Heterozygous Nonsense Mutation in the Nuclear Transport Factor KPNA7, a Maternal Factor Active in Embryonic Tissues,...

Otosclerosis is a common cause of conductive hearing loss thought to result from dysregulated bone remodeling in the embryonic tissues of the globuli interossei. Both familial and sporadic cases have been reported. To date, 10 published OTSC loci and four genes (FOXL1 (OTSC11), SMARCA4 (OTSC12), MEPE, SERPINF1) have been identified in autosomal dominant families. Using a combined genetic and genomics approach in five affected siblings, we identified a nonsense mutation in Karyopherin subunit α7 (KPNA7, c.49C>T, p.R17X), the newest of the importin-α family of nuclear transporters. KPNA7 is a key maternal factor involved in the classical transport of NLS-containing cargo proteins, active during early embryonic cleavage events and zygotic genome activation. So far, 377 cargo proteins associated with KPNA7 have been identified. Recessive KPNA7 variants cause skeletal abnormalities, epilepsy, intellectual disabilities and preimplantation embryo arrest (PREMBA). A closer look at the OTSC genes reveals their involvement in endochondral ossification signaling pathways. We explore how KPNA7 haploinsufficiency in the embryonic tissues of the otic capsule may cause dysregulated bone remodeling. This study expands the phenotypic spectrum of KPNA7 and provides new insights into the pathobiology of otosclerosis.