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

Lieselot Vanmarsenille, Maila Giannandrea, Nathalie Fieremans, Jelle Verbeeck, Stefanie Belet, Martine Raynaud, Annick Vogels, Katrin Männik, Katrin Õunap, Vigneron Jacqueline, Sylvain Briault, Hilde Van Esch, Patrizia D'Adamo, Guy Froyen

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)377-383
Number of pages7
JournalHuman Mutation
Volume35
Issue number3
DOIs
Publication statusPublished - 2014

Fingerprint

Neurons
X Chromosome Inactivation
Monomeric GTP-Binding Proteins
Homologous Recombination
Intellectual Disability
Synapses
Lymphocytes
Messenger RNA
Mutation
Genes
Cognitive Dysfunction
Problem Behavior

Keywords

  • Copy number gain
  • Intellectual disability
  • Neuronal branching
  • RAB39B
  • Xq28

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Vanmarsenille, L., Giannandrea, M., Fieremans, N., Verbeeck, J., Belet, S., Raynaud, M., ... Froyen, G. (2014). Increased dosage of RAB39B affects neuronal development and could explain the cognitive impairment in male patients with distal Xq28 copy number gains. Human Mutation, 35(3), 377-383. https://doi.org/10.1002/humu.22497

Increased dosage of RAB39B affects neuronal development and could explain the cognitive impairment in male patients with distal Xq28 copy number gains. / Vanmarsenille, Lieselot; Giannandrea, Maila; Fieremans, Nathalie; Verbeeck, Jelle; Belet, Stefanie; Raynaud, Martine; Vogels, Annick; Männik, Katrin; Õunap, Katrin; Jacqueline, Vigneron; Briault, Sylvain; Van Esch, Hilde; D'Adamo, Patrizia; Froyen, Guy.

In: Human Mutation, Vol. 35, No. 3, 2014, p. 377-383.

Research output: Contribution to journalArticle

Vanmarsenille, L, Giannandrea, M, Fieremans, N, Verbeeck, J, Belet, S, Raynaud, M, Vogels, A, Männik, K, Õunap, K, Jacqueline, V, Briault, S, Van Esch, H, D'Adamo, P & Froyen, G 2014, 'Increased dosage of RAB39B affects neuronal development and could explain the cognitive impairment in male patients with distal Xq28 copy number gains', Human Mutation, vol. 35, no. 3, pp. 377-383. https://doi.org/10.1002/humu.22497
Vanmarsenille, Lieselot ; Giannandrea, Maila ; Fieremans, Nathalie ; Verbeeck, Jelle ; Belet, Stefanie ; Raynaud, Martine ; Vogels, Annick ; Männik, Katrin ; Õunap, Katrin ; Jacqueline, Vigneron ; Briault, Sylvain ; Van Esch, Hilde ; D'Adamo, Patrizia ; Froyen, Guy. / Increased dosage of RAB39B affects neuronal development and could explain the cognitive impairment in male patients with distal Xq28 copy number gains. In: Human Mutation. 2014 ; Vol. 35, No. 3. pp. 377-383.
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