title: Increased dosage of RAB39B 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 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.
authors.forename: Lieselot
authors.initials: L
authors.lastname: Vanmarsenille
authors.forename: Maila
authors.initials: M
authors.lastname: Giannandrea
authors.forename: Nathalie
authors.initials: N
authors.lastname: Fieremans
authors.forename: Jelle
authors.initials: J
authors.lastname: Verbeeck
authors.forename: Stefanie
authors.initials: S
authors.lastname: Belet
authors.forename: Martine
authors.initials: M
authors.lastname: Raynaud
authors.forename: Annick
authors.initials: A
authors.lastname: Vogels
authors.forename: Katrin
authors.initials: K
authors.lastname: Männik
authors.forename: Katrin
authors.initials: K
authors.lastname: Õunap
authors.forename: Vigneron
authors.initials: V
authors.lastname: Jacqueline
authors.forename: Sylvain
authors.initials: S
authors.lastname: Briault
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.forename: Patrizia
authors.initials: P
authors.lastname: D'Adamo
authors.forename: Guy
authors.initials: G
authors.lastname: Froyen
mesh_terms: D000818:Animals; D001530:Belgium; D002454:Cell Differentiation; D002648:Child; D002874:Chromosome Mapping; D041321:Chromosomes, Human, X / Q000235:genetics*; D056915:DNA Copy Number Variations; D004957:Estonia; D020440:Gene Duplication; D005786:Gene Expression Regulation; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D044465:White People; D049951:X Chromosome Inactivation; D020691:rab GTP-Binding Proteins / Q000235:genetics*
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; C547812:Rab39B protein, human; D020691:rab GTP-Binding Proteins