OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy allele

Varga, Renée; Avenarius, Matthew R.; Kelley, Philip M.; Keats, Bronya J.B.; Berlín, Charles I.; Hood, Linda J.; Morlet, Thierry; Brashears, Shanda; Starr, Arnold; Cohn, Edward S.; Smith, Richard J.H.; Kimberling, William J.

doi:10.1136/jmg.2005.038612

Cited by 152 publications

(172 citation statements)

References 39 publications

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“…1 -4 Among all DFNB loci, the most prevalent one is DFNB1 (GJB2 and GJB6 genes, 5 -6 MIM 121011 and 604418) that accounts for up to 50% of recessive cases. Other loci with a significant number of different families associated are DFNB4 (SLC26A4 gene, 7 MIM 605646), DFNB9 (OTOF gene, 8 MIM 603681), DFNB12 (CDH23 gene, 9 MIM 605516), DFNB7/11 (TMC1 gene, 10 MIM 606706), followed by DFNB8/10 (TMPRSS3 gene, 11 MIM 605511) and DFNB3 (MYO15A gene, 12 MIM 602666).…”

Section: Introductionmentioning

confidence: 99%

Unexpected genetic heterogeneity in a large consanguineous Brazilian pedigree presenting deafness

et al. 2007

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Nonsyndromic autosomal recessive deafness accounts for 80% of hereditary deafness. To date, 52 loci responsible for autosomal recessive deafness have been mapped and 24 genes identified. Here, we report a large inbred Brazilian pedigree with 26 subjects affected by prelingual deafness. Given the extensive consanguinity found in this pedigree, the most probable pattern of inheritance is autosomal recessive. However, our linkage and mutational analysis revealed, instead of an expected homozygous mutation in a single gene, two different mutant alleles and a possible third undetected mutant allele in the MYO15A gene (DFNB3 locus), as well as evidence for other causes for deafness in the same pedigree. Among the 26 affected subjects, 15 were homozygous for the novel c.10573delA mutation in the MYO15A gene, 5 were compound heterozygous for the mutation c.10573delA and the novel deletion c.9957_9960delTGAC and one inherited only a single c.10573delA mutant allele, while the other one could not be identified. Given the extensive consanguinity of the pedigree, there might be at least one more deafness locus segregating to explain the condition in some of the subjects whose deafness is not clearly associated with MYO15A mutations, although overlooked environmental causes could not be ruled out. Our findings illustrate a high level of etiological heterogeneity for deafness in the family and highlight some of the pitfalls of genetic analysis of large genes in extended pedigrees, when homozygosity for a single mutant allele is expected.

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Section: Introductionmentioning

confidence: 99%

Unexpected genetic heterogeneity in a large consanguineous Brazilian pedigree presenting deafness

et al. 2007

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“…Thus, ablations of individual C2 domains by themselves can disrupt the overall function of the protein, indicating that these domains are not simply redundant components that additively increase the Ca 2+ binding property of the protein. Other deafness-causing missense mutations of the human otoferlin gene have been reported in the C-terminus (Varga et al, 2003) and in the coiled coil domain (Varga et al, 2006), demonstrating the importance of those regions as well. Human patients with congenital recessive deafness caused by mutations in the C2B domain of otoferlin have not yet been described, but the results presented here for deaf5 mutant mice suggest that clinical screening for mutations in this domain is warranted.…”

Section: Discussionmentioning

confidence: 99%

A missense mutation in the conserved C2B domain of otoferlin causes deafness in a new mouse model of DFNB9

et al. 2007

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Mutations of the otoferlin gene have been shown to underlie deafness disorders in humans and mice. Analysis of genetically engineered mice lacking otoferlin have demonstrated an essential role for this protein in vesicle exocytosis at the inner hair cell afferent synapse. Here, we report on the molecular and phenotypic characterization of a new ENU-induced missense mutation of the mouse otoferlin gene designated Otof deaf5Jcs . The mutation is a single T to A base substitution in exon 10 of Otof that causes a non-conservative amino acid change of isoleucine to asparagine in the C2B domain of the protein. Although strong immunoreactivity with an otoferlin-specific antibody was detected in cochlear hair cells of wild type mice, no expression was detected in mutant mice, indicating that the missense mutation has a severe effect on the stability of the protein and potentially its localization. Auditory brainstem response (ABR) analysis demonstrated that mice homozygous for the missense mutation are profoundly deaf, consistent with an essential role for otoferlin in inner hair cell neurotransmission. Vestibular-evoked potentials (VsEPs) of mutant mice, however, were equivalent to those of wild type mice, indicating that otoferlin is unnecessary for vestibular function even though it is highly expressed in both vestibular and cochlear hair cells.

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“…The magnitude of their speech comprehension deficits is larger than expected from the patients' degree of audibility changes, and reflects impaired processing of auditory temporal cues (Starr et al, 1996;Zeng et al, 2005). Specific etiologies for the disorder affect both pre-synaptic sites (e.g., impaired function of ribbon synapses of inner hair cells; Varga et al, 2006;Marlin et al, 2010) and post-synaptic sites (e.g., impaired function of auditory nerve fibers; Starr et al, 2003). Detailed analyses of the word processing errors in a group of AN subjects with Freidreich's ataxia, a post-synaptic disorder of neural transmission, showed abnormal identification of stop consonants distinguished by VOT (/tu//du/, /ba/ /pa/, /ka/ /ga/) but normal classification of sibilant consonants containing high frequencies (e.g., /s/ vs. /f/).…”

Section: Introductionmentioning

confidence: 99%

Auditory cortical activity in normal hearing subjects to consonant vowels presented in quiet and in noise

Dimitrijevic

Pratt

Starr

2013

Clinical Neurophysiology

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OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy allele

Abstract: Mutations in OTOF cause both profound hearing loss and a type of hearing loss where otoacoustic emissions are spared called auditory neuropathy.

Cited by 152 publications

References 39 publications

Unexpected genetic heterogeneity in a large consanguineous Brazilian pedigree presenting deafness

Unexpected genetic heterogeneity in a large consanguineous Brazilian pedigree presenting deafness

A missense mutation in the conserved C2B domain of otoferlin causes deafness in a new mouse model of DFNB9

Auditory cortical activity in normal hearing subjects to consonant vowels presented in quiet and in noise

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