A Mutation in SLC24A1 Implicated in Autosomal-Recessive Congenital Stationary Night Blindness

National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 53700, Pakistan.
The American Journal of Human Genetics (Impact Factor: 10.93). 10/2010; 87(4):523-31. DOI: 10.1016/j.ajhg.2010.08.013
Source: PubMed


Congenital stationary night blindness (CSNB) is a nonprogressive retinal disorder that can be associated with impaired night vision. The last decade has witnessed huge progress in ophthalmic genetics, including the identification of three genes implicated in the pathogenicity of autosomal-recessive CSNB. However, not all patients studied could be associated with mutations in these genes and thus other genes certainly underlie this disorder. Here, we report a large multigeneration family with five affected individuals manifesting symptoms of night blindness. A genome-wide scan localized the disease interval to chromosome 15q, and recombination events in affected individuals refined the critical interval to a 10.41 cM (6.53 Mb) region that harbors SLC24A1, a member of the solute carrier protein superfamily. Sequencing of all the coding exons identified a 2 bp deletion in exon 2: c.1613_1614del, which is predicted to result in a frame shift that leads to premature termination of SLC24A1 (p.F538CfsX23) and segregates with the disorder under an autosomal-recessive model. Expression analysis using mouse ocular tissues shows that Slc24a1 is expressed in the retina around postnatal day 7. In situ and immunohistological studies localized both SLC24A1 and Slc24a1 to the inner segment, outer and inner nuclear layers, and ganglion cells of the retina, respectively. Our data expand the genetic basis of CSNB and highlight the indispensible function of SLC24A1 in retinal function and/or maintenance in humans.

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    • "Mutations in RP1 were first shown to cause adRCD [9] [10] [11]; however, since 2005, articles have shed light on its implication in arRCD etiology [12] [13] [14] [15] [16] [17] [18] [19] [20]. RP1 mutations were shown to account for ≈5.5% and ≈1% of adRCD and arRCD cases, respectively [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]. Interestingly, Avila-Fernandez et al. [12] reported that a founder nonsense mutation in the Spanish population p.Ser542 * is responsible for 4.5% of arRCD cases suggesting that RP1 mutations are more prevalent in arRCD than previously thought [12]. "
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    ABSTRACT: We report ophthalmic and genetic findings in families with autosomal recessive rod-cone dystrophy (arRCD) and RP1 mutations. Detailed ophthalmic examination was performed in 242 sporadic and arRCD subjects. Genomic DNA was investigated using our customized next generation sequencing panel targeting up to 123 genes implicated in inherited retinal disorders. Stringent filtering coupled with Sanger sequencing and followed by cosegregation analysis was performed to confirm biallelism and the implication of the most likely disease causing variants. Sequencing identified 9 RP1 mutations in 7 index cases. Eight of the mutations were novel, and all cosegregated with severe arRCD phenotype, found associated with additional macular changes. Among the identified mutations, 4 belong to a region, previously associated with arRCD, and 5 others in a region previously associated with adRCD. Our prevalence studies showed that RP1 mutations account for up to 2.5% of arRCD. These results point out for the necessity of sequencing RP1 when genetically investigating sporadic and arRCD. It further highlights the interest of unbiased sequencing technique, which allows investigating the implication of the same gene in different modes of inheritance. Finally, it reports that different regions of RP1 can also lead to arRCD.
    BioMed Research International 01/2015; 2015:485624. DOI:10.1155/2015/485624 · 3.17 Impact Factor
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    • "In the Riggs type [3], rod adaptation is present, although it is slower, and cone responses are normal. This type may be inherited in an autosomal dominant (AD) or autosomal recessive trait [4-7]. The Schubert-Bornschein type is characterized by a negatively shaped dark-adapted ERG response to a bright flash in which the amplitude of the a-wave is normal but larger than that of the b-wave [8]. "
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    ABSTRACT: Congenital stationary night blindness (CSNB) is a non-progressive retinal disorder that shows genetic and clinical heterogeneity. CSNB is inherited as an autosomal recessive, autosomal dominant, or X-linked recessive trait and shows a good genotype-phenotype correlation. Clinically, CSNB is classified as the Riggs type and the Schubert-Bornschein type. The latter form is further sub-classified into complete and incomplete forms based on specific waveforms on the electroretinogram (ERG). There are no molecular genetic data for CSNB in the Indian population. Therefore, we present for the first time molecular profiling of eight families with complete CSNB (cCSNB). The index patients and their other affected family members were comprehensively evaluated for the phenotype, including complete ophthalmic evaluation, ERG, fundus autofluorescence, optical coherence tomography, and color vision test. The known gene defects for cCSNB, LRIT3, TRPM1, GRM6, GPR179, and NYX, were screened by PCR direct sequencing. Bioinformatic analyses were performed using SIFT and PolyPhen for the identified missense mutations. All eight affected index patients and affected family members were identified as having cCSNB based on their ERG waveforms. Mutations in the TRPM1 gene were identified in six index patients. The two remaining index patients each carried a GPR179 and GRM6 mutation. Seven of the patients revealed homozygous mutations, while one patient showed a compound heterozygous mutation. Six of the eight mutations identified are novel. This is the first report on molecular profiling of candidate genes in CSNB in an Indian cohort. As shown for other cohorts, TRPM1 seems to be a major gene defect in patients with cCSNB in India.
    Molecular vision 03/2014; 20:341-51. · 1.99 Impact Factor
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    • "SLC5A2 is a sodium-dependent glucose transporter and may be involved in diabetic retinal cell death [48]. Mutations in SLC24A1, a gene encoding the photoreceptor-specific sodium/calcium exchanger, have been linked to autosomal recessive congenital stationary night blindness [49]. "
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    ABSTRACT: To identify and characterize changes in gene expression associated with photoreceptor degeneration in the rd3 mouse model of Leber congenital amaurosis (LCA) type 12. Global genome expression profiling using microarray technology was performed on total RNA extracts from rd3 and wild-type control mouse retinas at postnatal day 21. Quantitative PCR analysis of selected transcripts was performed to validate the microarray results. Functional annotation of differentially regulated genes in the rd3 mouse defined key canonical pathways, including phototransduction, glycerophospholipid metabolism, tumor necrosis factor receptor 1 signaling, and endothelin signaling. Overall, 1,140 of approximately 55,800 transcripts were differentially represented. In particular, a large percentage of the upregulated transcripts encode proteins involved in the immune response; whereas the downregulated transcripts encode proteins involved in phototransduction and lipid metabolism. This analysis has elucidated several candidate genes and pathways, thus providing insight into the pathogenic mechanisms underlying the photoreceptor degeneration in the rd3 mouse retina and indicating directions for future studies.
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