The mitochondrial solute carrier SLC25A5 at Xq24 is a novel candidate gene for non-syndromic intellectual disability

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.

The stoichiometry and interactome of the Nucleosome Remodeling and Deacetylase (NuRD) complex are conserved across multiple cell lines

“…It has already been shown that MTA‐HDAC containing complexes can deacetylate non‐histone targets like p53 , ATF4 , and HIF1α . Finally we note that genetic studies on patients with intellectual disabilities have identified GATAD2 and SLC25A5 as possible co‐actors in this condition ; the direct interaction between GATAD2 and SLC25A5, as observed in our pull‐down assays, could thus have a role to play in this disease through a yet unknown mechanism.…”

X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes

“…Similarly, the GUCY2F [MIM 300041] and SLC25A43 [MIM 300641] truncating variants did not co-segregate with XLID in the family in which they were identified and other rare protein truncating variants were reported in ESP6500 and in other healthy male controls. 81, 82 Furthermore, COL4A6 is part of a contiguous gene deletion causing Alport syndrome [MIM 301050], a childhood onset progressive haematuric glomerulopathy with high-frequency sensorineural hearing loss and typical ocular signs, and for MAP3K15 other stop-gain variants have been identified in male controls. 3 CXorf64 and FATE1 [MIM 300450] truncating variants were identified in the same family and both did not co-segregate with XLID.…”

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

“…Its dysregulation leads to various movement disturbances, dementia and hypogonadotropic hypogonadism [44,45]. Thus, it is not surprising that a growing group of ID proteins are directly involved in UPS-mediated protein degradation, such as UBE3A [46] [47], UBE2A [48,49,50,51], UBE3B [52,47], HUWE1 [53,54,55], MID1 [56][57][58][59], CUL4B [60,[61][62][63], UBR1 [64,65,66], TRIP12 [67][68][69], and RNF216 [45,[70][71][72].…”