SLITRK6 mutations cause myopia and deafness in humans and mice
Mustafa Tekin, … , Jun Aruga, Andrew H. Crosby
Mustafa Tekin, … , Jun Aruga, Andrew H. Crosby
Published April 1, 2013
Citation Information: J Clin Invest. 2013;123(5):2094-2102. https://doi.org/10.1172/JCI65853.
View: Text | PDF
Research Article Ophthalmology

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

Mustafa Tekin, Barry A. Chioza, Yoshifumi Matsumoto, Oscar Diaz-Horta, Harold E. Cross, Duygu Duman, Haris Kokotas, Heather L. Moore-Barton, Kazuto Sakoori, Maya Ota, Yuri S. Odaka, Joseph Foster II, F. Basak Cengiz, Suna Tokgoz-Yilmaz, Oya Tekeli, Maria Grigoriadou, Michael B. Petersen, Ajith Sreekantan-Nair, Kay Gurtz, Xia-Juan Xia, Arti Pandya, Michael A. Patton, Juan I. Young, Jun Aruga, Andrew H. Crosby

×

Figure 4

Postnatal Slitrk6 expression in the murine eye.

Options: View larger image (or click on image) Download as PowerPoint
Postnatal Slitrk6 expression in the murine eye. Slitrk6 in situ hybrid...
Slitrk6 in situ hybridization (A, C, E, and G; purple stain) and hematoxylin and eosin staining (B, D, F, and H) in adjacent sections in P3, P10, and 11-week-old adult mice. (A–F) Retinal layers. (G and H) Horizontal sections through eye. (A and B) In the newborn, Slitrk6 mRNA was broadly detected in neural retina. (C and D) At P10, expression became enhanced at the inner nuclear layer (IN), whereas moderate expression continued in the ganglion cell layer (GC). Images are higher-magnification views of boxed regions in G and H. (E and F) Expression weakened as development proceeded, and expression was detected at the inner nuclear layer and in a subset of cells in the ganglion cell layer in adult mice. (G and H) In the tissues surrounding the eye, weak expression was detected in the hair root sheath (HS), lacrimal gland (LG), and olfactory epithelium (OE) at P10. The gray line in the outer plexiform layer (OP) and the layer containing outer and inner segments of photoreceptor cells (OS) in adults (E, asterisk) and the brown staining in the lens (L) at P10 (G, asterisk) were not authentic in situ hybridization signals. Parallel lines in H denote optic nerve. Cr, cornea; EM, extraocular muscle; IP, inner plexiform layer; N, retinal neuroblastic layer; ON, outer nuclear layer; R, retina; S, sclera. Scale bars: 100 μm (A–F); 1 mm (G and H).