Variants in USP48 encoding ubiquitin hydrolase are associated with autosomal dominant non-syndromic hereditary hearing loss

Bassani, S., Beelen, E., Rossel, M., Voisin, N., Morgan, A., Arribat, Y., Chatron, N., Chrast, J., Cocca, M., Delprat, B., Faletra, F., Giannuzzi, G., Guex, N., Machavoine, R., Pradervand, S., Smits, J.J., van de Kamp, J.M., Ziegler, A., Amati, F., Marlin, S., Kremer, H., Locher, H., Maurice, T., Gasparini, P., Girotto, G., Reymond, A.
Human molecular genetics   30(19): 1785-1796 (Journal)
Registered Authors
Arribat, Yoan, Kremer, Hannie, Rossel, Mireille
MeSH Terms
  • Animals
  • Hearing Loss*/genetics
  • Humans
  • Hydrolases
  • Reflex, Startle
  • Ubiquitin
  • Ubiquitin-Specific Proteases
  • Zebrafish*/genetics
34059922 Full text @ Hum. Mol. Genet.
Non-Syndromic Hereditary Hearing Loss (NSHHL) is a genetically heterogeneous sensory disorder with about 120 genes already associated. Through exome sequencing and data aggregation, we identified a family with six affected individuals and one unrelated NSHHL patient with predicted-to-be deleterious missense variants in USP48. We also uncovered an eighth patient presenting unilateral cochlear nerve aplasia and a de novo splice variant in the same gene. USP48 encodes a ubiquitin carboxyl-terminal hydrolase under evolutionary constraint. Pathogenicity of the variants is supported by in vitro assays that showed that the mutated proteins are unable to hydrolyze tetra-ubiquitin. Correspondingly, three-dimensional representation of the protein containing the familial missense variant affects a loop that controls binding to ubiquitin. Consistent with a contribution of USP48 to auditory function, immunohistology showed that the encoded protein is expressed in the developing human inner ear, specifically in the spiral ganglion neurons, outer sulcus, interdental cells of the spiral limbus, stria vascularis, Reissner's membrane, and in the transient Kolliker's organ that is essential for auditory development. Engineered zebrafish knocked-down for usp48, the USP48 ortholog, presented with a delayed development of primary motor neurons, less developed statoacoustic neurons innervating the ears, decreased swimming velocity and circling swimming behavior indicative of vestibular dysfunction and hearing impairment. Corroboratingly, acoustic startle response assays revealed a significant decrease of auditory response of zebrafish lacking usp48 at 600 Hz and 800 Hz wavelengths. In conclusion, we describe a novel autosomal dominant NSHHL gene through a multipronged approach combining exome sequencing, animal modeling, immunohistology and molecular assays.
Genes / Markers
Show all Figures
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes