Das Usher-Syndrom, eine Ziliopathie des Menschen

Abstract

The human Usher syndrome (USH) is a complex, rare disease manifesting in its most common form of inherited deaf-blindness. Due to the heterogeneous manifestation of the clinical symptoms, three clinical types (USH1-3) are distinguished according to the severity of the disease pattern. For a correct diagnosis, in addition to the auditory tests in early newborn screening, ophthalmological examinations and molecular genetic analysis are important. Ten known USH genes encode proteins, which are from heterogeneous protein families, interact in functional protein networks. In the eye and in the ear, USH proteins are expressed primarily in the mechano-sensitive hair cells and the rod and cone photoreceptor cells, respectively. In the hair cells, the USH protein networks are essential for the correct differentiation of the hair bundles as well as for the function of the mechano-electrical transduction complex in the matured cell. In the photoreceptor cells, USH proteins are located in the ciliary region and participate in intracellular transport processes. In addition, a USH protein network is present in the so-called calyceal processes. The lack of calyceal processes and the absence of a prominent visual phenotype in the mouse disqualifies mice as models for studies on the ophthalmic component of USH. While hearing impairments can be compensated with hearing aids and cochlear implants, there is no practical therapy for USH in the eye. Currently, gene-based therapy concepts, such as gene addition, applications of antisense oligonucleotides and TRIDs ("translational readthrough inducing drugs") for the readthrough of nonsense mutations are preclinically evaluated. For USH1B/MYO7A the UshStat gene therapy clinical trial is ongoing.

Lights and Shadows in the Genetics of Syndromic and Non-Syndromic Hearing Loss in the Italian Population

“…To date, about 170 loci and 117 genes (36 autosomal dominant (AD), 65 autosomal recessives (AR), 11 AD/AR, and 5 X-linked genes) have been reported as causative of Non-Syndromic Hearing Loss (NSHL) (Hereditary Hearing Loss Homepage; http://hereditaryhearingloss.org/), and more than 400 syndromes associated with hearing loss and other symptoms (Syndromic Hearing Loss-SHL) have been described [6]. In particular, among the syndromes identified so far, some of them appear more frequently than the others (e.g., Usher syndrome compared to Waardenburg syndrome) [7,8]), although, in some cases, the full spectrum of clinical features might be subtle, or even not present until later in life [9].…”

Putative Digenic <b><i>GJB2/MYO7A</i></b> Inheritance of Hearing Loss Detected in a Patient with 48,XXYY Klinefelter Syndrome

“…How- ever, an increasing body of evidence has indicated that both homozygotes and compound heterozygous for the p.V37I variant were associated with mild to moderate hearing impairment [16,17]. The MYO7A gene encodes the actin-based motor protein myosin-VIIa, which is especially crucial for the function of cochlear hair cells and eye development [18]. The myosin VIIa protein contains a conserved N-terminal actin-binding and ATPase domain (motor domain), a neck region containing five isoleucine-glutamine (IQ) motifs, and a short predicted coiled-coil domain, followed closely by two myosin tail homology 4 (MyTH4) domains, two band 4.1-ezrin-radixin-moesin (FERM) domains, and an SH3 domain [18].…”

“…The myosin VIIa protein contains a conserved N-terminal actin-binding and ATPase domain (motor domain), a neck region containing five isoleucine-glutamine (IQ) motifs, and a short predicted coiled-coil domain, followed closely by two myosin tail homology 4 (MyTH4) domains, two band 4.1-ezrin-radixin-moesin (FERM) domains, and an SH3 domain [18]. The MYO7A gene has long been associated with Usher syndrome type 1B (USH1B), which is characterized by sensorineural HL, retinitis pigmentosa, and vestibular dysfunction [18,19]. In 1997, Weil et al [20] and Liu et al [21] have identified that MYO7A gene variants are associated with DFNB2.…”

Detection of asymptomatic retinitis pigmentosa

“…Usually, RP is confined to the eye, however, some 20-30% of patients are associated with non-ocular diseases like Usher's syndrome, which is associated with hearing impairment and is the most frequent form of syndromic RP [5]. The patients of RP typically lose night vision in adolescence, side vision in young adulthood, and central vision in later life because of the progressive loss of rod and cone photoreceptor cells.…”