Increased Dosage of RAB39B Affects Neuronal Development and Could Explain the Cognitive Impairment in Male Patients with Distal Xq28 Copy Number Gains
Increased Dosage of RAB39B Affects Neuronal Development and Could Explain the Cognitive Impairment in Male Patients with Distal Xq28 Copy Number Gains
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DOI：
10.1002/humu.22497
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发表时间：
2014-03-01
期刊：
影响因子：
3.9
通讯作者：
Froyen, Guy
中科院分区：
文献类型：
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作者：
Vanmarsenille, Lieselot;Giannandrea, Maila;Froyen, Guy
Xq 28的拷贝数增加是X连锁智力残疾（XLID）的常见原因。在这里，我们报告了一个经常性的0.5Mb串联拷贝数增益在远端Xq 28不包括MECP 2，在4名男性患者的非综合征轻度ID和行为问题。该基因组区域在两个家族中重复，在第三个家族中重复三次，这反映了更独特的临床特征。携带者女性的X-失活模式与其临床症状相符。我们的映射数据证实，这种经常性的增益可能是介导的两个直接定向的Int 22 h重复之间的非等位基因同源重组。受影响的区域含有8个基因，其中RAB 39 B编码一个小的GTdR，是主要的候选者，因为功能丧失突变已被链接到ID。RAB 39 B在对照个体的淋巴细胞中以稳定的水平表达，表明严格的调节。我们患者的mRNA水平几乎增加了两倍。Rab 39 b在小鼠原代海马神经元中的过表达表明，与对照神经元相比，神经元分支以及突触数量显著减少。综上所述，我们提供的证据表明，增加剂量的RAB 39 B会导致神经元发育紊乱，从而导致具有这种复发性拷贝数增加的患者的认知障碍。2014年，第35卷，第377-383页。(C)2013 Wiley Periodicals，Inc.
Copy number gains at Xq28 are a frequent cause of X-linked intellectual disability (XLID). Here, we report on a recurrent 0.5Mb 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. Hum Mutat 35:377-383, 2014. (C) 2013 Wiley Periodicals, Inc.