Increased dosage of RAB39B affects neuronal development and could explain the cognitive impairment in male patients with distal Xq28 copy number gains.

Copy number gains at Xq28 are a frequent cause of X-linked intellectual disability (XLID). Here, we report on a recurrent 0.5 Mb tandem copy number gain at distal Xq28 not including MECP2, in four male patients with nonsyndromic mild ID and behavioral problems. The genomic region is duplicated in two families and triplicated in a third reflected by more distinctive clinical features. The X-inactivation patterns in carrier females correspond well with their clinical symptoms. Our mapping data confirm that this recurrent gain is likely mediated by nonallelic homologous recombination between two directly oriented Int22h repeats. The affected region harbors eight genes of which RAB39B encoding a small GTPase, was the prime candidate since loss-of-function mutations had been linked to ID. RAB39B is expressed at stable levels in lymphocytes from control individuals, suggesting a tight regulation. mRNA levels in our patients were almost two-fold increased. Overexpression of Rab39b in mouse primary hippocampal neurons demonstrated a significant decrease in neuronal branching as well as in the number of synapses when compared with the control neurons. Taken together, we provide evidence that the increased dosage of RAB39B causes a disturbed neuronal development leading to cognitive impairment in patients with this recurrent copy number gain.

Generation and characterization of an Nxf7 knockout mouse to study NXF5 deficiency in a patient with intellectual disability.

Members of the Nuclear eXport Factor (NXF) family are involved in the export of mRNA from the nucleus to the cytoplasm, or hypothesized to play a role in transport of cytoplasmic mRNA. We previously reported on the loss of NXF5 in a male patient with a syndromic form of intellectual disability. To study the functional role of NXF5 we identified the mouse counterpart. Based on synteny, mouse Nxf2 is the ortholog of human NXF5. However, we provide several lines of evidence that mouse Nxf7 is the actual functional equivalent of NXF5. Both Nxf7 and NXF5 are predominantly expressed in the brain, show cytoplasmic localization, and present as granules in neuronal dendrites suggesting a role in cytoplasmic mRNA metabolism in neurons. Nxf7 was primarily detected in the pyramidal cells of the hippocampus and in layer V of the cortex. Similar to human NXF2, mouse Nxf2 is highly expressed in testis and shows a nuclear localization. Interestingly, these findings point to a different evolutionary path for both NXF genes in human and mouse. We thus generated and validated Nxf7 knockout mice, which were fertile and did not present any gross anatomical or morphological abnormalities. Expression profiling in the hippocampus and the cortex did not reveal significant changes between wild-type and Nxf7 knockout mice. However, impaired spatial memory was observed in these KO mice when evaluated in the Morris water maze test. In conclusion, our findings provide strong evidence that mouse Nxf7 is the functional counterpart of human NXF5, which might play a critical role in mRNA metabolism in the brain.