The USH2A c. 2299delG mutation: dating its common origin in a Southern European population
The USH2A c. 2299delG mutation: dating its common origin in a Southern European population
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DOI：
10.1038/ejhg.2010.14
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发表时间：
2010-07-01
影响因子：
5.2
通讯作者：
Millan, Jose M.
中科院分区：
文献类型：
--
作者：
Aller, Elena;Larrieu, Lise;Millan, Jose M.
Usher综合征II型是Usher综合征最常见的形式。在这三种已知致病基因中，USH2A是主要的致病基因。它编码两种不同亚型的前列蛋白。这种蛋白质是相互作用体的一部分，在内耳毛细胞和感光细胞的发育和功能中起着至关重要的作用。该基因包含72个外显子，覆盖800 kb的区域。虽然已经描述了许多突变，但c.2299delG突变在几个人群中最常见。它的起源是在鉴定了编码短迎春素亚型的5‘端250 kb的共同核心单倍型后提出的。通过将单倍型分析扩展到USH2A基因800kb区域，总共14个基因内单核苷酸多态，我们已经能够定义10种不同的c.2299delG单倍型，表现出高度的变异性，但保留了先前描述的核心单倍型。一项详尽的c.2299delG/对照单倍型研究表明，USH2A基因变异的主要来源是重组。此外，我们已经证明了位于覆盖该基因3‘端的500kb区域的重组热点的数量是该区域的两倍，这解释了与5’区域的250kb相比，在该区域观察到的更高的变异性。我们的数据证实了c.2299delG突变的共同祖先来源。《欧洲人类遗传学杂志》(2010年)18788-793DOI：10.1038/ejhg.2010.14；2010年2月10日在线出版
Usher syndrome type II is the most common form of Usher syndrome. USH2A is the main responsible gene of the three known to be disease causing. It encodes two isoforms of the protein usherin. This protein is part of an interactome that has an essential role in the development and function of inner ear hair cells and photoreceptors. The gene contains 72 exons spanning over a region of 800 kb. Although numerous mutations have been described, the c.2299delG mutation is the most prevalent in several populations. Its ancestral origin was previously suggested after the identification of a common core haplotype restricted to 250 kb in the 5' region that encodes the short usherin isoform. By extending the haplotype analysis over the 800 kb region of the USH2A gene with a total of 14 intragenic single nucleotide polymorphisms, we have been able to define 10 different c.2299delG haplotypes, showing high variability but preserving the previously described core haplotype. An exhaustive c.2299delG/control haplotype study suggests that the major source of variability in the USH2A gene is recombination. Furthermore, we have evidenced twice the amount of recombination hotspots located in the 500 kb region that covers the 3' end of the gene, explaining the higher variability observed in this region when compared with the 250 kb of the 5' region. Our data confirm the common ancestral origin of the c.2299delG mutation. European Journal of Human Genetics (2010) 18, 788-793; doi: 10.1038/ejhg.2010.14; published online 10 February 2010