HGNC Approved Gene Symbol: SLITRK6
Cytogenetic location: 13q31.1 Genomic coordinates (GRCh38) : 13:85,792,790-85,799,419 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q31.1 | Deafness and myopia | 221200 | Autosomal recessive | 3 |
Members of the SLITRK family, such as SLITRK6, are integral membrane proteins with 2 N-terminal leucine-rich repeat (LRR) domains similar to those of SLIT proteins (see SLIT1; 603742). Most SLITRKs, including SLITRK6, also have C-terminal regions that share homology with neurotrophin receptors (see NTRK1; 191315). SLITRKs are expressed predominantly in neural tissues and have neurite-modulating activity (Aruga et al., 2003).
Aruga and Mikoshiba (2003) cloned several mouse Slitrk cDNAs, including Slitrk6. The deduced Slitrk6 protein contains an N-terminal signal peptide, followed by 2 LRR domains, a transmembrane domain, and a cytoplasmic domain with 2 putative tyrosine phosphorylation sites. Each LRR domain is flanked by cysteine-rich regions. In situ hybridization showed that, unlike other Slitrks, which are broadly expressed in developing mouse brain, Slitrk6 expression was restricted to ventral thalamus and lateral geniculate nucleus. Expression was strong in suprafascicular nucleus.
By database analysis, Aruga et al. (2003) identified human SLITRK6. The deduced 841-amino acid protein has a calculated molecular mass of 95.1 kD. It shares more than 95% homology with mouse Slitrk5 and has the same protein structure. Northern blot analysis detected a SLITRK6 transcript of 4.4 kb mainly in adult putamen and cerebellum and in fetal brain, lung, and liver. Highest expression was in adult putamen.
Tekin et al. (2013) investigated the temporospatial expression pattern of SLITRK6 during development. In newborn mice, Slitrk6 mRNA was broadly detected in neural retina, and was enhanced in the inner nuclear and outer plexiform layers at day 10. Expression weakened as development proceeded, and Slitrk6 mRNA was detected in the inner nuclear layer and in a subset of cells in the ganglion cell layer of adult mice.
Aruga et al. (2003) determined that the SLITRK6 gene contains 2 exons. Exon 1 is noncoding.
By genomic sequence analysis, Aruga et al. (2003) mapped the SLITRK6 gene to a region of chromosome 13q31 that also contains the SLITRK1 (609678) and SLITRK5 (609680) genes. The intervening sequences between the SLITRK genes are about 2 Mb. Aruga et al. (2003) mapped the mouse Slitrk6 gene to a region of chromosome 14E3 that shares homology of synteny with human chromosome 13q31.
By overexpression in murine pheochromocytoma and neuroblastoma cell lines, Aruga and Mikoshiba (2003) found that mouse Slitrk6 weakly suppressed neurite outgrowth.
In Slitrk6 -/- mice, Tekin et al. (2013) observed no overt abnormalities in gross layer organization in conventional histologic staining. However, examination of synapse markers, including Ribeye (see 602619) and Vglut1 (605208), showed significantly lower signaling in the inner and outer plexiform layers of the mutant retina compared to wildtype at day 10, when synaptogenesis was actively taking place. Retinal cell type-specific markers, however, did not show clear genotype-dependent changes during immunostaining. In addition, antineurofilament staining for retinal ganglion cell nerve fibers was reduced in mutants, although not significantly. Noting that these findings were indicative of delayed synaptogenesis in the Slitrk6 knockout retina, Tekin et al. (2013) concluded that SLITRK6 plays a role in synaptogenesis in vivo.
In affected members of 3 families with congenital sensorineural deafness and high myopia (DFNMYP; 221200), Tekin et al. (2013) identified homozygosity for 3 different nonsense mutations in the SLITRK6 gene (609681.0001-609681.0003).
In affected individuals from an Old Order Amish community with deafness and myopia, Morlet et al. (2014) identified homozygosity for the Q414X mutation (609681.0001) and found a 4.7% carrier frequency of the mutation within the community.
Using high-resolution small-animal MRI scanning, Tekin et al. (2013) studied 10- to 12-month-old Slitrk6 -/- mice and observed a significant increase in axial length, but not lens thickness, in mutant mice compared to controls. The size difference in axial length was not apparent in newborn mice, indicating that SLITRK6 regulates eye growth after birth. Tekin et al. (2013) concluded that Slitrk6 knockout mice appeared to closely mimic the human myopia phenotype, in association with previously documented deafness in Slitrk6-null mice (Matsumoto et al., 2011).
In 3 affected sibs from a consanguineous Old Order Amish family in Ohio with congenital sensorineural deafness and high myopia (DFNMYP; 221200), Tekin et al. (2013) identified homozygosity for a c.1240C-T transition in exon 2 of the SLITRK6 gene, resulting in a gln414-to-ter (Q414X) substitution. The mutation, which was present in heterozygosity in their unaffected parents and brother and was detected in heterozygosity in 1 of 80 Amish controls, was not found in 450 controls of European ancestry or in the dbSNP (build 135) or 1000 Genomes Project databases. Transfection studies in HEK293 cells showed defective cell surface localization with the Q414X mutant compared to wildtype.
In affected individuals from an Old Order Amish community in Pennsylvania with deafness and myopia mapping to chromosome 13q31, Morlet et al. (2014) identified homozygosity for the Q414X mutation in the SLITRK6 gene. Genotyping of 571 Old Order Amish control samples by high-resolution melt analysis revealed 27 carriers (4.7% carrier frequency). Heterologous overexpression in UB/OC-2 cells showed that wildtype SLITRK6 traffics through the major membrane system to the plasma membrane, whereas the Q414X mutant is a soluble protein fragment uniformly distributed throughout the cytosol.
In 4 affected sibs from a consanguineous Turkish family with congenital sensorineural deafness and high myopia (DFNMYP; 221200), Tekin et al. (2013) identified homozygosity for a c.890C-A transversion in exon 2 of the SLITRK6 gene, resulting in a ser297-to-ter (S297X) substitution. The mutation segregated fully with disease in the family and was not found in 330 Turkish controls. Transfection studies in HEK293 cells showed defective cell surface localization with the S297X mutant compared to wildtype.
In 2 brothers from a Greek family with congenital severe to profound sensorineural hearing loss (DFNMYP; 221200), Tekin et al. (2013) identified homozygosity for a c.541C-T transition in exon 2 of the SLITRK6 gene, resulting in an arg181-to-ter (R181X) substitution. Their unaffected parents were heterozygous for the mutation, which was not found in 300 Greek controls. Information regarding the brothers' vision status was not available. Transfection studies in HEK293 cells showed defective cell surface localization with the R181X mutant compared to wildtype.
Aruga, J., Mikoshiba, K. Identification and characterization of Slitrk, a novel neuronal transmembrane protein family controlling neurite outgrowth. Molec. Cell. Neurosci. 24: 117-129, 2003. [PubMed: 14550773] [Full Text: https://doi.org/10.1016/s1044-7431(03)00129-5]
Aruga, J., Yokota, N., Mikoshiba, K. Human SLITRK family genes: genomic organization and expression profiling in normal brain and brain tumor tissue. Gene 315: 87-94, 2003. [PubMed: 14557068] [Full Text: https://doi.org/10.1016/s0378-1119(03)00715-7]
Matsumoto, Y., Katayama, K., Okamoto, T., Yamada, K., Takashima, N., Nagao, S., Aruga, J. Impaired auditory-vestibular functions and behavioral abnormalities of Slitrk6-deficient mice. PLoS One 6: e16497, 2011. Note: Electronic Article. [PubMed: 21298075] [Full Text: https://doi.org/10.1371/journal.pone.0016497]
Morlet, T., Rabinowitz, M. R., Looney, L. R., Riegner, T., Greenwood, L. A., Sherman, E. A., Achilly, N., Zhu, A., Yoo, E., O'Reilly, R. C., Jinks, R. N., Puffenberger, E. G., Heaps, A., Morton, H., Strauss, K. A. A homozygous SLITRK6 nonsense mutation is associated with progressive auditory neuropathy in humans. Laryngoscope 124: 95-103, 2014. [PubMed: 23946138] [Full Text: https://doi.org/10.1002/lary.24361]
Tekin, M., Chioza, B. A., Matsumoto, Y., Diaz-Horta, O., Cross, H. E., Duman, D., Kokotas, H., Moore-Barton, H. L., Sakoori, K., Ota, M., Odaka, Y. S., Foster, J., II, and 13 others. SLITRK6 mutations cause myopia and deafness in humans and mice. J. Clin. Invest. 123: 2094-2102, 2013. [PubMed: 23543054] [Full Text: https://doi.org/10.1172/JCI65853]