Abstract
Hereditary Hearing Loss (HHL) is an extremely heterogeneous disorder. Approximately 30 out of 80 known HHL genes are associated with autosomal dominant forms. Here, we identified PSIP1/LEDGF (isoform p75) as a novel strong candidate gene involved in dominant HHL. Using exome sequencing we found a frameshift deletion (c.1554_1555del leading to p.E518Dfs*2) in an Italian pedigree affected by sensorineural mild-to-moderate HHL but also showing a variable eye phenotype (i.e. uveitis, optic neuropathy). This deletion led to a premature stop codon (p.T519X) with truncation of the last 12 amino acids. PSIP1 was recently described as a transcriptional co-activator regulated by miR-135b in vestibular hair cells of the mouse inner ear as well as a possible protector against photoreceptor degeneration. Here, we demonstrate that it is ubiquitously expressed in the mouse inner ear. The PSIP1 mutation is associated with a peculiar audiometric slope toward the high frequencies. These findings indicate that PSIP1 likely plays an important role in HHL.
Highlights
Hereditary Hearing Loss (HHL) is a common genetic disorder accounting for at least 60% of pre-lingual deafness in children
Click-Auditory Brain Response (ABR) audiometry is an effective tool in the evaluation of downsloping hearing loss, to discriminate between cochlear and retrocochlear involvement
ABR features are consistent with cochlear origin of the hearing loss in the proband (III:1)
Summary
Hereditary Hearing Loss (HHL) is a common genetic disorder accounting for at least 60% of pre-lingual deafness in children. In order to reveal the underlying genetic defect in these families, we performed targeted re-sequencing of known HHL genes following the strategy previously described on affected family members, but failed to identify any pathological mutations[7]. The first large kindred whose affected members showed sensorineural mild-to-moderate hearing loss was further investigated by whole-exome sequencing. Using this approach, we identified a heterozygous frameshift deletion in a transcriptional co-activator, PSIP1 ( called LEDGF), already known to be regulated by miR-135b in vestibular cells[8] and recently described as a regulator of gene expression in the epithelial cells of the lens[9]. Our findings identify a new interesting candidate gene for human HHL and possibly visual degeneration as well
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