Mutations in the fibrillar collagen genes COL11A1 and COL11A2 can cause sensorineural hearing loss associated with Stickler syndrome. There is a correlation of hearing loss severity, onset, progression and affected frequencies with the underlying mutated collagen gene. We sought to determine whether differences in spatial or temporal expression of these genes underlie this correlation, and to identify the cochlear cell populations expressing these genes and the structures likely to be affected by mutations.
We used in situ hybridization analysis of C57BL/6J mouse temporal bones.
Similar, diffuse expression of Col11a1 and Col11a2 mRNA was first observed in the cochlear duct at embryonic Day 15.5, with increasingly focal hybridization being noted at postnatal Days 1 and 5 in the greater epithelial ridge and lateral wall of the cochlea. The greater epithelial ridge appeared to be the main, if not only, source of mRNA encoding Col11a1 and Col11a2 in the tectorial membrane. At postnatal Day 13, Col11a1 and Col11a2 expression became more focal and co-localized in the inner sulcus, Claudius' cells and cells of Boettcher.
We did not observe spatial or temporal differences in mRNA expression that could account for the auditory phenotype genotype correlation. The expression patterns suggest essential roles for Col11a1 and Col11a2 in the basilar or tectorial membranes.
"Type XI collagen is associated with type II collagen and hybridization of their gene products can be found in the lateral wall of the developing mouse cochlea. It is suggested that mutations in COL11A1 may influence hearing due to their effects on the formation and function of the tectorial membrane
. Until now, it is not yet clarified how mutations in this gene can cause the above-mentioned type of hearing loss. "
[Show abstract][Hide abstract] ABSTRACT: Background
Stickler syndrome is a connective tissue disorder characterized by ocular, skeletal, orofacial and auditory defects. It is caused by mutations in different collagen genes, namely COL2A1, COL11A1 and COL11A2 (autosomal dominant inheritance), and COL9A1 and COL9A2 (autosomal recessive inheritance). The auditory phenotype in Stickler syndrome is inconsistently reported. Therefore we performed a systematic review of the literature to give an up-to-date overview of hearing loss in Stickler syndrome, and correlated it with the genotype.
English-language literature was reviewed through searches of PubMed and Web of Science, in order to find relevant articles describing auditory features in Stickler patients, along with genotype. Prevalences of hearing loss are calculated and correlated with the different affected genes and type of mutation.
313 patients (102 families) individually described in 46 articles were included. Hearing loss was found in 62.9%, mostly mild to moderate when reported. Hearing impairment was predominantly sensorineural (67.8%). Conductive (14.1%) and mixed (18.1%) hearing loss was primarily found in young patients or patients with a palatal defect. Overall, mutations in COL11A1 (82.5%) and COL11A2 (94.1%) seem to be more frequently associated with hearing impairment than mutations in COL2A1 (52.2%).
Hearing impairment in patients with Stickler syndrome is common. Sensorineural hearing loss predominates, but also conductive hearing loss, especially in children and patients with a palatal defect, may occur. The distinct disease-causing collagen genes are associated with a different prevalence of hearing impairment, but still large phenotypic variation exists. Regular auditory follow-up is strongly advised, particularly because many Stickler patients are visually impaired.
"(Baijens et al., 2004) Mutations in the fibrillar collagen genes COL11A1 and COL11A2 can cause sensorineural hearing loss probably due to the essential role these two genes have in the function of the basilar or tectorial membranes. There seems to be a correlation of hearing loss severity, onset, progression and affected frequencies with the underlying mutated collagen gene (Shpargel et al, 2004). In the study by Admiraal et al the mean sensorineural hearing threshold in Stickler patients with COL11A2 mutation was about 40 dB HL and was liable to increase at the highest frequencies. "
"In addition to secreted proteins, ECM components including collagens may control cochlear outgrowth. Collagens provide integrity and elasticity to developing tissues, mediate cell adhesion and epithelial morphogenesis (for reviews see Heino (2007) and Rozario and Desimone (2009)) and constitute central components of the ECM of the developing periotic mesenchyme and its derivatives (Van De Water and Galinovic-Schwartz, 1987; Berggren et al., 1997; Shpargel et al., 2004; Asamura et al., 2005). In particular, Collagen II deposition is remarkably increased during periotic mesenchyme condensation at E12.5 (D'Amico-Martel et al., 1987) and disruption of its spatiotemporal distribution pattern alters morphogenesis of the inner ear (Van De Water and Galinovic-Schwartz, 1987). "
[Show abstract][Hide abstract] ABSTRACT: Sox9 encodes an HMG-domain transcription factor that is critically required in numerous developmental processes such as chondrogenesis and otic placode formation. Here, we show that Sox9 is expressed in the mesenchyme surrounding the developing cochlea in the mouse suggesting that Sox9 may also control development of the otic fibrocyte compartment and the surrounding otic capsule. Tissue-specific inactivation of Sox9 in the periotic mesenchyme using a Tbx18(Cre) mouse line results in arrest of early chondrogenesis and consequently, in a lack of cochlear otic capsule formation. Furthermore, loss of Sox9 severely compromises expansion, differentiation and remodeling of the otic fibrocyte compartment. Early cell proliferation defects in the entire periotic mesenchyme of Sox9-deficient inner ears suggest a cell-autonomous function of Sox9 for the development of the inner mesenchymal compartment. Abnormal cochlear duct morphogenesis in Sox9 mutants including disruption of the coiling process is tightly associated with the onset of mesenchymal defects whereas the absence of major differentiation defects in the otic epithelium suggests that Sox9-dependent mesenchymal signals primarily control epithelial morphogenesis.
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