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Increased Dosage of RAB 39 B Affects Neuronal Development and Could Explain the Cognitive Impairment in Male Patients with Distal X q28 Copy Number Gains
Author(s) -
Vanmarsenille Lieselot,
Giannandrea Maila,
Fieremans Nathalie,
Verbeeck Jelle,
Belet Stefanie,
Raynaud Martine,
Vogels Annick,
Männik Katrin,
Õunap Katrin,
Jacqueline Vigneron,
Briault Sylvain,
Esch Hilde,
D'Adamo Patrizia,
Froyen Guy
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22497
Subject(s) - biology , hippocampal formation , mecp2 , xq28 , x chromosome , dosage compensation , gene dosage , non allelic homologous recombination , genetics , copy number variation , neuroscience , gene , phenotype , genome , gene expression , genetic recombination , recombination
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 MECP 2 , 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 RAB 39 B encoding a small GTP ase, was the prime candidate since loss‐of‐function mutations had been linked to ID . RAB 39 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 RAB 39 B causes a disturbed neuronal development leading to cognitive impairment in patients with this recurrent copy number gain.