Molecular Genetics of U sher Syndrome: Current State of Understanding

Abstract

Usher syndrome affects hearing, vision and balance. The syndrome is genetically heterogeneous and mutations in ten genes have been identified to be disease causing. Proteins encoded by these genes cofunction with each other and with other proteins, composing an Usher interactome with diverse functions including structural support, transport and potentially signalling at different subcellular locations in hair cells of the inner ear and in photoreceptors of the retina. In hair cells, Usher proteins mainly contribute to the formation of fibrous links, including the tip link, that connect stereocilia and stereocilia to the kinocilium. In addition, Usher proteins are found in the synaptic region where they might contribute to signal transduction by regulating the cell surface levels of Ca v 1.3 Ca 2+ channels and exocytosis. In photoreceptor cells, the Usher proteins are seen in the region of the connecting cilium including the periciliary region, the basal body, accessory centriole and calyceal processes. Also here, Usher proteins are present in the synaptic region. Although the function of Usher proteins in photoreceptors and hair cells is not yet fully understood, promising therapeutic developments are ongoing to alleviate the phenotypic burden resulting from mutations in any of the Usher genes. Key Concepts Usher syndrome is clinically and genetically heterogeneous. Usher syndrome type I (USH1) and type II (USH2) proteins interact and form highly dynamic protein networks. Usher protein networks fulfil a role in providing structural support, play a role in intracellular transport mechanisms and are suggested to be involved in cellular signalling cascades. A range of cellular and animal models are used to unravel the molecular pathogenesis of Usher syndrome and to evaluate promising therapeutic strategies. Promising progress in the development of (pre)clinical genetic (i.e. gene augmentation, splice modulation, translational read‐through and gene editing) and nongenetic (i.e. small compounds, neurotrophic factors and cell replacement) therapeutic strategies have been published for Usher syndrome.

Usherin defects lead to early-onset retinal dysfunction in zebrafish

“…Prior to this study, several USH mouse models were generated, which all presented with early-onset hearing defects, with or without vestibular dysfunction, closely resembling human inner ear USH defects (Slijkerman et al, 2017). These models have contributed significantly to understanding the molecular pathology underlying USH-associated hearing loss (Schwander et al, 2009; Tian et al, 2010; Yang et al, 2010).…”

USH2A-retinopathy: From genetics to therapeutics

“…In addition to its central role in Usher 2 complex formation, whirlin integrates the Usher 1 protein network by interacting with the unconventional actin-based motor protein myosin VIIa (USH1B), cadherin-23 (USH1D) and protocadherin-15 (USH1F), the scaffold protein SANS (USH1G) and the calcium/integrin binding-protein CIB2 (USH1J). Harmonin (USH1C), SANS (USH1G) and PDZD7, as well as whirlin, are key assembler scaffold proteins at the centre of the Usher protein network ( Chen et al, 2014 ; Reiners et al, 2005a ; Slijkerman et al, 2017 ; Sorusch et al, 2017 ; van Wijk et al, 2006 ; Yang et al, 2010 ; Zou et al, 2011 , 2015 ). Harmonin has been shown to interact with all Usher 1 proteins (except CIB2) and is linked to the Usher 2 complex via ADGRV1 and usherin binding ( Reiners et al, 2005b ).…”