A Recurrent Deletion of DPY19L2 Causes Infertility in Man by Blocking Sperm Head Elongation and Acrosome Formation
A Recurrent Deletion of DPY19L2 Causes Infertility in Man by Blocking Sperm Head Elongation and Acrosome Formation
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DOI：
10.1016/j.ajhg.2011.02.007
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发表时间：
2011-03-11
影响因子：
9.8
通讯作者：
Ray, Pierre F.
中科院分区：
文献类型：
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作者：
Harbuz, Radu;Zouari, Raoudha;Ray, Pierre F.
越来越多的夫妇需要医疗帮助才能怀孕，西方国家现在有2%以上的分娩是通过辅助生殖技术实现的。为了确定导致男性不育的遗传变异，我们对表现为完全球形精子症的患者进行了全基因组SNP扫描，这是一种原发性不育表型，其特征在于射精中存在100%圆形无顶体精子。这种策略使我们能够在大多数患者（15/20）中鉴定出仅包含DPY 19 L2的200 kb纯合缺失，DPY 19 L2在睾丸中高度表达。虽然DPY 19 L2在人类中的功能尚不清楚，但先前的工作表明其在C. elegans与细胞极性有关。在人类中，DPY 19 L2区域已被描述为拷贝数变体（CNV），发现在健康个体中重复和异源缺失。我们在这里表明，断点的缺失位于一个高度同源的28 kb低拷贝重复（LCR）序列上的每一侧的DPY 19 L2，表明所确定的缺失可能产生的非等位基因同源重组（NAHR）这两个区域之间。我们证明，球形精子症患者有一个纯合缺失DPY 19 L2，从而表明DPY 19 L2是必要的男性精子头部伸长和顶体形成。现在可以对受影响的男性进行分子诊断;缺失的存在证实了球形精子症的诊断，并为体外受精的成功预后不良。
An increasing number of couples require medical assistance to achieve a pregnancy, and more than 2% of the births in Western countries now result from assisted reproductive technologies. To identify genetic variants responsible for male infertility, we performed a whole-genome SNP scan on patients presenting with total globozoospermia, a primary infertility phenotype characterized by the presence of 100% round acrosomeless spermatozoa in the ejaculate. This strategy allowed us to identify in most patients (15/20) a 200 kb homozygous deletion encompassing only DPY19L2, which is highly expressed in the testis. Although there was no known function for DPY19L2 in humans, previous work indicated that its ortholog in C. elegans is involved in cell polarity. In man, the DPY19L2 region has been described as a copy-number variant (CNV) found to be duplicated and heterozygously deleted in healthy individuals. We show here that the breakpoints of the deletions are located on a highly homologous 28 kb low copy repeat (LCR) sequence present on each side of DPY19L2, indicating that the identified deletions were probably produced by nonallelic homologous recombination (NAHR) between these two regions. We demonstrate that patients with globozoospermia have a homozygous deletion of DPY19L2, thus indicating that DPY19L2 is necessary in men for sperm head elongation and acrosome formation. A molecular diagnosis can now be proposed to affected men; the presence of the deletion confirms the diagnosis of globozoospermia and assigns a poor prognosis for the success of in vitro fertilization.