Mutations in OTOF
, encoding otoferlin, cause non-syndromic recessive hearing loss at theDFNB9
-related hearing loss (OMIM 60381) is frequently associated with intact otoacoustic emissions as part of a distinctive phenotype referred to as auditory neuropathy/dys-synchrony (AN/AD) (2
). There are different hypotheses for the pathogenesis of the DFNB9 phenotype (7
): some, but not all, authors believe that it reflects a role for otoferlin solely in exocytosis at the cochlear inner hair cell synapse.
There are ‘long’ and ‘short’ isoforms of OTOF
that result from utilization of alternative transcription start sites either at exon 1 for the long isoform of OTOF
or in two locations in the sequence of exon 20, respectively (11
). The long isoform encodes a protein containing six predicted C2 domains and a C-terminal transmembrane domain (11
). The long isoform is thought to be required for normal hearing because it is affected by all DFNB9
mutations, whereas only some mutations also affect the short isoform (11
Alternative splicing also contributes to OTOF
transcript diversity. There are two classes of transcripts in which either exon 47 or exon 48 encodes alternative C-termini and translation stop codons (11
). The only reported human full-length long isoform is a brain-derived transcript that utilizes exon 47 (GenBank AF183185.1), whereas other human (brain, kidney and heart) transcripts utilizing exon 48 have been detected only in short isoforms (11
). The existence of transcripts utilizing exon 48 in human cochlea was initially suggested by the presence of such a transcript in mouse cochlea (11
) and further supported by the detection of probable DFNB9
mutations in the open reading frame encoded by exon 48 (2
), although such a transcript has not been reported in human cochlea.
Rodríguez-Ballesteros et al. demonstrated that the p.Q829X mutation of OTOF
accounts for about 5.1% of recessive prelingual deafness in the Spanish population (3
). More recently, biallelic OTOF
mutations were identified in approximately 3.1% of Spanish and Caucasian families segregating recessive non-syndromic hearing loss (5
). However, these studies may have overestimated the prevalence ofDFNB9hearing loss due to an ascertainment bias for subjects with a clinical diagnosis of AN/AD.
Our previously reported Pakistani study population is a powerful resource for recessive hearing loss studies because their large, consanguineous family structures support statistically significant linkage scores (12
). The families in our study are ascertained without otoacoustic emissions testing and are thus unselected with regard to AN/AD. We have already estimated the contributions of several other DFNB genes to recessive, severeto-profound, congenital or prelingual-onset deafness in this population (13
). Mutations of GJB2
each account for 0.3–6.1% of recessive deafness in this population. These results reflect the extensive genetic heterogeneity and large genetic load of deafness that is still unaccounted for in this and other populations. The goal of our current study was to characterize the identities and frequencies of OTOF
mutations in 557 Pakistani families segregating recessive deafness.