Donders Institute for Brain, Cognition and Behaviour
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Theme 2: Perception, Action and Control - sensory disorders

Usher syndrome: Genetics and Functional Genomics

Hannie Kremer's research themes are:
- Hereditary hearing impairment (or deafness)
- Usher syndrome

Hereditary hearing impairment (or deafness)
Hereditary hearing impairment (or deafness) is among the most common monogenic disorders but can also be multifactorial as is the case for age-related hearing loss. Clinical and genetic heterogeneity of hearing impairment is enormous. We largely concentrate on the genetics of nonsyndromic deafness. Dominant, recessive, X-linked, Y-linked and mitochondrial inheritance patterns can be seen. Although more than 60 deafness genes are known already, it is estimated that more than hundred additional genes await identification. The aim of our studies is to identify genetic defects that underlie hereditary hearing impairment in the Netherlands and to unravel the molecular pathogenesis. To reach this goal, we include families from Pakistan and Turkey via collaborations with researchers in these countries. Hearing impairment often has a genetic cause also when there is only one hearing impaired individual in a family. Therefore, we study hearing impairment in families and in single cases. Linkage analysis, homozygosity mapping, and whole exome sequencing are performed and combined by using state-of-the-art techniques. Clinical characterization of the hearing loss in families enables us to establish genotype-phenotype correlations for hearing loss. The function of novel deafness genes is unraveled by studying the encoded protein with several techniques including the search for interaction partners. Identification of deafness genes facilitates adequate counseling of patients and their families and provides knowledge on inner ear function. Furthermore, it will provide handles for the development of future therapy. The research is a close collaboration between the ENT department and the departments of Human Genetics.

Usher syndrome
Patients suffering from Usher syndrome (USH) live an isolated life in a society that is based on fast communication and mobility. USH is a severe genetic disorder characterized by hearing impairment, occasionally vestibular impairment, and progressive retina degeneration. The hearing loss can be partly compensated by providing patients with hearing aids or cochlear implants but for the loss of vision currently no treatment is available. However, since the retina degeneration is slowly progressive, there is a time window for therapeutic intervention. Usher syndrome type IIa (USH2a), the most common type, is caused by mutations in the USH2A gene. Other genes involved in Usher syndrome are MYO7A, USH1C, CDH23, PCDH15 and USH1G (type I), GPR98 and DFNB31 (type II) and USH3A (type III). Also, defects in the USH2A gene are an important cause of non-syndromic retinitis pigmentosa. Usher proteins co-function in a protein network which explains why defects in genes encoding functionally different proteins are causative for one and the same disorder. We have a specific interest in the USH2A protein and whirlin.

Research lines
Our Usher syndrome research focuses on two lines of research:
1) Unravelling the pathogenic mechanisms underlying the disorder;
2) Therapeutic development.

Pathogenesis
Recently, we have shown that NINL, which we identified as an interaction partner of USH2A, connects proteins involved in different retinal degeneration disorders (Usher syndrome, Leber congenital amaurosis and Joubert syndrome). This suggests an overlap in the molecular pathogenesis of these disorders. Further unravelling of the USH protein network is ongoing by using yeast two-hybrid screening and tandem affinity purification (TAP). The mechanisms of hearing impairment in Usher syndrome are (at least partly) understood. Those of retinal degeneration in Usher syndrome are largely unknown but the localization of the Usher proteins in the region of the connecting cilium of photoreceptor cells suggests that dysfunction of this structure which heavily functions in transport, is involved.

Therapy
The therapeutic potential of three strategies is currently being explored: antisense oligonucleotide (AON)-based therapy, gene augmentation therapy using mini-genes, and interfering with the USH disease mechanism using chemical compounds. For further information please visit our EUR-USH consortium website: http://eur-ush.eu/.

Zebrafish
To assess the efficacy of potential therapies at the level of the organism, animal models are needed. Although mutant mouse models are commonly used to study inherited disorders, in several cases the retinal phenotype in these models does not mimic that of patients with mutations in the orthologous gene (e.g. Ush2a knock-out mice). Zebrafish has emerged as a pre-eminent model for studying inherited retinal disease. They are easy to genetically manipulate, have a retinal structure comparable to humans, and are ideal for our initial studies. To evaluate the therapeutic potential of our different strategies in vivo, we therefore aim to generate and characterize zebrafish models for a selection of frequently found Usher syndrome-causing mutations.

The USH2A protein

Defects in the USH2A gene not only are an important cause of Usher syndrome but also of non-syndromic retinitis pigmentosa. Usher proteins co-function in a protein network which explains why defects in genes encoding functionally different proteins are causative for one and the same disorder. We have a specific interest in the USH2A protein and whirlin. Recently, we have shown that NINL, which we identified as an interaction partner of USH2A, connects proteins involved in different retinal degeneration disorders (Usher syndrome, Leber congenital amaurosis and Bardet Biedl syndrome). This suggests an overlap in the molecular pathogenesis of these disorders.

Strategies

Further unravelling of the USH protein network is ongoing by using yeast-two-hybrid screening and tandem affinity purification (TAP). The mechanisms of retinal pathogenesis in Usher syndrome are largely unknown but the localization of the Usher proteins in the region of the connecting cilium of photoreceptor cells suggests that dysfunction of this structure which is heavily involved in transport, is affected. To further study the function of Usher proteins and the mechanisms of retinal degeneration we are introducing zebrafish as a model organism.

Mutation chip

To facilitate DNA diagnostics an Usher mutation chip has been developed in collaboration with Asper Biotech. With the chip all known mutations in all Usher genes identified so far, can be detected. The chip is being  updated every 2-3 years and is available for DNA diagnostics via Asper Biotech. The research is a close collaboration between the departments of Otorhinolaryngology and Human Genetics.

Contact
Name: Hannie Kremer
Telephone: 024-3610487
Email: Hannie.Kremer@radboudumc.nl
Visiting address:

Department of Genetics / Route 855
Geert Grooteplein zuid 10 
6525 GA Nijmegen
Netherlands

Postal address:

Publications
1. NINL and DZANK1 Co-function in Vesicle Transport and Are Essential for Photoreceptor Development in Zebrafish.
Author(s): Dona, Margo; Bachmann-Gagescu, Ruxandra; Texier, Yves; et al.
Source: PLoS genetics Volume: 11 Issue: 10 Pages: e1005574 Published: 2015-Oct 1.

2. The Ciliopathy Protein CC2D2A Associates with NINL and Functions in RAB8-MICAL3-Regulated Vesicle Trafficking.
Author(s): Bachmann-Gagescu, Ruxandra; Dona, Margo; Hetterschijt, Lisette; et al.
Source: PLoS genetics Volume: 11 Issue: 10 Pages: e1005575 Published: 2015-Oct

3. A Novel Locus Harbouring a Functional CD164 Nonsense Mutation Identified in a Large Danish Family with Nonsyndromic Hearing Impairment
Author(s): Nyegaard, Mette; Rendtorff, Nanna D.; Nielsen, Morten S.; et al.
Source: Plos Genetics Volume: 11 Issue: 7 Published: JUL 2015

4. Nonsyndromic Hearing Loss Caused by USH1G Mutations: Widening the USH1G Disease Spectrum
Author(s): Oonk, Anne Marthe Maria; van Huet, Ramon A. C.; Leijendeckers, Joop M.; et al.
Source: Ear and Hearing Volume: 36 Issue: 2 Pages: 205-211 Published: MAR-APR 2015

5. Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5
Author(s): Seco, Celia Zazo; Oonk, Anne M. M.; Dominguez-Ruiz, Maria; et al.
Source: European Journal of Human Genetics Volume: 23 Issue: 2 Pages: 189-194 Published: FEB 2015

Links

Hereditaryhearingloss.org. (A comprehensive overview of genes involved in hearing impairment)
Cochlear.com. (The structure and function of the inner ear is extensively illustrated)


Back to:
Research Theme 2:
Perception, Action and Decision-making

Donders
Research Group
Sensory Disorders -


Principal Investigator
Hannie Kremer (ENT Department and Genetics Department)

Hereditary deafness: the genetic defects - group members

Senior Researcher
Patrick Huygen

Postdoc
Margit Schraders

Research Technician
Jaap Oostrik

Clinical Geneticist; Genetics Department
Ilse Feenstra

Otorhinolaryngolists
Ronald Admiraal (Otorhinolaryngolist)
Dirk Kunst (Otorhinolaryngologist)
Ronald Pennings (Otorhinolaryngologist)

PhD students
Eline van Beelen
Anne Oonk
Celia Zazo Seco

Usher Syndrome: Genetics, Functional Genomics and Therapeutic Strategies

Postdocs
Theo Peters
Erwin van Wijk

PhD students
Margo Dona
Bas Hartel
Ralph Slijkerman
Erik de Vrieze

Research Technician
Lisette Hetterschijt

Otorhinolaryngologists
Jan Keunen
Ronald Pennings

Molecular Biologist; Genetics Department
Ronald Roepman

Clinical Molecular Geneticist; Genetics Department
Helger Yntema