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CLRN1 Is Nonessential in the Mouse Retina but Is Required for Cochlear Hair Cell Development

Journal Article · · PLoS Genetics
 [1];  [2];  [3];  [3];  [3];  [4];  [4];  [5];  [5];  [5];  [5];  [6];  [3];  [7];  [7];  [8];  [2]
  1. Univ. of California, Berkeley, CA (United States). Helen Wills Neuroscience Inst.; DOE/OSTI
  2. Univ. of California, Berkeley, CA (United States). Helen Wills Neuroscience Inst.; Univ. of California, Berkeley, CA (United States). Vision Science
  3. Univ. of California, Berkeley, CA (United States). Helen Wills Neuroscience Inst.
  4. Tel Aviv Univ., Ramat Aviv (Israel). Sackler School of Medicine. Dept. of Human Molecular Genetics and Biochemistry
  5. Univ. of Washington, Seattle, WA (United States). School of Medicine. Dept. of Biological Structure
  6. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division
  7. Univ. of Helsinki (Finland). Biomedicum Helsinki. Dept. of Medical Genetics. Folkhalsan Inst. of Genetics
  8. Univ. of Helsinki (Finland). Biomedicum Helsinki. Dept. of Medical Genetics. Folkhalsan Inst. of Genetics; Univ. of Helsinki (Finland). Eye Hospital
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Mutations in the CLRN1 gene cause Usher syndrome type 3 (USH3), a human disease characterized by progressive blindness and deafness. Clarin 1, the protein product of CLRN1, is a four-transmembrane protein predicted to be associated with ribbon synapses of photoreceptors and cochlear hair cells, and recently demonstrated to be associated with the cytoskeleton. To study Clrn1, we created a Clrn1 knockout (KO) mouse and characterized the histological and functional consequences of Clrn1 deletion in the retina and cochlea. Clrn1 KO mice do not develop a retinal degeneration phenotype, but exhibit progressive loss of sensory hair cells in the cochlea and deterioration of the organ of Corti by 4 months. Hair cell stereocilia in KO animals were longer and disorganized by 4 months, and some Clrn1 KO mice exhibited circling behavior by 5–6 months of age. Clrn1 mRNA expression was localized in the retina using in situ hybridization (ISH), laser capture microdissection (LCM), and RT–PCR. Retinal Clrn1 transcripts were found throughout development and adulthood by RT– PCR, although expression peaked at P7 and declined to undetectable levels in adult retina by ISH. LCM localized Clrn1 transcripts to the retinas inner nuclear layer, and WT levels of retinal Clrn1 expression were observed in photoreceptor-less retinas. Examination of Clrn1 KO mice suggests that CLRN1 is unnecessary in the murine retina but essential for normal cochlear development and function. This may reflect a redundancy in the mouse retina not present in human retina. In contrast to mouse KO models of USH1 and USH2, our data indicate that Clrn1 expression in the retina is restricted to the Múller glia. This is a novel finding, as most retinal degeneration associated proteins are expressed in photoreceptors, not in glia. If CLRN1 expression in humans is comparable to the expression pattern observed in mice, this is the first report of an inner retinal protein that, when mutated, causes retinal degeneration.

Research Organization:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division; European Commission (EC)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1627277
Journal Information:
PLoS Genetics, Journal Name: PLoS Genetics Journal Issue: 8 Vol. 5; ISSN 1553-7404
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (9)

Clarin‐1 expression in adult mouse and human retina highlights a role of Müller glia in Usher syndrome journal December 2019
Gene Transfer with AAV9-PHP.B Rescues Hearing in a Mouse Model of Usher Syndrome 3A and Transduces Hair Cells in a Non-human Primate journal June 2019
Discovery of Molecular Markers to Discriminate Corneal Endothelial Cells in the Human Body journal March 2015
A small molecule mitigates hearing loss in a mouse model of Usher syndrome III journal April 2016
Non-syndromic retinal ciliopathies: translating gene discovery into therapy journal July 2012
Genome-wide association study reveals the locus responsible for microtia in Valle del Belice sheep breed journal August 2018
Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome journal July 2018
Ablation of Whirlin Long Isoform Disrupts the USH2 Protein Complex and Causes Vision and Hearing Loss journal May 2010
Clarin‐2 is essential for hearing by maintaining stereocilia integrity and function journal August 2019

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