Genetics Research News
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21 pathogenic mutations in the USH2A gene have been identified in 11 Chinese families by using the targeted next-generation sequencing (NGS) technology. We identified 21 pathogenic mutations, of which 13, including 5 associated with RP and 8 with USH II, have not be been previously reported. Visual impairment and retinopathy were consistent between the USH II and non-syndromic RP patients with USH2A mutations. These findings provide a basis for investigating genotype-phenotype relationships in Chinese USH II and RP patients and for clarifying the pathophysiology and molecular mechanisms of the diseases associated with USH2A mutations.
What this means for Usher syndrome: This study provides additional genetic information about Usher syndrome type 2.
When Kevin Booth started his thesis at the University of Iowa, there were 10 genes linked to Usher syndrome, including the CIB2 gene (USH1J). Interested in understanding whether mutations in the CIB2 gene cause Usher, he started his investigation in the Molecular Otolaryngology and Renal Research Laboratory with Professor Richard J. Smith. Working with clinicians and collaborators, Booth identified and examined the results of thousands of patients with the CIB2 mutation. The in-depth examinations revealed that patients had perfectly healthy retinas and no balance issues but the genetic evidence refuting CIB2’s role in Usher syndrome was not enough for Booth. Along with a team of scientists from the Institut Pasteur in Paris, Booth utilized a comprehensive approach, which included phenotyping, cutting edge genomic technologies, murine mutant models, and functional assays, that showed mutations in CIB2 do not cause Usher syndrome.
What this means for Usher Syndrome: This means that CIB2 does not cause Usher syndrome and USH1J is no longer considered a subtype of Usher syndrome. Parents of deaf children with mutations in CIB2 will no longer be told that their child will also develop retinitis pigmentosa. The counseling that these families will receive after the genetic results will change accordingly.
This study used the highly sensitive RNAscope in situ hybridization assay and single-cell RNA-sequencing techniques to investigate the distribution of Clrn1 and CLRN1 in mouse and human retina respectively. The pattern of Clrn1 mRNA cellular expression is similar in both mouse and adult human retina, with CLRN1 transcription being localized in Müller glia and photoreceptors. The study generated a novel knock-in mouse with a hemagglutinin (HA) epitope-tagged CLRN1 and showed that CLRN1 is expressed continuously at the protein level in the retina. Following enzymatic de-glycosylation and immunoblotting analysis, scientists detected a single CLRN1-specific protein band in homogenates of mouse and human retina, consistent in size with the main CLRN1 isoform. Taken together, their results implicate Müller glia in USH3 pathology, for future mechanistic and therapeutic studies to prevent vision loss in this disease.
What this means for Usher syndrome: As shown in previous studies of the USH1C protein in zebrafish, Müller glia, in addition to photoreceptors, may be involved in Usher syndrome.
As part of the Human Cell Atlas Project, Australian scientists created the world’s most detailed gene map of the human retina. Dr. Wong says, “By creating a genetic map of the human retina, we can understand the factors that enable cells to keep functioning and contribute to healthy vision.” The map provides a detailed gene profile of individual retinal cell types that will help us study how those genes impact different kinds of cells. Scientists can have a clear benchmark to assess the quality of the cells derived from stem cells to determine whether they have the correct genetic code which will enable them to function.
What this means for Usher syndrome: By having this atlas of healthy cells and their interconnections, researchers will be able to predict the effect of different drugs to treat eye diseases, including Usher syndrome.
Drug repurposing is a new and attractive aspect of therapy development that could offer low-cost and accelerated establishment of new treatment options. The enzyme poly-ADP-ribose-polymerase (PARP) has important roles for many forms of DNA repair and it also participates in transcription, chromatin remodeling and cell death signaling. Currently, some PARP inhibitors are approved for cancer therapy, by means of canceling DNA repair processes and cell division.
Excessive PARP activity is also involved in neurodegenerative diseases including the currently untreatable and blinding retinitis pigmentosa group of inherited retinal photoreceptor degenerations. Hence, repurposing of known PARP inhibitors for patients with non-oncological diseases might provide a facilitated route for a novel retinitis pigmentosa therapy.
What this means for Usher syndrome: PARP inhibitors are approved for their use in cancer therapy, suggesting they can be repurposed to treat retinitis pigmentosa at a very low cost and shorter waiting times compared to novel drugs.
Researchers at Children’s Hospital of Philadelphia (CHOP) reported a more sensitive method for capturing the footprint of AAV vectors — the range of sites where the vectors transfer new genetic material. AAV vectors are bioengineered tools that use a harmless virus to transport modified genetic material safely into tissues and cells. To use these vectors safely and effectively, researchers must have a complete picture of where in the body the virus delivers the gene. Current methods to define gene transfer rely on fluorescent reporter genes that glow under a microscope, highlighting cells that take up and express the delivered genetic material. Unfortunately, these methods reveal only cells with stable, high levels of cargo. This new technology provides a better and more sensitive method for researchers to detect where the gene is expressed, even if it is expressed at low levels or for only a short time. To address this gap, Beverly L. Davidson, PhD and her laboratory developed a new AAV screening technique that uses sensitive editing-reporter transgenic mice that are marked even with a short burst of expression.
What this means for Usher syndrome: This new method will help to improve the safety of AAV-gene editing approaches because it better defines sites where the vector expresses the modified gene. AAV-gene editing might be developed into a treatment for Usher syndrome.
“Researchers have developed a significantly improved delivery mechanism for the CRISPR/Cas9 gene editing method in the liver. The delivery uses biodegradable synthetic lipid nanoparticles that carry the molecular editing tools into the cell to alter the cells’ genetic code precisely with as much as 90 percent efficiency. The nanoparticles could help overcome technical hurdles to enable gene editing in a broad range of clinical therapeutic applications.”
What this means for Usher syndrome: This technique may provide a means for delivering gene therapies to the retina in Usher syndrome patients.
RNA, the short-lived cousin to its better-known partner, DNA, is the blueprint for protein production in cells. Joshua Rosenthal told researchers about how the squid and octopuses make prolific use of an enzyme called ADAR to catalyze thousands of single-letter changes to the RNA code. These minor edits alter the structure and activity of proteins that control electrical impulses in the animals’ nerves. Rosenthal’s studies on squids inspired him to hijack ADAR and program it for making precise edits to the human RNA. Additionally, the editing of RNA is reversible, since cells are constantly churning out new copies of RNA. If Rosenthal’s RNA editors work in humans, they could be used repeatedly to treat genetic diseases without confronting the unknown, long-term risks of permanent DNA editing with CRISPR.
What this means for Usher syndrome: Although too early to say, RNA-reversibly editing can develop in an alternative strategy for the repair of point mutations in Usher genes.
A team of scientists from Sechenov First Moscow State Medical University (MSMU), together with colleagues from leading scientific centers in India and Moscow, described several genetic mutations causing Usher syndrome.
What this means for Usher syndrome: These previously unstudied genetic mutations will allow us to identify new targets for specific therapies.
Scientists at the Francis Crick Institute have discovered a set of simple rules that can determine the precision of CRISPR/Cas9 genome editing in human cells. These rules could help to improve the efficiency and safety of genome editing in both the lab and the clinic. By examining the effect of CRISPR genome editing at 1491 target sites across 450 genes in human cells, the team have discovered that the outcomes can be predicted based on simple rules. In this study, researchers have found that the outcome of a particular gene edit depends on the fourth letter from the end of the RNA guide, synthetic molecules made up of about 20 genetic letters (A, T, C, G). “The team discovered that if this letter is an A or a T, there will be a very precise genetic insertion; a C will lead to a relatively precise deletion and a G will lead to many imprecise deletions. Thus, simply avoiding sites containing a G makes genome editing much more predictable.”
What this means for Usher syndrome: Scientists will theoretically be able to repair the mutation present in an Usher gene by selecting the correct genetic letter from the end of the RNA guide.
Usher syndrome is the most common cause of deafness associated with visual loss of a genetic origin. The purpose of this paper is to report very severe phenotypic features of type 1B Usher syndrome in a Saudi family affected by a positive homozygous splice site mutation in MYO7A gene. This mutation manifested with advanced retinal degeneration at a young age.
What this means for Usher syndrome: Individuals with this particular mutation may experience more severe symptoms than other Usher 1B patients.
Qing Fu, Mingchu Xu, Xue Chen, Xunlun Sheng, Zhisheng Yuan, Yani Liu, Huajin Li, Zixi Sun, Huiping Li, Lizhu Yang, Keqing Wang, Fangxia Zhang ,Yumei Li, Chen Zhao, Ruifang Sui, Rui Chen.
This study aimed to identify the novel disease-causing gene of a distinct subtype of Usher syndrome.
Zong, Chen, Wu, Liu, Jiang.
Identification of novel mutation in compound heterozygosity in MYO7A gene revealed the genetic origin of Usher syndrome type 2 in this Han family.
Researchers study genotype–phenotype correlations and compared visual prognosis in Usher syndrome type IIa and nonsyndromic RP.
Hidekane Yoshimura, Maiko Miyagawa, Kozo Kumakawa, Shin-ya Nishio, and Shin-ichi Usami.
This first report describing the frequency (1.3–2.2%) of USH1 among non-syndromic deaf children highlights the importance of comprehensive genetic testing for early disease diagnosis.
Maha S. Zaki, Raoul Heller, Michaela Thoenes, Gudrun Nürnberg, Gabi Stern-Schneider, Peter Nürnberg, Srikanth Karnati, Daniel Swan, Ekram Fateen, Kerstin Nagel-Wolfrum, Mostafa I. Mostafa, Holger Thiele, Uwe Wolfrum, Eveline Baumgart-Vogt, Hanno J. Bolz.
This paper found that a family with severe enamel dysplasia that was initially diagnosed with Usher syndrome didn’t have Usher syndrome but instead had mutations in the PEX6 gene.
Lichun Jiang, Xiaofang Liang, Yumei Li, Jing Wang, Jacques Eric Zaneveld, Hui Wang, Shan Xu, Keqing Wang, Binbin Wang, Rui Chen and Ruifang Sui.
Researchers applied next generation sequencing to characterize the mutation spectrum in 67 independent Chinese families with at least one member diagnosed with USH.
Zhai, Jin, Gong, Qu, Zhao, Li
Ophthalmic examinations and audiometric tests were performed to identify the pathogenic mutations in a Chinese pedigree affected with Usher syndrome type II (USH2), which revealed distinguished clinical phenotypes associated with MYO7A and expanded the spectrum of clinical phenotypes of the MYO7A mutations.
Researchers investigated the proportion of exon deletions and duplications in PCDH15 and USH2A in 20 USH1 and 30 USH2 patients from Denmark.
Previous cell culture studies have suggested that CLRN1, the causative gene for USH3A, is localized to the plasma membrane and interacts with the cytoskeleton. However, less is known about CLRN1’s role with vision because the mouse model does not exhibit a retinal phenotype and expression studies in murine retinas have provided conflicting results. This study described the cloning and expression analysis of the zebrafish CLRN1 gene, and report protein localization of CLRN1 in auditory and visual cells from embryonic through adult stages. The data provide a foundation for exploring the role of CLRN1 in retinal cell function and survival in a diurnal, cone-dominant species.
What this means for Usher syndrome: Zebrafish may provide a good model for studies of USH3A.
Steele-Stallard, Le Quesne Stabej P, Lenassi E, Luxon LM, Claustres M, Roux AF, Webster AR, Bitner-Glindzicz M..
Screening for duplications, deletions and a common intronic mutation detects 35% of second mutations in patients with USH2A monoallelic mutations on Sanger sequencing. An overview of a study to improve the molecular diagnosis in families with USH2A by screening USH2A for duplications.
A team of researchers from multiple institutions reported a novel type of gene (CIB2) associated with Usher syndrome in the November 2012 issue of Nature Genetics.
Researchers conducting a genetic study of Old Order Amish and Mennonite populations have identified five new genes in which defects cause congenital diseases, including a previously unidentified type of Usher syndrome, type 3B.
"Researchers from the National Institute on Deafness and Other Communication Disorders and the National Eye Institute have now found that an alteration of an Usher gene that causes only deafness can preserve sight and balance when in combination with another alteration of the same gene that causes Usher syndrome, or deaf-blindness. This research has important implications for genetic counselors and may open new prospects for future therapies for vision loss."
EU-funded scientists have succeeded in awakening dormant vision cones, an achievement that may lead to saving millions of people from going blind.
Dr Hanno Bolz says that his team's research challenges the traditional view that USH was inherited as a single gene disorder, and shows that it may result from at least two different genetic mutations.
A new clinical test called the OtoChipTM Test for Hearing Loss and Usher Syndrome was launched by the Laboratory for Molecular Medicine, Partners Healthcare Center for Personalized Genetic Medicine on June 22, 2009. This test sequences ~70,000 bases of DNA across 19 genes involved in hearing loss and Usher syndrome.
It has been discovered that a myosin protein connected to Usher syndrome works differently from many other myosins.
The Coxsackievirus and Adenovirus Receptor (CAR) is an essential regulator of cell growth and adhesion during development. The gene for CAR, CXADR, is located within the genetic locus for USH1E. Based on this and a physical interaction with harmonin, the protein responsible for USH1C, researchers hypothesized that CAR may be involved in cochlear development and that mutations in CXADR may be responsible for USH1E.
What this means for Usher syndrome: We have potentially identified CXADR as the gene responsible for USH1E.