Haploinsufficiency of KPNA7 causes otosclerosis, likely due to the release of import inhibition of PTHrP and the reactivation of chondrogenesis in the globuli interossei

Otosclerosis is a genetic bone disorder restricted to the otic capsule and a common cause of conductive hearing loss with both familial and sporadic cases. To date, 14 genomic loci (OTSC) and four underlying OTSC genes (MEPE, SERPINF1, FOXL1, SMARCA4) have been identified in autosomal dominant families. A combined genetic/genomics approach on five affected siblings of Northern European ancestry from the island of Newfoundland, Canada identified a premature stop mutation in Karyopherin subunit α7 (KPNA7, c.49C>T, p.R17X). KPNA7 maps to OTSC2 (7q22.1), is the newest of the seven-member importin-α family of nuclear transporters and plays a critical role in early embryonic cleavage events and zygotic genome activation. So far, homozygous KPNA7 variants cause both a syndromic bone disorder of partial agenesis of the corpus callosum and cerebellar vermis hypoplasia with posterior fossa cysts and preimplantation embryo arrest (PREMBA) (OMIM 614107). Interestingly, KPNA7 is exclusively expressed in embryonic tissues and likely inhibits non-classical NLS transport of PTHrP, a known activator of chondrogenesis. We propose that KPNA7 haploinsufficiency causes a failure in transport inhibition of PTHrP in the quiescent embryonic cells of the globuli interossei and re-activates chondrogenesis. The KPNA7 discovery challenges the central theme that otosclerosis is due to dysregulated bone remodeling suppression involving the RANK/RANKL/OPG pathway and offers new insights into its pathophysiology.