title: Distinct expression and function of whirlin isoforms in the inner ear and retina: an insight into pathogenesis of USH2D and DFNB31.
abstract: Usher syndrome (USH) is the most common inherited deaf-blindness with the majority of USH causative genes also involved in nonsyndromic recessive deafness (DFNB). The mechanism underlying this disease variation of USH genes is unclear. Here, we addressed this issue by investigating the DFNB31 gene, whose mutations cause USH2D or DFNB31 depending on their position. We found that the mouse DFNB31 ortholog (Dfnb31) expressed different mRNA variants and whirlin protein isoforms in the cochlea and retina, where these isoforms played different roles spatially and temporally. Full-length (FL-) whirlin in photoreceptors and hair cell stereociliary bases is important for the USH type 2 protein complex, while FL- and C-terminal (C-) whirlins in hair cell stereociliary tips participate in stereociliary elongation. Mutations in the whirlin N-terminal region disrupted FL-whirlin isoform in the inner ear and retina but not C-whirlin in the inner ear, and led to retinal degeneration as well as moderate to severe hearing loss. By contrast, a mutation in the whirlin C-terminal region eliminated all normal whirlin isoforms but generated a truncated N-terminal whirlin protein fragment, which was partially functional in the retina and thus prevented retinal degeneration. Mice with this mutation had profound hearing loss. In summary, disruption of distinct whirlin isoforms by Dfnb31 mutations leads to a variety of phenotype configurations and may explain the mechanism underlying the different disease manifestations of human DFNB31 mutations. Our findings have a potential to improve diagnosis and treatment of USH disease and quality of life in USH patients.
authors: Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT 84132, USA, Department of Neurobiology and Anatomy, University of Utah, 20 North 1900 East, Salt Lake City, UT 84132, USA.
authors: Pranav Dinesh
authors: PD
authors: Mathur
authors: Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT 84132, USA.
authors: Junhuang
authors: J
authors: Zou
authors: Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT 84132, USA.
authors: Tihua
authors: T
authors: Zheng
authors: Department of Communication Sciences and Disorders, University of Utah, 390 South 1530 East, Salt Lake City, UT 84112, USA.
authors: Ali
authors: A
authors: Almishaal
authors: Division of Otolaryngology, Department of Surgery, University of Utah, 50 North Medical Drive, Salt Lake City, UT 84132, USA.
authors: Yong
authors: Y
authors: Wang
authors: Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT 84132, USA.
authors: Qian
authors: Q
authors: Chen
authors: Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT 84132, USA, The First Affiliated Hospital, Jilin University, Changchun, Jilin 130061, China and.
authors: Le
authors: L
authors: Wang
authors: Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT 84132, USA.
authors: Deepti
authors: D
authors: Vashist
authors: Mammalian Genetics Unit, Medical Research Council, Harwell, Oxfordshire OX11 ORD, UK.
authors: Steve
authors: S
authors: Brown
authors: Division of Otolaryngology, Department of Surgery, University of Utah, 50 North Medical Drive, Salt Lake City, UT 84132, USA.
authors: Albert
authors: A
authors: Park
authors: Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT 84132, USA, Department of Neurobiology and Anatomy, University of Utah, 20 North 1900 East, Salt Lake City, UT 84132, USA, Division of Otolaryngology, Department of Surgery, University of Utah, 50 North Medical Drive, Salt Lake City, UT 84132, USA, jun.yang@hsc.utah.edu.
authors: Jun
authors: J
authors: Yang
mesh_terms: D000818:Animals; D003051:Cochlea / Q000378:metabolism*; D006198:Hair Cells, Auditory / Q000378:metabolism; D006319:Hearing Loss, Sensorineural / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D020033:Protein Isoforms / Q000096:biosynthesis / Q000502:physiology; D012333:RNA, Messenger; D012160:Retina / Q000378:metabolism*; D059547:Stereocilia / Q000473:pathology; D052245:Usher Syndromes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D008565:Membrane Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; C477218:Whrn protein, mouse