Targeted disruption of mouse Coch provides functional evidence that DFNA9 hearing loss is not a COCH haploinsufficiency disorder

Makishima, Tomoko; Rodrı́guez, Clara I.; Robertson, Nahid G.; Stewart, Colin L.; Griffith, Andrew J.

doi:10.1007/s00439-005-0001-4

Cited by 33 publications

(30 citation statements)

References 26 publications

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“…Mutations in the gene have since been found to be responsible for DFNA9 in a number of families around the world (Robertson et al, 1998;de Kok et al, 1999;Fransen et al, 1999;Kamarinos et al, 2001;Usami et al, 2003;Nagy et al, 2004;Kemperman et al, 2005;Street et al, 2005;Collin et al, 2006;Pauw et al, 2007). But, although this relationship is well-established, mice deficient in Coch do not exhibit hearing loss (Makishima et al, 2005). This discrepancy may be because of the differences in the physiology between mouse and human or may be due to the specific mutations causing a gain-of-function effect that will only be observed from knock-in studies.…”

Section: Discussionmentioning

confidence: 99%

Expression studies of osteoglycin/mimecan (OGN) in the cochlea and auditory phenotype of Ogn-deficient mice

et al. 2008

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Genes involved in the hearing process have been identified through both positional cloning efforts following genetic linkage studies of families with heritable deafness and by candidate gene approaches based on known functional properties or inner ear expression. The latter method of gene discovery may employ a tissue-or organ-specific approach. Through characterization of a human fetal cochlear cDNA library, we have identified transcripts that are preferentially and/or highly expressed in the cochlea. High expression in the cochlea may be suggestive of a fundamental role for a transcript in the auditory system. Herein we report the identification and characterization of a transcript from the cochlear cDNA library with abundant cochlear expression and unknown function that was subsequently determined to represent osteoglycin (OGN). Ogn-deficient mice, when analyzed by auditory brainstem response and distortion product otoacoustic emissions, have normal hearing thresholds. Keywords mimecan/osteoglycin; proteoglycan; hearing loss #Correspondence to: Cynthia C. Morton, PhD, Brigham and Women's Hospital, NRB 160,

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Section: Discussionmentioning

confidence: 99%

Expression studies of osteoglycin/mimecan (OGN) in the cochlea and auditory phenotype of Ogn-deficient mice

et al. 2008

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“…Cochlin is the target of mutation in families with DFNA9, an autosomal dominant, nonsyndromic hereditary progressive hearing loss with vestibular pathology (Manolis et al 1996;Robertson et al 1997;Robertson et al 1998;Bom et al 1999;de Kok et al 1999;Verhagen et al 2000;Fransen et al 2001;Kamarinos et al 2001;Nagy et al 2004). Mutations in COCH (Coch-5B2) lead to hearing impairment that generally begins in adulthood and progresses with time (Manolis et al 1996).…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in COCH (Coch-5B2) lead to hearing impairment that generally begins in adulthood and progresses with time (Manolis et al 1996). Missense mutations of the LCCL domain or a mutation affecting a C-terminal cysteine (Street et al 2005) appear to affect protein folding (Liepinsh et al 2001) and aberrant protein accumulation (Grabski et al 2003;Robertson et al 2003) that are related to dysfunction and hearing loss (Robertson et al 2001;Robertson et al 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Missense mutations of the LCCL domain or a mutation affecting a C-terminal cysteine (Street et al 2005) appear to affect protein folding (Liepinsh et al 2001) and aberrant protein accumulation (Grabski et al 2003;Robertson et al 2003) that are related to dysfunction and hearing loss (Robertson et al 2001;Robertson et al 2006). Hearing loss is thought to be the result of accumulation of the misfolded protein rather than haploinsufficiency, as cochlin knock-out mice have no auditory or vestibular defects (Makishima et al 2005).…”

Section: Discussionmentioning

confidence: 99%

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Cochlin Isoforms and Their Interaction with CTL2 (SLC44A2) in the Inner Ear

Kommareddi

Nair

Raphael

et al. 2007

JARO

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Choline transporter-like protein 2 (CTL2) is a multitransmembrane protein expressed on inner ear supporting cells that was discovered as a target of antibody-induced hearing loss. Its function is unknown. A 64 kDa band that consistently co-precipitates with CTL2 from inner ear extracts was identified by mass spectroscopy as cochlin. Cochlin is an abundant inner ear protein expressed as multiple isoforms. Its function is also unknown, but it is suspected to be an extracellular matrix component. Cochlin is mutated in individuals with DFNA9 hearing loss. To investigate the CTL2-cochlin interaction, antibodies were raised to a cochlin-specific peptide. The antibodies identify several cochlin polypeptides on western blots and are specific for cochlin. We show that the heterogeneity of the cochlin isoforms is caused, in part, by in vivo posttranslational modification by N-glycosylation and, in part, caused by alternative splicing. We verified that antibody to CTL2 co-immunoprecipitates cochlin from the inner ear and antibody to cochlin coimmunoprecipitates CTL2. Using cochlear crosssections, we show that CTL2 is more widely distributed than previously described, and its prominent expression on cells facing the scala media suggests a possible role in homeostasis. A prominent but previously unreported ribbon-like pattern of cochlin in the basilar membrane was demonstrated, suggesting an important role for cochlin in the structure of the basilar membrane. CTL2 and cochlin are expressed in close proximity in the inner sulcus, the spiral prominence, vessels, limbus, and spiral ligament. The possible functional significance of CTL2-cochlin interactions remains unknown.

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“…The deletion leads to the replacement of two amino acids, Lys and Thr, by a single amino acid, Asn, in the mutated protein (Pace et al, 1997). Dmm mice expressed a reduced level of collagen II and suffered from cartilage defects (Robertson et al, 1998) NS (Makishima et al, 2005) Coch -/-(KO) C homolog, cochlin most abundant protein in cochlea.…”

Section: Extracellular Matrix Components: Cartilage and Tectorial Memmentioning

confidence: 99%

Mouse models to study inner ear development and hereditary hearing loss

Friedman¹,

Dror²,

Avraham³

2007

Int. J. Dev. Biol.

101

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Hereditary sensorineural hearing loss, derived from inner ear defects, is the most common hereditary disability with a prevalence of 1 in 1000 children, although it can be present in up to 15% of births in isolated communities. The mouse serves as an ideal animal model to identify new deafness-related genes and to study their roles in vivo. This review describes mouse models for genes that have been linked with hearing impairment (HI) in humans. Mutations in several groups of genes have been linked with HI in both mice and humans. Mutant mice have been instrumental in elucidating the function and mechanisms of the inner ear. For example, the roles of collagens and tectorins in the tectorial membrane, as well as the necessity of intact links between the hair cell projections, stereocilia and kinocilia, have been discovered in mice. Accurate endolymph composition and the proteins which participate in its production were found to be crucial for inner ear function, as well as several motor proteins such as prestin and myosins. Two systematic projects, KOMP and EUCOMM, which are currently being carried out to create knockout and conditional mutants for every gene in the mouse genome, promise that many additional deafness-related genes will be identified in the next years, providing models for all forms of human deafness.

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Targeted disruption of mouse Coch provides functional evidence that DFNA9 hearing loss is not a COCH haploinsufficiency disorder

Cited by 33 publications

References 26 publications

Expression studies of osteoglycin/mimecan (OGN) in the cochlea and auditory phenotype of Ogn-deficient mice

Expression studies of osteoglycin/mimecan (OGN) in the cochlea and auditory phenotype of Ogn-deficient mice

Cochlin Isoforms and Their Interaction with CTL2 (SLC44A2) in the Inner Ear

Mouse models to study inner ear development and hereditary hearing loss

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