Genetics and pathological mechanisms of Usher syndrome

Abstract

Usher syndrome (USH) comprises a group of autosomal recessively inherited disorders characterized by a dual sensory impairment of the audiovestibular and visual systems. Three major clinical subtypes (USH type I, USH type II and USH type III) are distinguished on the basis of the severity of the hearing loss, the presence or absence of vestibular dysfunction and the age of onset of retinitis pigmentosa (RP). Since the cloning of the first USH gene (MYO7A) in 1995, there have been remarkable advances in elucidating the genetic basis for this disorder, as evidence for 11 distinct loci have been obtained and genes for 9 of them have been identified. The USH genes encode proteins of different classes and families, including motor proteins, scaffold proteins, cell adhesion molecules and transmembrane receptor proteins. Extensive information has emerged from mouse models and molecular studies regarding pathogenesis of this disorder and the wide phenotypic variation in both audiovestibular and/or visual function. A unifying hypothesis is that the USH proteins are integrated into a protein network that regulates hair bundle morphogenesis in the inner ear. This review addresses genetics and pathological mechanisms of USH. Understanding the molecular basis of phenotypic variation and pathogenesis of USH is important toward discovery of new molecular targets for diagnosis, prevention and treatment of this debilitating disorder.

Figure 1

Schematic representation of the Usher proteins and their major isoforms. (a) Myosin VIIa consists of a motor head domain, followed by a neck region composed of five IQ (isoleucine-glutamine) motifs. The tail is composed of a coiled-coil domain, two FERM domains, two MyTH4 domains and an homology 3 (SH3) domain. (b) The USH1C protein, harmonin isoform B contains three PDZ (PSD95, discs large, ZO-1) domains (PDZ1, 2 and 3), coiled-coil domains and a proline, serine, threonine-rich region (PST). (c) The isoform A of CDH23 is composed of 27 extracellular cadherin (EC) repeats (EC1-27), a membrane proximal extracellular cadherin domain (MPED), a transmembrane domain (TM) and intracellular domain with a C-terminal class PDZ-binding motif (PBM). (d) PCDH15 (isoform A) has 11 EC repeats, a transmembrane domain and a C-terminal class I PBM. (e) The scaffold protein SANS consists of three ankyrin (ANK)-like repeats, a central region (CENT), a sterile α-motif (SAM) and a C-terminal class I PBM. (f) The isoform B of USH2A protein is composed of an N-terminal thrombospondin/pentaxin/laminin G-like domain (LamGL), a laminin N-terminal (LamNT) domain, 10 laminin type EGF-like (EGF Lam), four fibronection type III (FN3) domains, two laminin G (LamG), 35 FN3, a transmembrane domain and an intracellular domain with a C-terminal class I PBM. (g) The isoform B of the very large G-coupled protein receptor, VLGR1, has a thrombospondin/pentaxin/laminin G-like domain, 35 Ca²⁺-binding calcium exchanger β (Calx) domains, six EAR/EPTP repeats, a seven-transmembrane region and an intracellular domain containing C-terminal class I PBM. (h) Whirlin is composed of three PDZ domains (PDZ1, 2 and 3) and a praline-rich region. (i) Clarin-1, the USH3A protein (isoform A), has four transmembrane (TM) domains.

Figure 2

(a) Diagram of a developing hair bundle. Stereocilia are held together and to the kinocilium by diverse side-links. Tip links (TL) are thought to gate the mechanoelectrical transduction channel. (b) The diagram shows the localization of CDH23 and PCDH15 at tip links. The binding of harmonin B to CDH23, PCDH15 and F-actin could anchor the interstereocilia links to the stereocilia actin core. Myo7a is believed to use long filaments of actin as tracks along which to transport other USH complex molecules. Sans located below the cuticular plate may have a role in trafficking molecules of the USH complex. Both Usherin and VLGR1 are members of the ankle links (AL) that are tethered to the actin stereocilia core through the scaffold proteins whirlin and possibly harmonin B.