HGNC Approved Gene Symbol: OTOF
Cytogenetic location: 2p23.3 Genomic coordinates (GRCh38) : 2:26,457,203-26,558,756 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p23.3 | Auditory neuropathy, autosomal recessive, 1 | 601071 | Autosomal recessive | 3 |
| Deafness, autosomal recessive 9 | 601071 | Autosomal recessive | 3 |
Using a candidate gene approach in the critical region of chromosome 2p23.1 for a form of nonsyndromic deafness (DFNB9; 601071), Yasunaga et al. (1999) identified a novel human gene, which they called OTOF. ESTs in this region were submitted to rounds of 5-prime RACE-PCR and the deduced amino acids were compared with clones isolated from 2 subtracted mouse cochlear cDNA libraries. The human OTOF gene encodes a 4,954-bp transcript with a 3,690-bp open reading frame and a 1,038-bp 3-prime untranslated region with a polyadenylation signal at position 4934. The deduced 1,230-amino acid protein has a calculated molecular mass of 140.5 kD. It has 3 C2 domains and a single carboxy-terminal transmembrane domain. The protein is homologous to the C. elegans spermatogenesis factor FER-1 and human dysferlin (603009), prompting the authors to name it 'otoferlin.' The homology suggests the otoferlin is involved in vesicle membrane fusion. Otof expression was identified by RT-PCR in mouse cochlea, vestibule, and brain. By in situ hybridization, Otof labeling was seen in the inner hair cells, and faintly in the outer hair cells and spiral ganglion cells, at embryonic day 19.5, P0, and P2. Neuroepithelia of the utricle, saccule, and semicircular canals expressed Otof during the same days. Type I cells, but not type II cells or supporting cells, expressed Otof.
By Northern blot analysis, Yasunaga et al. (2000) detected a 7-kb otoferlin mRNA in the human brain. They isolated a corresponding cDNA, which was predicted to encode a 1,977-long form of otoferlin with 6 C2 domains. Other alternatively spliced transcripts were detected, which predicted several long isoforms (with 6 C2 domains) in humans and mice and short isoforms (3 C2 domains) only in humans.
Choi et al. (2009) demonstrated the existence of an alternative splice isoform of OTOF expressed in the human cochlea, and observed that human cochlear transcripts exclusively used exon 48 to encode the C-terminal 60 amino acids of this isoform, which lacks exon 47. The authors concluded that this isoform must be required for human hearing because it encodes a unique alternative C terminus affected by some DFNB9 mutations.
Yasunaga et al. (1999) found that the OTOF gene extends over 21 kb and contains at least 28 coding exons, a 5-prime UTR exon, and a 3-prime UTR exon.
Yasunaga et al. (2000) found that the OTOF gene contains 48 coding exons and spans approximately 90 kb.
By analysis of a contig containing 8 YACs, 12 BACs, and 4 PACs, Yasunaga and Petit (2000) refined the mapping of OTOF and its surrounding genes on 2p23-p22. The authors oriented the 5-prime region of OTOF as centromeric.
Roux et al. (2006) showed that otoferlin expression in mouse hair cells correlated with afferent synaptogenesis, and they found that otoferlin localized to ribbon-associated synaptic vesicles. Otoferlin bound Ca(2+) and displayed Ca(2+)-dependent interactions with the SNARE proteins syntaxin-1 (STX1A; 186590) and SNAP25 (600322).
Otoferlin has been proposed to be the calcium sensor in hair cell exocytosis, compensating for the classic synaptic fusion proteins synaptotagmin-1 (SYT1; 185605) and synaptotagmin-2 (SYT2; 600104). Heidrych et al. (2009) demonstrated in a yeast 2-hybrid assay that myosin VI (MYO6; 600970) is a novel otoferlin-binding partner. Coimmunoprecipitation assay and coexpression suggested an interaction of both proteins within the basolateral part of inner hair cells (IHCs). Comparison of Otof-mutant and Myo6-mutant mice indicated noncomplementary and complementary roles of myosin VI and otoferlin for synaptic maturation. IHCs from Otof-mutant mice exhibited a decoupling of Ctbp2 (602619) and CaV1.3 (CACNA1D; 114206) and severe reduction of exocytosis. Myo6-mutant IHCs failed to transport BK channels to the membrane of the apical cell regions, and the exocytotic Ca(2+) efficiency did not mature, and Otof- and Myo6-mutant IHCs showed a reduced basolateral synaptic surface area and altered active zone topography. Membrane infoldings in Otof-mutant inner hair cells indicated disturbed transport of endocytotic membranes and linked the above morphologic changes to a complementary role of otoferlin and myosin VI in transport of intracellular compartments to the basolateral inner hair cell membrane.
Yasunaga et al. (1999) identified a nonsense mutation (tyr703 to ter; 603681.0001) in the OTOF gene in all affected members of 4 unrelated Lebanese families.
Yasunaga et al. (2000) studied a consanguineous family originating from India in which 3 sibs suffered from severe to profound hearing loss. By segregation analysis with polymorphic markers of the DFNB9 chromosomal region, they concluded that an OTOF mutation was likely to underlie deafness in this family. By sequencing the 48 OTOF coding exons in members of this family, they identified a splice mutation in intron 8 (603681.0002). These studies demonstrated that the long otoferlin isoforms are required for inner ear function.
Adato et al. (2000) studied the molecular basis of hearing impairment in 4 Druze families from the same village in northern Galilee. The Druze are a small, isolated population practicing endogamous marriage. Thus it was expected that a single mutation would account for hearing impairment in all these families. The results, however, showed that at least 4 different genes were involved. One was a new mutation in the OTOF gene (603681.0003), the second was a mutation in the SLC26A4 gene (thr193 to ile; 605646.0019), and the third was a 35delG mutation in the GJB2 gene (121011.0005). In the fourth family, linkage was excluded from all known hearing impairment loci (recessive and dominant), as well as from markers covering chromosomes 11 through 22, pointing therefore to the existence of another nonsyndromic recessive hearing loss locus on chromosomes 1 through 10.
In 1 Cuban family, 2 Spanish families, and 8 sporadic Spanish patients with nonsyndromic sensorineural hearing loss, Migliosi et al. (2002) identified a gln829-to-ter mutation in exon 22 of the OTOF gene (Q829X; 603681.0004). Migliosi et al. (2002) determined that the Q829X mutation was responsible for 4.4% of recessive familial or sporadic cases of deafness in the Spanish population, and presented evidence for a founder effect.
Rodriguez-Ballesteros et al. (2003) extended the screening for the Q829X mutation to 289 additional unrelated families, finding 15 new cases, 9 of which were homozygous and 6 of which were heterozygous. All of them had a mode of inheritance compatible with an autosomal recessive pattern. Four previously undescribed mutations were identified. A total of 37 subjects with mutations in OTOF were studied clinically. They were phenotypically homogeneous, having profound hearing impairment with very early onset, as shown by pure-tone audiometry and auditory brainstem responses. No inner ear malformation was demonstrated by MRI and CT. Cochlear implants had been successfully provided in 10 subjects. They found that transient evoked otoacoustic emissions (TEOAEs) were present, either bilaterally or unilaterally, in 11 subjects. This raises questions about universal screening programs that use TEOAEs as the first detection test for hearing impairment in newborns, since this technique may overlook a nonnegligible proportion of cases.
Almontashiri et al. (2018) screened 33 Saudi hearing loss probands for mutations in hearing loss genes and identified mutations in 21 probands. One of 2 mutations in the OTOF gene, glu57-to-ter (603681.0014) and arg1792-to-his (603681.0015), was present in one-third of these individuals (7/21). Only 1 of the 33 probands had a homozygous GJB6 (604418) deletion, and no sequence variants were detected in GJB2 (121011).
Matsunaga et al. (2012) identified an R1939Q (603681.0012) mutation in the OTOF gene, in 13 (56.5%) of 23 Japanese patients with early-onset auditory neuropathy. Seven patients were homozygous for the mutation, 4 were compound heterozygous for R1939Q and a truncating or splice site mutation in OTOF, 1 was compound heterozygous for R1939Q and a nontruncating mutation in OTOF, and 1 was heterozygous for the R1939Q mutation. Haplotype analysis indicated a founder effect for the R1939Q mutation. Those who were homozygous for R1939Q or compound heterozygous for R1939Q and a truncating mutation had a consistent and severe phenotype, whereas the patient who was compound heterozygous for R1939Q and a nontruncating mutation had a less severe phenotype, with moderate hearing loss at age 29 years and sloping audiograms. The findings suggested that the R1939Q variant likely causes a severe impairment of protein function, and that, in general, truncating mutations cause a more severe phenotype than nontruncating mutations.
Among 64 patients with OTOF-related hearing loss from a large Japanese database, Iwasa et al. (2022) found that all 27 patients homozygous for the R1939Q mutation, as well as 22 compound heterozygotes for R1939Q and a truncating mutation and 1 patient with 2 truncating mutations, showed profound hearing loss. Among patients with one or more nontruncating mutations other than R1939Q, almost half had mild to moderate hearing loss. The genotype-phenotype correlation in nontruncating mutations was unclear, with the same mutation sometimes causing different phenotypes.
Roux et al. (2006) found that Otof -/- mice were profoundly deaf. Exocytosis in Otof -/- auditory inner hair cells was almost completely abolished, despite normal ribbon synapse morphogenesis and Ca(2+) current. Roux et al. (2006) concluded that OTOF is essential for a late step of synaptic vesicle exocytosis and may act as the major Ca(2+) sensor triggering membrane fusion at the auditory inner hair cell ribbon synapse.
In members of 4 unrelated Lebanese families (F, AB, K1, and K2) of disparate geographic origin affected with autosomal recessive deafness-9 (DFNB9; 601071), Yasunaga et al. (1999) identified a homozygous T-to-A transversion at position 2416 in exon 18 of the OTOF gene, causing a tyr-to-stop substitution at codon 730. The mutation was not identified in 106 unrelated, unaffected individuals living in Lebanon. Family F was originally reported by Chaib et al. (1996).
In a family from southwestern India, Yasunaga et al. (2000) showed that deafness (DFNB9; 601071) was due to homozygosity for an A-to-G transition at the intron 8/exon 9 junction (IVS8-2A-G) of the OTOF gene.
Adato et al. (2000) found that nonsyndromic deafness (DFNB9; 601071) in a Druze family was due to homozygosity for a G-to-A transition at position +1, the first intronic nucleotide in the splice donor site of exon 5.
Among 28 unrelated Spanish families with nonsyndromic sensorineural hearing loss (601071), Migliosi et al. (2002) identified 1 family with a mutation in the OTOF gene: a 2485C-T transition in exon 22, resulting in a premature stop codon, gln829 to ter (Q829X). Both parents were carriers of the mutation and their 2 affected children were homozygous. The mutation was not present in 200 unrelated Spanish controls with normal hearing. Genetic analysis of another 269 unrelated patients with hearing loss revealed 11 more cases (8 sporadic and 3 familial) of the Q829X mutation. One of these families was compound heterozygous for Q829X and P1825A (603681.0005). Migliosi et al. (2002) determined that the Q829X mutation was responsible for 4.4% of recessive familial or sporadic cases of deafness in the Spanish population, and presented evidence for a founder effect.
Varga et al. (2006) found the Q829X mutation in 2 families. They referred to Q829X as the Hispanic mutation, it having been found in a group of Spanish families and 1 Cuban family as noted. They described it in a family from England with no known Hispanic ancestry. In a family of Mexican ancestry, the Q829X mutation was present in heterozygous state.
In a Spanish family with sensorineural hearing loss (601071), Migliosi et al. (2002) identified compound heterozygosity for mutations in the OTOF gene: a 5473C-G transversion in exon 44, resulting in a pro1825-to-ala (P1825A) substitution, and Q829X (603681.0004). The authors noted that P1825A was the first missense mutation identified in the OTOF gene, and that it alters a conserved residue in the sixth C2 domain of the long isoforms, a domain expected to bind calcium.
In a family with nonsyndromic recessive auditory neuropathy (see 601071) characterized by hearing loss with normal function of the outer hair cells, Varga et al. (2003) identified compound heterozygosity for mutations in the OTOF gene: a 1-bp deletion (1778G) in exon 16, leading to a stop codon, and a 6141G-A change, resulting in an arg-to-gln substitution in exon 48 (603681.0007).
For discussion of the 6141G-A change in the OTOF gene that was found in compound heterozygous state in patients with nonsyndromic recessive auditory neuropathy (see 601071) by Varga et al. (2003), see 603681.0006.
In a family with nonsyndromic recessive auditory neuropathy (see 601071) characterized by hearing loss with normal function of the outer hair cells, Varga et al. (2003) identified a heterozygous G-C transversion in the donor splice site of intron 39, which is predicted to result in a truncated protein.
In a family with nonsyndromic recessive auditory neuropathy (see 601071) characterized by hearing loss with normal function of the outer hair cells, Varga et al. (2003) identified a heterozygous 6285C-G change in the OTOF gene, resulting in a pro50-to-arg (P50R) substitution.
In 3 Turkish sibs with nonsyndromic recessive auditory neuropathy (see 601071), Tekin et al. (2005) identified a homozygous 3032T-C transition in exon 26 of the OTOF gene, resulting in a leu1011-to-pro (L1011P) substitution in the fourth C2 domain (C2D) of the protein. The consanguineous parents were heterozygous for the mutation.
Mirghomizadeh et al. (2002) described a consanguineous family from eastern Turkey in which members had profound prelingual hearing loss (see 601071) and a 1544T-C transition in the OTOF gene causing an ile515-to-thr (I515T) substitution. Affected members of the family were homozygous for the I515T mutation and a second missense mutation, inherited in cis. Both mutations were in the C2C domain (third C2 domain), which is predicted to bind calcium. The alignment of otoferlin and otoferlin-related proteins revealed remarkable conservation of amino acids within the human and mouse C2C domains. Mirghomizadeh et al. (2002) predicted that either of the 2 mutations would severely disrupt the structure of the C2C domain, with the I515T mutation resulting in the creation of a new myristylation site.
Varga et al. (2006) reported the I515T mutation in heterozygous state in an individual who was observed to be temperature-sensitive for the auditory neuropathy phenotype (see 601071). In the family reported by Starr et al. (1998), Varga et al. (2006) found that the proband had abnormal auditory brainstem response (ABR), present otoacoustic emissions (OAE), and relatively normal hearing until she became febrile, when OAE remained normal but hearing degraded, and ABR worsened from abnormal with unidentified waves I-III and delayed latency of the wave IV-V complex to being totally absent. The amount of decline in hearing in the proband was dependent on the degree of fever. A mild to moderate hearing loss was present when she had the temperature of 37.8 degrees centigrade and profound hearing loss was present at 38.1 degrees centigrade. The proband's brother, who also carried the mutation, experienced similar hearing loss when febrile.
In 13 (56.5%) of 23 Japanese patients with early-onset auditory neuropathy (see 601071), Matsunaga et al. (2012) identified a 5816G-A transition in exon 50 of the OTOF gene, resulting in an arg1939-to-gln (R1939Q) substitution. Seven patients were homozygous for the mutation, 4 were compound heterozygous for R1939Q and a truncating or splice site mutation in OTOF, 1 was compound heterozygous for R1939Q and a nontruncating mutation in OTOF, and 1 was heterozygous for the R1939Q mutation. Haplotype analysis indicated a founder effect for the R1939Q mutation. The R1939Q mutation was found in 1 of 189 control individuals. Those who were homozygous for R1939Q or compound heterozygous for R1939Q and a truncating mutation had a consistent and severe phenotype, whereas the patient who was compound heterozygous for R1939Q and a nontruncating mutation had a less severe phenotype, with moderate hearing loss at age 29 years and sloping audiograms.
Among the 64 patients with DFNB9 identified in a large Japanese database, Iwasa et al. (2022) found that 27 (42%) were homozygous for the R1939Q variant, and 29 (45%) were compound heterozygous for the R1939Q variant and another mutation.
In a 26-year-old Japanese man, born of consanguineous parents, with temperature-sensitive auditory neuropathy (see 601071), Matsunaga et al. (2012) identified a homozygous 1621G-A transition in exon 15 of the OTOF gene, resulting in a gly541-to-ser (G541S) substitution that was specific to the long isoform. The mutation was not found in 376 control individuals. The patient complained of difficulty in understanding conversation and reported that his hearing deteriorated when he became febrile or was exposed to loud noise. Pure-tone audiometry when he was afebrile revealed mild hearing loss with a flat configuration.
In a 2-year-old child from a multiplex Libyan family with profound prelingual sensorineural hearing loss (DFNB9; 601071), Rodriguez-Ballesteros et al. (2008) detected homozygosity for a c.2239G-T transversion in exon 20 of the OTOF gene that resulted in a glu747-to-ter (E747X) amino acid substitution. The authors noted that the mutation affected both the long and the short isoforms of OTOF.
In a Saudi Arabian brother and sister with severe to profound hearing impairment, Dallol et al. (2016) identified homozygosity for a c.2239G-T transversion (c.2239G-T, NM_194248) in the OTOF gene that resulted in an E747X amino acid substitution. The mutation was identified by targeted sequencing of 87 genes known to be involved in hearing impairment, and confirmed by Sanger sequencing.
In 3 Saudi families (F-7, F-25, and F-27) with autosomal recessive prelingual sensorineural hearing loss, Almontashiri et al. (2018) identified homozygosity for the E747X mutation in the OTOF gene, which they designated c.169G-T (GLU57TER, E57X). The mutation was identified by targeted sequencing and confirmed by Sanger sequencing. Almontashiri et al. (2018) observed this variant in 1 of 251,632 alleles from non-Middle Eastern populations in the gnomAD database.
In affected members from 4 (F-18, F-22, F-31, and F-32) of 33 Saudi families with autosomal recessive prelingual sensorineural hearing loss (DFNB9; 601071), Almontashiri et al. (2018) identified homozygosity for a c.5375G-A transition in the OTOF gene that resulted in an arg1792-to-his (R1792H) amino acid substitution. Almontashiri et al. (2018) observed this variant in 1 of 252,426 alleles from non-Middle Eastern populations in the gnomAD database.
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