15.1-15.2, which partially overlapped with the previously described DFNB18 locus. However, no putative pathogenic variants were found in USH1C, the gene mutated in DFNB18 hearing impairment. The homozygous region contained 12 additional annotated genes including OTOG, the gene encoding otogelin, a component of the tectorial membrane. It is thought that otogelin contributes to the stability and strength of this membrane through interaction or stabilization of its constituent fibers. The murine orthologous gene was already known to cause hearing loss when defective. Analysis of OTOG in the Dutch family revealed a homozygous 1 bp deletion, c.5508delC, which leads to a shift in the reading frame and a premature stop codon, p.Ala1838ProfsX31. Further screening of 60 unrelated probands from Spanish arNSHI families detected compound heterozygous OTOG mutations in one family, c.6347C>T (p.Pro2116Leu) and c. 6559C>T (p.Arg2187X). The missense mutation p.Pro2116Leu affects a highly conserved residue in the fourth von Willebrand factor type D domain of otogelin. The subjects with OTOG mutations have a moderate hearing impairment, which can be associated with vestibular dysfunction. The flat to shallow "U" or slightly downsloping shaped audiograms closely resembled audiograms of individuals with recessive mutations in the gene encoding α-tectorin, another component of the tectorial membrane. This distinctive phenotype may represent a clue to orientate the molecular diagnosis.
The transmembrane recognition complex (TRC40) pathway mediates the insertion of tail‐anchored (TA) proteins into membranes. Here, we demonstrate that otoferlin, a TA protein essential for hair cell ...exocytosis, is inserted into the endoplasmic reticulum (ER) via the TRC40 pathway. We mutated the TRC40 receptor tryptophan‐rich basic protein (Wrb) in hair cells of zebrafish and mice and studied the impact of defective TA protein insertion. Wrb disruption reduced otoferlin levels in hair cells and impaired hearing, which could be restored in zebrafish by transgenic Wrb rescue and otoferlin overexpression. Wrb‐deficient mouse inner hair cells (IHCs) displayed normal numbers of afferent synapses, Ca2+ channels, and membrane‐proximal vesicles, but contained fewer ribbon‐associated vesicles. Patch‐clamp of IHCs revealed impaired synaptic vesicle replenishment. In vivo recordings from postsynaptic spiral ganglion neurons showed a use‐dependent reduction in sound‐evoked spiking, corroborating the notion of impaired IHC vesicle replenishment. A human mutation affecting the transmembrane domain of otoferlin impaired its ER targeting and caused an auditory synaptopathy. We conclude that the TRC40 pathway is critical for hearing and propose that otoferlin is an essential substrate of this pathway in hair cells.
Synopsis
Otoferlin, a tail‐anchored protein of sensory hair cells, uses the transmembrane recognition complex (TRC40) pathway for ER membrane insertion. Disruption of the TRC40 receptor Wrb in hair cells impaired vesicle replenishment and hearing, most likely by reducing otoferlin levels.
Hearing requires membrane insertion of tail‐anchored (TA) proteins by the TRC40 pathway in hair cells.
The TA protein otoferlin, essential for hair cell exocytosis and defective in human deafness, utilizes the TRC40 pathway.
Deletion of TRC40 receptor WRB reduces otoferlin levels and impairs synaptic structure and function.
Reduced vesicle replenishment in WRB‐deficient hair cells impairs sound encoding.
ER membrane insertion of the sensory hair cell component otoferlin depends on the tail‐anchored protein insertion TRC40 pathway, whose disruption impairs synaptic vesicle replenishment and hearing.
Glycogen synthase kinase 3β (GSK3β) is a core protein, with a relevant role in many neurodegenerative disorders including Alzheimer's disease. The enzyme has been largely studied as a potential ...therapeutic target for several neurological diseases. Unfortunately, preclinical and clinical studies with several GSK3β inhibitors have failed due to many reasons such as excessive toxicity or lack of effects in human subjects. We previously reported that meridianins are potent GSK3β inhibitors without altering neuronal viability. In the present work, we examine whether meridianins are capable to inhibit neural GSK3β
and if such inhibition induces improvements in the 5xFAD mouse model of Alzheimer's Disease. Direct administration of meridianins in the third ventricle of 5xFAD mice induced robust improvements of recognition memory and cognitive flexibility as well as a rescue of the synaptic loss and an amelioration of neuroinflammatory processes. In summary, our study points out meridianins as a potential compound to treat neurodegenerative disorders associated with an hyperactivation of GSK3β such as Alzheimer's disease.
Pathogenic variants in GJB2 are the most common cause of autosomal recessive sensorineural hearing loss. The classification of c.101T>C/p.Met34Thr and c.109G>A/p.Val37Ile in GJB2 are controversial. ...Therefore, an expert consensus is required for the interpretation of these two variants.
The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants. Functional, computational, allelic, and segregation data were also obtained. Case-control statistical analyses were performed.
The panel reviewed the synthesized information, and classified the p.Met34Thr and p.Val37Ile variants utilizing professional variant interpretation guidelines and professional judgment. We found that p.Met34Thr and p.Val37Ile are significantly overrepresented in hearing loss patients, compared with population controls. Individuals homozygous or compound heterozygous for p.Met34Thr or p.Val37Ile typically manifest mild to moderate hearing loss. Several other types of evidence also support pathogenic roles for these two variants.
Resolving controversies in variant classification requires coordinated effort among a panel of international multi-institutional experts to share data, standardize classification guidelines, review evidence, and reach a consensus. We concluded that p.Met34Thr and p.Val37Ile variants in GJB2 are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and incomplete penetrance.
The human mitochondrial 12S ribosomal RNA (rRNA) A1555G mutation has been associated with aminoglycoside-induced and nonsyndromic deafness in many families worldwide. Our previous investigation ...revealed that the A1555G mutation is a primary factor underlying the development of deafness but is not sufficient to produce a deafness phenotype. However, it has been proposed that nuclear-modifier genes modulate the phenotypic manifestation of the A1555G mutation. Here, we identified the nuclear-modifier gene
TRMU, which encodes a highly conserved mitochondrial protein related to transfer RNA (tRNA) modification. Genotyping analysis of
TRMU in 613 subjects from 1 Arab-Israeli kindred, 210 European (Italian pedigrees and Spanish pedigrees) families, and 31 Chinese pedigrees carrying the A1555G or the C1494T mutation revealed a missense mutation (G28T) altering an invariant amino acid residue (A10S) in the evolutionarily conserved N-terminal region of the TRMU protein. Interestingly, all 18 Arab-Israeli/Italian-Spanish matrilineal relatives carrying both the TRMU A10S and 12S rRNA A1555G mutations exhibited prelingual profound deafness. Functional analysis showed that this mutation did not affect importation of TRMU precursors into mitochondria. However, the homozygous A10S mutation leads to a marked failure in mitochondrial tRNA metabolisms, specifically reducing the steady-state levels of mitochondrial tRNA. As a consequence, these defects contribute to the impairment of mitochondrial-protein synthesis. Resultant biochemical defects aggravate the mitochondrial dysfunction associated with the A1555G mutation, exceeding the threshold for expressing the deafness phenotype. These findings indicate that the mutated
TRMU, acting as a modifier factor, modulates the phenotypic manifestation of the deafness-associated 12S rRNA mutations.
The fact that hereditary hearing loss is the most common sensory disorder in humans is reflected by, among other things, an extraordinary allelic and nonallelic genetic heterogeneity. X-chromosomal ...hearing impairment represents only a minor fraction of all cases. In a study of a Spanish family the locus for one of the X-chromosomal forms was assigned to Xp22 (DFNX4). We mapped the disease locus in the same chromosomal region in a large German pedigree with X-chromosomal nonsyndromic hearing impairment by using genome-wide linkage analysis. Males presented with postlingual hearing loss and onset at ages 3–7, whereas onset in female carriers was in the second to third decades. Targeted DNA capture with high-throughput sequencing detected a nonsense mutation in the small muscle protein, X-linked (SMPX) of affected individuals. We identified another nonsense mutation in SMPX in patients from the Spanish family who were previously analyzed to map DFNX4. SMPX encodes an 88 amino acid, cytoskeleton-associated protein that is responsive to mechanical stress. The presence of Smpx in hair cells and supporting cells of the murine cochlea indicates its role in the inner ear. The nonsense mutations detected in the two families suggest a loss-of-function mechanism underlying this form of hearing impairment. Results obtained after heterologous overexpression of SMPX proteins were compatible with this assumption. Because responsivity to physical force is a characteristic feature of the protein, we propose that long-term maintenance of mechanically stressed inner-ear cells critically depends on SMPX function.
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