CLRN1 is nonessential in the mouse retina but is required for cochlear hair cell development.
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 Müller 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.
Geller
Scott F
SF
Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA. drgeller@gmail.com
Guerin
Karen I
KI
Visel
Meike
M
Pham
Aaron
A
Lee
Edwin S
ES
Dror
Amiel A
AA
Avraham
Karen B
KB
Hayashi
Toshinori
T
Ray
Catherine A
CA
Reh
Thomas A
TA
Bermingham-McDonogh
Olivia
O
Triffo
William J
WJ
Bao
Shaowen
S
Isosomppi
Juha
J
Västinsalo
Hanna
H
Sankila
Eeva-Marja
EM
Flannery
John G
JG
D000818:Animals; D003051:Cochlea / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D006198:Hair Cells, Auditory / Q000378:metabolism*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021381:Protein Transport; D012160:Retina / Q000254:growth & development / Q000378:metabolism*
C512668:Clrn1 protein, mouse; D008565:Membrane Proteins
Hum Mol Genet. 2008 Jan 1;17(1):71-86
17906286
Orphanet J Rare Dis. 2007 Feb 01;2:7
17270046
Am J Ophthalmol. 1994 Sep 15;118(3):368-76
7916177
J Comp Neurol. 2002 Aug 12;450(1):94-102
12124769
Acta Ophthalmol Scand. 2006 Feb;84(1):36-41
16445437
Orphanet J Rare Dis. 2006 Oct 11;1:40
17032466
Curr Opin Neurol. 2009 Feb;22(1):19-27
19165952
Int J Audiol. 2005 May;44(5):307-16
16028794
Am J Hum Genet. 2004 Jan;74(1):128-38
14681825
Exp Eye Res. 2006 Jul;83(1):97-119
16545802
Int Ophthalmol. 1995-1996;19(5):307-11
8864816
Hum Mol Genet. 2003 Mar 1;12(5):453-61
12588793
Hum Genet. 2007 Apr;121(2):203-11
17171570
Invest Ophthalmol Vis Sci. 2007 Jun;48(6):2868-76
17525223
Invest Ophthalmol Vis Sci. 2008 Jun;49(6):2651-60
18281613
J Chronic Dis. 1983;36(8):595-603
6885960
Nat Genet. 1999 Dec;23(4):466-70
10581037
J Neurosci. 1999 Jul 15;19(14):5889-97
10407028
Hum Mol Genet. 2003 Dec 1;12(23):3075-86
14519688
Mol Vis. 2005 May 12;11:347-55
15928608
Methods Cell Biol. 1993;38:289-324
8246785
Proc Natl Acad Sci U S A. 2001 Jul 3;98(14):7718-23
11427722
Nat Genet. 1998 Dec;20(4):344-51
9843205
Hum Mol Genet. 1995 Jan;4(1):93-8
7711740
Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4413-8
17360538
Eur J Hum Genet. 2002 Jun;10(6):339-50
12080385
Am J Med Genet. 1994 Mar 1;50(1):32-8
8160750
Nat Genet. 2001 Jan;27(1):99-102
11138007
Nat Med. 1998 Aug;4(8):967-71
9701253
Nat Genet. 2000 May;25(1):67-73
10802659
Mol Vis. 2008 Apr 23;14:691-705
18437242
Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8322-6
1656438
Nature. 1995 Mar 2;374(6517):62-4
7870172
EMBO J. 2001 Jan 15;20(1-2):12-8
11226150
Vision Res. 2002 Feb;42(4):517-25
11853768
J Chronic Dis. 1969 Aug;22(3):133-51
4897966
Hum Mol Genet. 2009 Aug 1;18(15):2748-60
19414487
Exp Eye Res. 2003 Dec;77(6):731-9
14609561
Clin Genet. 2004 Dec;66(6):525-9
15521980
Nucleic Acids Res. 1999 Sep 1;27(17):e16
10446259
Mamm Genome. 2004 Sep;15(9):686-97
15389316
Hum Mol Genet. 2006 Oct 15;15 Spec No 2:R262-70
16987892
Invest Ophthalmol Vis Sci. 2005 Dec;46(12):4788-95
16303980
Invest Ophthalmol Vis Sci. 1978 Jun;17(6):489-98
659071
Nat Rev Drug Discov. 2008 Sep;7(9):747-58
18758472
Prog Brain Res. 2001;131:617-27
11420975
Dev Dyn. 2007 Feb;236(2):525-33
17117437
Annu Rev Genomics Hum Genet. 2001;2:271-97
11701652
Nature. 1990 Oct 18;347(6294):677-80
1977087
Cell. 2001 Nov 30;107(5):579-89
11733058
J Comp Neurol. 2008 Sep 20;510(3):237-50
18626943
Hum Mol Genet. 2005 Dec 15;14(24):3933-43
16301216
Curr Opin Cell Biol. 2005 Feb;17(1):55-61
15661519
Am J Hum Genet. 2002 Sep;71(3):607-17
12145752
Science. 1992 May 8;256(5058):804-8
1589761
Hear Res. 2009 Sep;255(1-2):109-20
19539019
Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):736-41
9892703
Laryngoscope. 2001 Jan;111(1):84-6
11192904
Mol Cell Biol. 2008 Mar;28(5):1702-12
18160714
Invest Ophthalmol Vis Sci. 2006 Jul;47(7):3074-84
16799054
J Biol Chem. 2009 Jul 10;284(28):18980-93
19423712
Audiol Neurootol. 1997 Jul-Aug;2(4):175-85
9390831
Vision Res. 2008 Feb;48(3):433-41
17936325
Ann Otol Rhinol Laryngol. 2003 Jun;112(6):525-30
12834121
Invest Ophthalmol Vis Sci. 2001 Mar;42(3):770-8
11222540
Am J Hum Genet. 2001 Oct;69(4):673-84
11524702
Nat Genet. 2001 Jan;27(1):103-7
11138008
Hum Mol Genet. 2008 Aug 1;17(15):2405-15
18463160
Mol Vis. 2005 Feb 28;11:152-62
15765048
J Med Genet. 2003 Oct;40(10):767-72
14569126
Invest Ophthalmol Vis Sci. 2001 Sep;42(10):2217-24
11527933
J Cell Biol. 2006 Jun 19;173(6):975-83
16785325