A splice donor mutation in NAA10 results in the dysregulation of the retinoic acid signalling pathway and causes Lenz microphthalmia syndrome.
A splice donor mutation in NAA10 results in the dysregulation of the retinoic acid signalling pathway and causes Lenz microphthalmia syndrome.
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DOI：
10.1136/jmedgenet-2013-101660
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发表时间：
2014-03
影响因子：
4
通讯作者：
Huang T
中科院分区：
文献类型：
--
作者：
Esmailpour T;Riazifar H;Liu L;Donkervoort S;Huang VH;Madaan S;Shoucri BM;Busch A;Wu J;Towbin A;Chadwick RB;Sequeira A;Vawter MP;Sun G;Johnston JJ;Biesecker LG;Kawaguchi R;Sun H;Kimonis V;Huang T
伦茨小眼综合征（LMS）是一种遗传异质性X连锁疾病，其特征为小眼/无眼、骨骼异常、泌尿生殖系统畸形以及指、耳和牙齿异常。在大约60%的受影响男性中可以看到智力残疾和癫痫症。迄今为止，没有基因已被确定为LMS在小眼综合征1基因座（MCOPS 1）。在这项研究中，我们的目标是找到这种疾病的致病基因。通过对一个有三个患病兄弟的家庭进行外显子组测序，我们发现了N-乙酰转移酶NAA 10基因内含子7剪接供体位点（c.471+ 2 T →A）的突变。NAA 10先前已被证明在奥格登综合征患者中发生突变，奥格登综合征在临床上与LMS不同。对该家系的连锁分析将致病基因定位在Xq 27-Xq 28，与NAA 10位点一致。突变与表型共分离，cDNA分析显示异常转录本。患者成纤维细胞缺乏全长NAA 10蛋白的表达，并显示细胞增殖缺陷。表达阵列研究显示，与无眼症的遗传形式相关的基因（如BMP 4、STRA 6）以及BCOR和经典WNT通路的下游靶基因存在显著的失调。特别是，STRA 6是一种视黄醇结合蛋白受体，介导细胞摄取视黄醇/维生素A，并在调节视黄酸信号通路中起主要作用。视黄醇摄取测定显示患者细胞中视黄醇摄取减少。我们的结论是，NAA 10突变是导致LMS在这个家庭，可能是通过失调的视黄酸信号通路。
Lenz microphthalmia syndrome (LMS) is a genetically heterogeneous X-linked disorder characterised by microphthalmia/anophthalmia, skeletal abnormalities, genitourinary malformations, and anomalies of the digits, ears, and teeth. Intellectual disability and seizure disorders are seen in about 60% of affected males. To date, no gene has been identified for LMS in the microphthalmia syndrome 1 locus (MCOPS1). In this study, we aim to find the disease-causing gene for this condition. Using exome sequencing in a family with three affected brothers, we identified a mutation in the intron 7 splice donor site (c.471+2T→A) of the N-acetyltransferase NAA10 gene. NAA10 has been previously shown to be mutated in patients with Ogden syndrome, which is clinically distinct from LMS. Linkage studies for this family mapped the disease locus to Xq27-Xq28, which was consistent with the locus of NAA10. The mutation co-segregated with the phenotype and cDNA analysis showed aberrant transcripts. Patient fibroblasts lacked expression of full length NAA10 protein and displayed cell proliferation defects. Expression array studies showed significant dysregulation of genes associated with genetic forms of anophthalmia such as BMP4, STRA6, and downstream targets of BCOR and the canonical WNT pathway. In particular, STRA6 is a retinol binding protein receptor that mediates cellular uptake of retinol/vitamin A and plays a major role in regulating the retinoic acid signalling pathway. A retinol uptake assay showed that retinol uptake was decreased in patient cells. We conclude that the NAA10 mutation is the cause of LMS in this family, likely through the dysregulation of the retinoic acid signalling pathway.
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DOI：
10.1016/j.bbrc.2005.12.018
发表时间：
2006-02-10
影响因子：
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作者：
Kim, SH;Park, JA;Kim, KW
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影响因子：
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