Das Usher-Syndrom, eine Ziliopathie des Menschen

Zusammenfassung

Das humane Usher-Syndrom (USH) ist eine seltene, komplexe genetische Erkrankung, die sich in kombinierter Taubblindheit manifestiert. Aufgrund der Ausprägung des Krankheitsbilds werden 3 klinische Typen (USH1 – 3) unterschieden. Für eine korrekte Diagnose sind zusätzlich zu den auditorischen Tests im Zuge des Neugeborenenscreens auch frühe ophthalmologische Untersuchungen und eine molekulargenetische Abklärung notwendig. Die bislang 10 bekannten USH-Gene codieren für heterogene Proteine, die in Proteinnetzwerken miteinander in Funktionseinheiten kooperieren. Im Auge und im Ohr werden USH-Proteine vor allem in den mechanosensitiven Haarsinneszellen und den Stäbchen- und Zapfenphotorezeptorzellen exprimiert. In den Haarzellen sind die USH-Proteinnetzwerke sowohl für die korrekte Differenzierung der reizaufnehmenden Haarbündel als auch für den mechanisch-elektrischen Transduktionskomplex essenziell. In den Photorezeptorzellen sind USH-Proteine im Bereich des Ciliums lokalisiert, wo sie an intrazellulären Transportprozessen beteiligt sein dürften. Darüber hinaus ist ein USH-Proteinnetzwerk in den sog. „calyceal processes“, die das Außensegment der Photorezeptorzellen stabilisieren, zu finden. Das Fehlen der „calyceal processes“ und eines prominenten visuellen Phänotyps in der Maus disqualifiziert Mausmodelle als Modelle für die ophthalmologische Komponente von USH. Während Hörstörungen mit Hörgeräten und Cochleaimplantaten kompensiert werden können, gibt es für USH im Auge bislang keine praktikable Therapie. Derzeit werden genbasierte Therapiekonzepte, wie bspw. Genaddition, Applikationen von Antisense-Oligonukleotiden und TRIDs („translational readthrough inducing drugs“) zum Überlesen von Nonsense-Mutationen präklinisch evaluiert. Für USH1B/MYO7A läuft bereits die UshStat-Gentherapie als klinische Studie.

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.

Schlüsselwörter

Genetik - Taubblindheit - Proteinnetzwerke - Retinitis pigmentosa - Schwerhörigkeit

Key words

genetics - retinitis pigmentosa - deaf-blindness - protein networks - deafness

• Literatur

• 1 Wolfrum U. Protein Networks related to the Usher Syndrome gain Insights in the molecular Basis of the Disease. In: Ahuja S. ed. Usher Syndrome: Pathogenesis, Diagnosis and Therapy. New York, USA: Nova Science Publishers Inc; 2011: 51-73
• 2 Jansen F, Kalbe B, Scholz P. et al. Impact of the Usher syndrome on olfaction. Hum Mol Genet 2016; 25: 524-533
• 3 Ribeiro JC, Oliveiros B, Pereira P. et al. Accelerated age-related olfactory decline among type 1 Usher patients. Sci Rep 2016; 6: 28309
• 4 Mathur P, Yang J. Usher syndrome: hearing loss, retinal degeneration and associated abnormalities. Biochim Biophys Acta 2015; 1852: 406-420
• 5 Reiners J, Nagel-Wolfrum K, Jürgens K. et al. Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease. Exp Eye Res 2006; 83: 97-119
• 6 Saihan Z, Webster AR, Luxon L. et al. Update on Usher syndrome. Curr Opin Neurol 2009; 22: 19-27
• 7 Riazuddin S, Belyantseva IA, Giese AP. et al. Alterations of the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1 J and nonsyndromic deafness DFNB48. Nat Genet 2012; 44: 1265-1271
• 8 Michel V, Booth KT, Patni P. et al. CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival. EMBO Mol Med 2017; 9: 1711-1731
• 9 McMillan DR, White PC. Studies on the very large G protein-coupled receptor: from initial discovery to determining its role in sensorineural deafness in higher animals. Adv Exp Med Biol 2010; 706: 76-86
• 10 Wang Y, Fan X, Zhang W. et al. Deficiency of very large G-protein-coupled receptor-1 is a risk factor of tumor-related epilepsy: a whole transcriptome sequencing analysis. J Neurooncol 2015; 121: 609-616
• 11 Otterstedde CR, Spandau U, Blankenagel A. et al. A new clinical classification for Usherʼs syndrome based on a new subtype of Usherʼs syndrome type I. Laryngoscope 2001; 111: 84-86
• 12 Khateb S, Zelinger L, Mizrahi-Meissonnier L. et al. A homozygous nonsense CEP250 mutation combined with a heterozygous nonsense C2orf71 mutation is associated with atypical Usher syndrome. J Med Genet 2014; 51: 460-469
• 13 Puffenberger EG, Jinks RN, Sougnez C. et al. Genetic mapping and exome sequencing identify variants associated with five novel diseases. PloS One 2012; 7: e28936 doi:10.1371/journal.pone.0028936
• 14 Nishimura DY, Baye LM, Perveen R. et al. Discovery and functional analysis of a retinitis pigmentosa gene, C2ORF71. Am J Hum Genet 2010; 86: 686-695
• 15 Ebermann I, Phillips JB, Liebau MC. et al. PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome. J Clin Invest 2010; 120: 1812-1823
• 16 Seeliger MW, Fischer MD, Pfister M. [Usher syndrome: clinical features, diagnostic options, and therapeutic prospects]. Ophthalmologe 2009; 106: 505-511
• 17 Malm E, Ponjavic V, Möller C. et al. Alteration of rod and cone function in children with Usher syndrome. Eur J Ophthalmol 2011; 21: 30-38
• 18 Testa F, Melillo P, Bonnet C. et al. Clinical presentation and disease course of Usher syndrome because of mutations in MYO7A or USH2A. Retina 2017; 37: 1581-1590
• 19 Cremers FP, Kimberling WJ, Külm M. et al. Development of a genotyping microarray for Usher syndrome. J Med Genet 2007; 44: 153-160
• 20 Licastro D, Mutarelli M, Peluso I. et al. Molecular diagnosis of Usher syndrome: application of two different next generation sequencing-based procedures. PLoS One 2012; 7: e43799 doi:10.1371/journal.pone.0043799
• 21 Besnard T, García-García G, Baux D. et al. Experience of targeted Usher exome sequencing as a clinical test. Mol Genet Genomic Med 2014; 2: 30-43
• 22 Bolz HJ. Next-Generation Sequencing: Quantensprung für Forschung und Diagnostik in der Ophthalmologie. Klin Monatsbl Augenheilkd 2017; 234: 280-288
• 23 Overlack N, Goldmann T, Wolfrum U. et al. Current therapeutic Strategies for human Usher Syndrome. In: Ahuja S. ed. Usher Syndrome: Pathogenesis, Diagnosis and Therapy. New York, USA: Nova Science Publishers Inc.; 2011: 377-395
• 24 Henricson C, Wass M, Lidestam B. et al. Cognitive skills in children with Usher syndrome type 1 and cochlear implants. Int J Pediatr Otorhinolaryngol 2012; 76: 1449-1457
• 25 Guinand N, van de Berg R, Cavuscens S. et al. Vestibular implants: 8 years of experience with electrical stimulation of the vestibular nerve in 11 patients with bilateral vestibular loss. ORL J Otorhinolaryngol Relat Spec 2015; 77: 227-240
• 26 Duncan JL, Richards TP, Arditi A. et al. Improvements in vision-related quality of life in blind patients implanted with the Argus II Epiretinal Prosthesis. Clin Exp Optom 2017; 100: 144-150
• 27 Tucker BA, Mullins RF, Streb LM. et al. Patient-specific iPSC-derived photoreceptor precursor cells as a means to investigate retinitis pigmentosa. Elife 2013; 2: e00824 doi:10.7554/eLife.00824
• 28 Slijkerman RW, Vaché C, Dona M. et al. Antisense oligonucleotide-based splice correction for USH2A-associated retinal degeneration caused by a frequent deep-intronic mutation. Mol Ther Nucleic Acids 2016; 5: e381
• 29 Lentz JJ, Jodelka FM, Hinrich AJ. et al. Rescue of hearing and vestibular function by antisense oligonucleotides in a mouse model of human deafness. Nat Med 2013; 19: 345-350
• 30 Vijayakumar S, Depreux FF, Jodelka FM. et al. Rescue of peripheral vestibular function in Usher syndrome mice using a splice-switching antisense oligonucleotide. Hum Mol Genet 2017; 26: 3482-3494
• 31 Mort M, Ivanov D, Cooper DN. et al. A meta-analysis of nonsense mutations causing human genetic disease. Hum Mutat 2008; 29: 1037-1047
• 32 Wiechers L, Samanta A, Nagel-Wolfrum K. Das Überlesen von Nonsense-Mutationen. Med Genet 2017; 29: 217-224
• 33 Goldmann T, Overlack N, Möller F. et al. A comparative evaluation of NB30, NB54 and PTC124 in translational read-through efficacy for treatment of an USH1C nonsense mutation. EMBO Mol Med 2012; 4: 1186-1199
• 34 Nagel-Wolfrum K, Möller F, Penner I. et al. Targeting nonsense mutations in diseases with translational read-through-inducing drugs (TRIDs). BioDrugs 2016; 30: 49-74
• 35 Liu XZ, Walsh J, Tamagawa Y. et al. Autosomal dominant non-syndromic deafness caused by a mutation in the myosin VIIA gene. Nat Genet 1997; 17: 268-269
• 36 Sorusch N, Bauss K, Plutniok J. et al. Characterization of the ternary Usher syndrome SANS/ush2a/whirlin protein complex. Hum Mol Genet 2017; 26: 1157-1172
• 37 Gregory FD, Bryan KE, Pangršič T. et al. Harmonin inhibits presynaptic Cav1.3 Ca²⁺ channels in mouse inner hair cells. Nat Neurosci 2011; 14: 1109-1111
• 38 El-Amraoui A, Petit C. Usher I syndrome: unravelling the mechanisms that underlie the cohesion of the growing hair bundle in inner ear sensory cells. J Cell Sci 2005; 118: 4593-4603
• 39 Zhao B, Müller U. The elusive mechanotransduction machinery of hair cells. Curr Opin Neurobiol 2015; 34: 172-179
• 40 Gibbs D, Kitamoto J, Williams DS. Abnormal phagocytosis by retinal pigmented epithelium that lacks myosin VII a, the Usher syndrome 1B protein. Proc Natl Acad Sci U S A 2003; 100: 6481-6646
• 41 May-Simera H, Nagel-Wolfrum K, Wolfrum U. Cilia – The sensory antennae in the eye. Prog Retin Eye Res 2017; 60: 144-180
• 42 Maerker T, van Wijk E, Overlack N. et al. A novel Usher protein network at the periciliary reloading point between molecular transport machineries in vertebrate photoreceptor cells. Hum Mol Genet 2008; 17: 71-86
• 43 Zou J, Luo L, Shen Z. et al. Whirlin replacement restores the formation of the USH2 protein complex in whirlin knockout photoreceptors. Invest Ophthalmol Vis Sci 2011; 52: 2343-2351
• 44 Overlack N, Kilic D, Bauss K. et al. Direct interaction between Usher syndrome 1 G protein SANS and myomegalin in mammalian photoreceptor cells. Biochim Biophys Acta 2011; 1813: 1883-1893
• 45 Papal S, Cortese M, Legendre K. et al. The giant spectrin βV couples the molecular motors to phototransduction and Usher syndrome type I proteins along their trafficking route. Hum Mol Genet 2013; 22: 3773-3788
• 46 Bauss K, Knapp B, Jores P. et al. Phosphorylation of the Usher syndrome 1 G protein SANS controls Magi2-mediated endocytosis. Hum Mol Genet 2014; 23: 3923-3942
• 47 Williams DS. Usher syndrome: animal models, retinal function of Usher proteins, and prospects for gene therapy. Vision Res 2008; 48: 433-441
• 48 Sahly I, Dufour E, Schietroma C. et al. Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice. J Cell Biol 2012; 199: 381-399
• 49 Schietroma C, Parain K, Estivalet A. et al. Usher syndrome type 1-associated cadherins shape the photoreceptor outer segment. J Cell Biol 2017; 216: 1849-1864
• 50 Roepman R, Wolfrum U. Protein networks and complexes in photoreceptor cilia. Subcell Biochem 2007; 43: 209-235
• 51 Boldt K, van Reeuwijk J, Lu Q. et al. An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. Nat Commun 2016; 7: 11491