Hum Mol Genet.: auth.: group Reymond and co-auth.: GTF & BICC

Hum Mol Genet. 2021 May 31;ddab145. doi: 10.1093/hmg/ddab145. 

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

Sissy Bassani 1 2Edward Beelen 3Mireille Rossel 4Norine Voisin 1Anna Morgan 2 5Yoan Arribat 6Nicolas Chatron 1 7Jacqueline Chrast 1Massimiliano Cocca 5Benjamin Delprat 4Flavio Faletra 5Giuliana Giannuzzi 1Nicolas Guex 8Roxane Machavoine 9Sylvain Pradervand 1Jeroen J Smits 10Jiddeke M van de Kamp 11Alban Ziegler 9Francesca Amati 6Sandrine Marlin 9Hannie Kremer 10Heiko Locher 3Tangui Maurice 4Paolo Gasparini 2 5Giorgia Girotto 2 5Alexandre Reymond 1


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.