Usher Syndrome

Abstract

Usher syndrome (USH) is the most common genetic condition responsible for combined loss of hearing and vision. Balance disorders and bilateral vestibular areflexia are also observed in some cases. The syndrome was first described by Albrecht von Graefe in 1858, but later named by Charles Usher, who presented a large number of cases with hearing loss and retinopathy in 1914. USH has been grouped into three main clinical types: 1, 2, and 3, which are caused by mutations in different genes and are further divided into different subtypes. To date, nine causative genes have been identified and confirmed as responsible for the syndrome when mutated: MYO7A, USH1C, CDH23, PCDH15, and USH1G (SANS) for Usher type 1; USH2A, ADGRV1, and WHRN for Usher type 2; CLRN1 for Usher type 3. USH is inherited in an autosomal recessive pattern. Digenic, bi-allelic, and polygenic forms have also been reported, in addition to dominant or nonsyndromic forms of genetic mutations. This narrative review reports the causative forms, diagnosis, prognosis, epidemiology, rehabilitation, research, and new treatments of USH.

Keywords: Usher syndrome; ciliopathies; genetic hearing loss.

Figure 1

Schematic and simplified representation of a sensorineural cell in the inner ear.

Figure 2

Simplified and schematic representation of structures, genes, and proteins involved in Usher syndrome. (A) The picture shows the main structures of a sensorineural inner ear cell. (B) Different genes and proteins have been identified, some responsible for different USH subtypes. It should be noted that clarin-1 protein (in red) is a four-transmembrane protein that is synthetized and collected in the cytosol and then moves to cellular membrane during maturation processes; in the membranes, clarin protein acts as a modulator of mechano-transduction. In the figure, clarin-1 is intentionally pictured inside the cytosol to keep it separated from other proteins. Hars protein (in dark green) is a cytoplasmatic enzyme. The role of HARS1 gene in USH type 3 must be confirmed. HARS protein = histidine–tRNA ligase, cytoplasmic. Even if is not reported in the figure, myosin 7A seems to also interact with proteins of the ankle link complex.

Figure 3

Simplified and schematic representation of the maturation process that involves sensorineural cells in the inner ear. Only one kinocilium and many different stereocilia (stereovilli) for each cell are presented. Kinocilia are intracellular, transmembrane, and extracellular proteins that drive maturation and orientation of stereocilia in the sensorineural epithelium. Inner and outer hair cells, and vestibular type II hair cells lose their kinocilium during maturation; the kinocilium disappears in the final form. Transient links degenerate, and tip links, top connectors, and ankle links assume their final functional form. This reorganization of tip links, transient lateral links, top connectors, kinociliary links, and ankle links refers to the normal functions of actin filaments and several Usher proteins. Centrioles are also very important in leading a vital process during cell life. Hearing loss and equilibrium disorders may be derived from mutations in different genes that express proteins involved in different levels and in different times of maturation of the sensorineural cells. Clarin-1 protein (in red) is a four-transmembrane protein that is synthetized and collected in the cytosol and then transported to cellular membrane during maturation processes. The role of HARS1 gene in USH type 3 must be confirmed. HARS protein = histidine -- tRNA ligase, cytoplasmic. Myosin7A seems to interact with ankle link proteins in vitro. Its role in vivo is less clear. It has not been shown to be necessary in photoreceptors.

Figure 4

Usher Syndrome: audiometry profiles of patients with Usher type 1, 2, and 3. Hearing loss is bilateral, symmetric, and sensorineural for all types.