title: SLITRK6 mutations cause myopia and deafness in humans and mice.
abstract: Myopia is by far the most common human eye disorder that is known to have a clear, albeit poorly defined, heritable component. In this study, we describe an autosomal-recessive syndrome characterized by high myopia and sensorineural deafness. Our molecular investigation in 3 families led to the identification of 3 homozygous nonsense mutations (p.R181X, p.S297X, and p.Q414X) in SLIT and NTRK-like family, member 6 (SLITRK6), a leucine-rich repeat domain transmembrane protein. All 3 mutant SLITRK6 proteins displayed defective cell surface localization. High-resolution MRI of WT and Slitrk6-deficient mouse eyes revealed axial length increase in the mutant (the endophenotype of myopia). Additionally, mutant mice exhibited auditory function deficits that mirrored the human phenotype. Histological investigation of WT and Slitrk6-deficient mouse retinas in postnatal development indicated a delay in synaptogenesis in Slitrk6-deficient animals. Taken together, our results showed that SLITRK6 plays a crucial role in the development of normal hearing as well as vision in humans and in mice and that its disruption leads to a syndrome characterized by severe myopia and deafness.
authors.affiliation: John P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida 33136, USA. mtekin@med.miami.edu
authors.forename: Mustafa
authors.initials: M
authors.lastname: Tekin
authors.forename: Barry A
authors.initials: BA
authors.lastname: Chioza
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Oscar
authors.initials: O
authors.lastname: Diaz-Horta
authors.forename: Harold E
authors.initials: HE
authors.lastname: Cross
authors.forename: Duygu
authors.initials: D
authors.lastname: Duman
authors.forename: Haris
authors.initials: H
authors.lastname: Kokotas
authors.forename: Heather L
authors.initials: HL
authors.lastname: Moore-Barton
authors.forename: Kazuto
authors.initials: K
authors.lastname: Sakoori
authors.forename: Maya
authors.initials: M
authors.lastname: Ota
authors.forename: Yuri S
authors.initials: YS
authors.lastname: Odaka
authors.forename: Joseph
authors.initials: J
authors.lastname: Foster
authors.forename: F Basak
authors.initials: FB
authors.lastname: Cengiz
authors.forename: Suna
authors.initials: S
authors.lastname: Tokgoz-Yilmaz
authors.forename: Oya
authors.initials: O
authors.lastname: Tekeli
authors.forename: Maria
authors.initials: M
authors.lastname: Grigoriadou
authors.forename: Michael B
authors.initials: MB
authors.lastname: Petersen
authors.forename: Ajith
authors.initials: A
authors.lastname: Sreekantan-Nair
authors.forename: Kay
authors.initials: K
authors.lastname: Gurtz
authors.forename: Xia-Juan
authors.initials: XJ
authors.lastname: Xia
authors.forename: Arti
authors.initials: A
authors.lastname: Pandya
authors.forename: Michael A
authors.initials: MA
authors.lastname: Patton
authors.forename: Juan I
authors.initials: JI
authors.lastname: Young
authors.forename: Jun
authors.initials: J
authors.lastname: Aruga
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Crosby
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D018389:Codon, Nonsense; D005260:Female; D006309:Hearing; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation; D009216:Myopia / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017434:Protein Structure, Tertiary; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D008565:Membrane Proteins; C581991:Slitrk6 protein, human; C488353:Slitrk6 protein, mouse
references.citation: Invest Ophthalmol Vis Sci. 2005 Sep;46(9):3074-80
references.pmid: 16123404
references.citation: Neuron. 2004 Aug 19;43(4):447-68
references.pmid: 15312645
references.citation: Invest Ophthalmol Vis Sci. 2006 Nov;47(11):4756-61
references.pmid: 17065484
references.citation: Bioinformatics. 2010 Mar 1;26(5):589-95
references.pmid: 20080505
references.citation: ILAR J. 1999 Mar;40(2):59-77
references.pmid: 11304585
references.citation: J Med Genet. 2000 Mar;37(3):227-31
references.pmid: 10777361
references.citation: Arch Ophthalmol. 2008 Aug;126(8):1111-9
references.pmid: 18695106
references.citation: JAMA. 1994 May 4;271(17):1323-7
references.pmid: 8158816
references.citation: Mol Cell Neurosci. 2003 Sep;24(1):117-29
references.pmid: 14550773
references.citation: Arch Dis Child Educ Pract Ed. 2010 Feb;95(1):14-23
references.pmid: 20145014
references.citation: Clin Genet. 2011 Apr;79(4):301-20
references.pmid: 21155761
references.citation: Arch Ophthalmol. 2004 Apr;122(4):495-505
references.pmid: 15078666
references.citation: Ophthalmology. 2011 Feb;118(2):368-75
references.pmid: 21095009
references.citation: Am J Hum Genet. 2011 Sep 9;89(3):438-45
references.pmid: 21885030
references.citation: Arch Otolaryngol Head Neck Surg. 2002 Nov;128(11):1303-6
references.pmid: 12431176
references.citation: Gene Expr Patterns. 2003 Dec;3(6):727-33
references.pmid: 14643680
references.citation: Gene. 2003 Oct 2;315:87-94
references.pmid: 14557068
references.citation: Trends Neurosci. 2011 Mar;34(3):143-53
references.pmid: 21315458
references.citation: Genome Res. 2010 Sep;20(9):1297-303
references.pmid: 20644199
references.citation: Invest Ophthalmol Vis Sci. 2010 Jan;51(1):21-7
references.pmid: 19661239
references.citation: Curr Opin Ophthalmol. 2009 Sep;20(5):356-62
references.pmid: 19587595
references.citation: Nat Genet. 2010 Oct;42(10):897-901
references.pmid: 20835239
references.citation: Nat Genet. 2011 May;43(5):491-8
references.pmid: 21478889
references.citation: J Neurosci. 2007 May 16;27(20):5461-73
references.pmid: 17507568
references.citation: Ann Acad Med Singap. 2004 Jan;33(1):27-33
references.pmid: 15008558
references.citation: Invest Ophthalmol Vis Sci. 2003 Jul;44(7):3211-8
references.pmid: 12824273
references.citation: Nat Genet. 2010 Oct;42(10):902-5
references.pmid: 20835236
references.citation: Am J Hum Genet. 2011 Jun 10;88(6):805-813
references.pmid: 21640322
references.citation: Ophthalmologica. 2011;225(3):127-34
references.pmid: 20948239
references.citation: Invest Ophthalmol Vis Sci. 2002 Dec;43(12):3633-40
references.pmid: 12454029
references.citation: Nat Neurosci. 2012 Jan 29;15(3):389-98, S1-2
references.pmid: 22286174
references.citation: PLoS One. 2011 Jan 26;6(1):e16497
references.pmid: 21298075
references.citation: BMJ. 2002 May 18;324(7347):1195-9
references.pmid: 12016188
references.citation: PLoS One. 2009 Nov 11;4(11):e7786
references.pmid: 19936227
references.citation: Dev Dyn. 2009 Dec;238(12):3285-96
references.pmid: 19924824
references.citation: Nat Genet. 2007 Aug;39(8):957-9
references.pmid: 17632512
references.citation: PLoS One. 2012;7(2):e32000
references.pmid: 22363784
references.citation: Trends Neurosci. 2005 Jan;28(1):20-9
references.pmid: 15626493