Increased Dosage of RAB39 B Affects Neuronal Development and Could Explain the Cognitive Impairment in Male Patients with Distal Xq28 Copy Number Gains.

ABSTRACT 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 RAB39 B encoding a small GTPase, was the prime candidate since loss-of-function mutations had been linked to ID. RAB39 B is expressed at stable levels in lymphocytes from control individuals, suggesting a tight regulation. m RNA 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 RAB39 B causes a disturbed neuronal development leading to cognitive impairment in patients with this recurrent copy number gain. [ABSTRACT FROM AUTHOR]