Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, LINKED MENTAL-RETARDATION, UBE2A, DEFICIENCY, MUTATIONS, PHENOTYPE, SEIZURES, DOSAGE, HUWE1, XLMR, Adenine Nucleotide Translocator 2, Alu Elements, Base Sequence, Brain, Child, Preschool, Chromosome Deletion, Chromosomes, Human, X, Cohort Studies, DNA Mutational Analysis, Female, Heterozygote, Humans, Infant, Intellectual Disability, Male, Mitochondria, Molecular Sequence Data, Pedigree, X Chromosome Inactivation, 0604 Genetics, 1104 Complementary and Alternative Medicine, 1114 Paediatrics and Reproductive Medicine, 3105 Genetics, 3215 Reproductive medicine

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.