Deletion of exon 20 of the Familial Dysautonomia gene Ikbkap in mice causes developmental delay, cardiovascular defects, and early embryonic lethality.
Deletion of exon 20 of the Familial Dysautonomia gene Ikbkap in mice causes developmental delay, cardiovascular defects, and early embryonic lethality.
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DOI：
10.1371/journal.pone.0027015
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Dragatsis I
中科院分区：
文献类型：
--
作者：
Dietrich P;Yue J;E S;Dragatsis I
家族性自主神经功能障碍（FD）是一种常染色体隐性遗传疾病，影响德系犹太人人口中1/3，600的活产婴儿，并导致40岁之前死亡。这种疾病的特征是感觉和自主神经系统的异常发育和进行性变性。Ikbkap基因的内含子20中的单个碱基对取代占FD病例的98%，并且导致低水平的全长mRNA表达，同时表达异常剪接的mRNA，其中外显子20缺失。到目前为止，还没有这种疾病的动物模型，IKAP的基本细胞功能-由Ikbkap编码的蛋白质-仍然未知。为了更好地了解IKAP的正常功能，并努力产生FD的小鼠模型，我们通过同源重组靶向小鼠Ikbkap基因。我们创建了两个不同的等位基因，其导致Ikbkap表达的丧失或仅缺乏外显子20的mRNA的表达。任何一种突变的纯合性都会导致发育迟缓、心血管和脑畸形，并伴有早期胚胎死亡。我们的分析表明，IKAP是必不可少的特定基因参与心脏形态发生的表达，心力衰竭是异常血管发育和胚胎死亡的可能原因。我们的研究结果还表明，外显子20的缺失废除基因功能。这意味着在FD患者中表达的截短的IKAP蛋白不保留任何显著的生物学功能。
Familial Dysautonomia (FD) is an autosomal recessive disorder that affects 1/3,600 live births in the Ashkenazi Jewish population, and leads to death before the age of 40. The disease is characterized by abnormal development and progressive degeneration of the sensory and autonomic nervous system. A single base pair substitution in intron 20 of the Ikbkap gene accounts for 98% of FD cases, and results in the expression of low levels of the full-length mRNA with simultaneous expression of an aberrantly spliced mRNA in which exon 20 is missing. To date, there is no animal model for the disease, and the essential cellular functions of IKAP - the protein encoded by Ikbkap - remain unknown. To better understand the normal function of IKAP and in an effort to generate a mouse model for FD, we have targeted the mouse Ikbkap gene by homologous recombination. We created two distinct alleles that result in either loss of Ikbkap expression, or expression of an mRNA lacking only exon 20. Homozygosity for either mutation leads to developmental delay, cardiovascular and brain malformations, accompanied with early embryonic lethality. Our analyses indicate that IKAP is essential for expression of specific genes involved in cardiac morphogenesis, and that cardiac failure is the likely cause of abnormal vascular development and embryonic lethality. Our results also indicate that deletion of exon 20 abolishes gene function. This implies that the truncated IKAP protein expressed in FD patients does not retain any significant biological function.
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影响因子：
14.9
作者：
Dragatsis, I;Zeitlin, S
通讯作者：
Zeitlin, S
影响因子：
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Chariot, Alain
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作者：
Chester, N;Kuo, F;Leder, P
通讯作者：
Leder, P