TECTA

Abstract: Hereditary deafness has proved to be extremely heterogeneous genetically with more than 40 genes mapped or cloned for non-syndromic dominant deafness and 30 for autosomal recessive non-syndromic deafness. In spite of significant advances in the understanding of the molecular basis of hearing loss, identifying the precise genetic cause in an individual remains difficult. Consequently, it is important to exclude syndromic causes of deafness by clinical and special investigation and to use all available phenotypic clues for diagnosis. A clinical approach to the aetiological investigation of individuals with hearing loss is suggested, which includes ophthalmology review, renal ultrasound scan and neuro-imaging of petrous temporal bone. Molecular screening of the GJB2 (Connexin 26) gene should be undertaken in all cases of non-syndromic deafness where the cause cannot be identified, since it is a common cause of recessive hearing impairment, the screening is straightforward, and the phenotype unremarkable. By the same token, mitochondrial inheritance of hearing loss should be considered in all multigeneration families, particularly if there is a history of exposure to aminoglycoside antibiotics, since genetic testing of specific mitochondrial genes is technically feasible. Most forms of non-syndromic autosomal recessive hearing impairment cause a prelingual hearing loss, which is generally severe to profound and not associated with abnormal radiology. Exceptions to this include DFNB2 (MYO7A), DFNB8/10 (TMPRSS3) and DFNB16 (STRC) where age of onset may sometimes be later on in childhood, DFNB4 (SLC26A4) where there may be dilated vestibular aqueducts and endolymphatic sacs, and DFNB9 (OTOF) where there may also be an associated auditory neuropathy. Unusual phenotypes in autosomal dominant forms of deafness, include low frequency hearing loss in DFNA1 (HDIA1) and DFNA6/14/38 (WFS1), mid-frequency hearing loss in DFNA8/12 (TECTA), DFNA13 (COL11A2) and vestibular symptoms and signs in DFNA9 (COCH) and sometimes in DFNA11 (MYO7A). Continued clinical evaluation of types and course of hearing loss and correlation with genotype is important for the intelligent application of molecular testing in the next few years.

Abstract: In our efforts to identify new loci responsible for non-syndromic autosomal recessive forms of deafness, DFNB loci, we have pursued the analysis of large consanguineous affected families living in geographically isolated areas. Here, we report on the study of a Lebanese family comprising nine members presenting with a pre-lingual severe to profound sensorineural isolated form of deafness. Linkage analysis led to the characterization of a new locus, DFNB21, which was assigned to chromosome 11q23-25. Already mapped to this chromosomal region was TECTA. This gene encodes alpha-tectorin, a 2155 amino acid protein which is a component of the tectorial membrane. This gene recently has been shown to be responsible for a dominant form of deafness, DFNA8/12. Sequence analysis of the TECTA gene in the DFNB21-affected family revealed a G to A transition in the donor splice site (GT) of intron 9, predicted to lead to a truncated protein of 971 amino acids. This establishes that alpha-tectorin mutations can be responsible for both dominant and recessive forms of deafness. Comparison of the phenotype of the DFNB21 heterozygous carriers with that of DFNA8/12-affected individuals supports the hypothesis that the TECTA mutations which cause the dominant form of deafness have a dominant-negative effect. The present results provide genetic evidence for alpha-tectorin forming homo- or heteromeric structures.

Abstract: Summary Disease characteristics. Several hundred genes are known to cause hereditary hearing loss and deafness. The hearing loss may be conductive, sensorineural, or a combination of both; syndromic or nonsyndromic; and prelingual (before language develops) or postlingual (after language develops). Diagnosis/testing. Genetic forms of hearing loss must be distinguished from acquired (non-genetic) causes of hearing loss. The genetic forms of hearing loss are diagnosed by otologic, audiologic, and physical examination, family history, ancillary testing (such as CT examination of the temporal bone), and molecular genetic testing. Molecular genetic tests are available for many types of syndromic and nonsyndromic deafness, often only on a research basis. On a clinical basis, molecular genetic testing is available for the diagnosis of branchiootorenal (BOR) syndrome (EYA1 gene), Mohr-Tranebjaerg syndrome (deafnessdystonia-optic atrophy syndrome; TIMM8A gene), Pendred syndrome (SLC26A4 gene), Usher syndrome type 2A (USH2A gene), Usher syndrome type 3 (one mutation in USH3A), DFNA3 and DFNB1 (GJB2 and GJB6 genes), DFN3 (POU3F4 gene), DFNB4 (SLC26A4 gene), DFNA6/14 (WFS1 gene), DFNA8/12, DFNB9 (OTOF gene), and DFNB21 (TECTA gene). Testing for deafness-causing mutations in the GJB2 gene (which encodes the protein connexin 26) and GJB6 (which encodes the protein connexin 30) plays a prominent role in diagnosis and genetic counseling. Management. Hereditary hearing loss is managed by a team including an otolaryngologist, an audiologist, a clinical geneticist, and a pediatrician, and sometimes an educator of the Deaf, a neurologist, and a pediatric ophthalmologist. Treatment includes hearing aids and vibrotactile devices; cochlear implantation is considered in children over

Abstract: Frequency tuning in the cochlea is determined by the passive mechanical properties of the basilar membrane and active feedback from the outer hair cells, sensory-effector cells that detect and amplify sound-induced basilar membrane motions. The sensory hair bundles of the outer hair cells are imbedded in the tectorial membrane, a sheet of extracellular matrix that overlies the cochlea's sensory epithelium. The tectorial membrane contains radially organized collagen fibrils that are imbedded in an unusual striated-sheet matrix formed by two glycoproteins, alpha-tectorin (Tecta) and beta-tectorin (Tectb). In Tectb(-/-) mice the structure of the striated-sheet matrix is disrupted. Although these mice have a low-frequency hearing loss, basilar-membrane and neural tuning are both significantly enhanced in the high-frequency regions of the cochlea, with little loss in sensitivity. These findings can be attributed to a reduction in the acting mass of the tectorial membrane and reveal a new function for this structure in controlling interactions along the cochlea.