Abstract
Loss-of-function mutations in several different neuronal pathways have been related to intellectual disability (ID). Such mutations often are found on the X chromosome in males since they result in functional null alleles. So far, microdeletions at Xq24 reported in males always have been associated with a syndromic form of ID due to the loss of UBE2A. Here, we report on overlapping microdeletions at Xq24 that do not include UBE2A or affect its expression, in patients with non-syndromic ID plus some additional features from three unrelated families. The smallest region of overlap, confirmed by junction sequencing, harbors two members of the mitochondrial solute carrier family 25, SLC25A5 and SLC25A43. However, identification of an intragenic microdeletion including SLC25A43 but not SLC25A5 in a healthy boy excluded a role for SLC25A43 in cognition. Therefore, our findings point to SLC25A5 as a novel gene for non-syndromic ID. This highly conserved gene is expressed ubiquitously with high levels in cortex and hippocampus, and a presumed role in mitochondrial exchange of ADP/ATP. Our data indicate that SLC25A5 is involved in memory formation or establishment, which could add mitochondrial processes to the wide array of pathways that regulate normal cognitive functions.
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Acknowledgments
We thank the families for their willingness to participate in this study. This work was supported by a grant from the University of Leuven (GOA/12/015). JV and NF are PhD fellows from the IWT (Agentschap voor Innovatie door Wetenschap en Technologie), Belgium. MB is a post-doctoral fellow and HVE and KD are clinical investigators of the FWO-Vlaanderen, Belgium.
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439_2013_1322_MOESM2_ESM.tif
Fig. S1. Pedigree of the family with the polymorphic deletion in SLC25A43. A. Family of individual D, who presents with ID, in whom the deletion including exons 1 to 3 of SLC25A43 was detected. This deletion was also present in his healthy mother (I.2) and older brother (II.1). B. Detailed view of the oligo-array data at the SLC25A43 locus (bottom right) and zoomed-in view (top) obtained for individual D showing the location and extent of the microdeletion at Xq24. The deletion removes part of SLC25A43 but does not include SLC25A5. Positions here are based on UCSC Hg18. Supplementary material 2 (TIFF 673 kb)
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Vandewalle, J., Bauters, M., Van Esch, H. et al. The mitochondrial solute carrier SLC25A5 at Xq24 is a novel candidate gene for non-syndromic intellectual disability. Hum Genet 132, 1177–1185 (2013). https://doi.org/10.1007/s00439-013-1322-3
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DOI: https://doi.org/10.1007/s00439-013-1322-3