Loss of function of KIAA2022 causes mild to severe intellectual disability with an autism spectrum disorder and impairs neurite outgrowth
Loss of function of KIAA2022 causes mild to severe intellectual disability with an autism spectrum disorder and impairs neurite outgrowth
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DOI：
10.1093/hmg/ddt187
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发表时间：
2013-08-15
影响因子：
3.5
通讯作者：
Man, Heng-Ye
中科院分区：
文献类型：
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作者：
Van Maldergem, Lionel;Hou, Qingming;Man, Heng-Ye
我们在2004年报道过，在一个XLID家族中，由于KIAA2022缺乏，存在一种离散的新型x连锁智力残疾（XLID）综合征，这一问题受到了KIAA2022因x染色体周中心反转而中断的质疑。在对XLID家族病例进行系统平行测序或对散发性智力缺陷（ID）病例进行常规阵列- cgh评估的框架内，发现了另外三个可能具有致病性KIAA2022突变的家族。通过x染色体外显子组测序鉴定了c.186delC和c.3597dupA KIAA2022截断突变，而阵列CGH在第三家族中发现了包含KIAA2022外显子1的70 kb微重复。这种重复使患者淋巴细胞中的KIAA2022 mRNA水平降低了60%。对所有患者的详细临床检查，包括最初报道的两名患者，表明中度至重度的ID具有自闭症特征，所有患者都有斜视，除了婴儿时期的圆脸外，没有其他特殊的畸形特征，磁共振成像（MRI）显示没有脑结构异常。有趣的是，KIAA2022表达减少的患者只有轻度的ID，严重的语言延迟和重复行为落在自闭症谱系障碍（ASD）的范围内。由于对KIAA2022的功能知之甚少，我们对培养的大鼠海马神经元进行了形态计量学研究。我们发现sirna介导的KIAA2022敲低导致包括树突和轴突在内的神经突生长明显受损，这表明KIAA2022在神经元发育和脑功能中起着重要作用。
Existence of a discrete new X-linked intellectual disability (XLID) syndrome due to KIAA2022 deficiency was questioned by disruption of KIAA2022 by an X-chromosome pericentric inversion in a XLID family we reported in 2004. Three additional families with likely pathogenic KIAA2022 mutations were discovered within the frame of systematic parallel sequencing of familial cases of XLID or in the context of routine array-CGH evaluation of sporadic intellectual deficiency (ID) cases. The c.186delC and c.3597dupA KIAA2022 truncating mutations were identified by X-chromosome exome sequencing, while array CGH discovered a 70 kb microduplication encompassing KIAA2022 exon 1 in the third family. This duplication decreased KIAA2022 mRNA level in patients lymphocytes by 60. Detailed clinical examination of all patients, including the two initially reported, indicated moderate-to-severe ID with autistic features, strabismus in all patients, with no specific dysmorphic features other than a round face in infancy and no structural brain abnormalities on magnetic resonance imaging (MRI). Interestingly, the patient with decreased KIAA2022 expression had only mild ID with severe language delay and repetitive behaviors falling in the range of an autism spectrum disorder (ASD). Since little is known about KIAA2022 function, we conducted morphometric studies in cultured rat hippocampal neurons. We found that siRNA-mediated KIAA2022 knockdown resulted in marked impairment in neurite outgrowth including both the dendrites and the axons, suggesting a major role for KIAA2022 in neuron development and brain function.