Cavarocchi Emma, Sayou Camille, Lorès Patrick, Cazin Caroline, Stouvenel Laurence, El Khouri Elma, Coutton Charles, Kherraf Zine-Eddine, Patrat Catherine, Govin Jérôme, Thierry-Mieg Nicolas, Whitfield Marjorie, Ray Pierre F, Dulioust Emmanuel, Touré Aminata
Institute for Advanced Biosciences, INSERM U 1209, CNRS UMR 5309, Université Grenoble Alpes, 38000 Grenoble, France.
Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Cité, 75014 Paris, France.
iScience. 2023 Jul 10;26(8):107354. doi: 10.1016/j.isci.2023.107354. eCollection 2023 Aug 18.
Sperm fertilization ability mainly relies on proper sperm progression through the female genital tract and capacitation, which involves phosphorylation signaling pathways triggered by calcium and bicarbonate. We performed exome sequencing of an infertile asthenozoospermic patient and identified truncating variants in , encoding a microtubule-associated protein, and , encoding a protein of unknown function with enzymatic and signaling features. We demonstrate the deleterious impact of both variants on sperm transcripts and proteins from the patient. We show that, , patient spermatozoa could not induce the phosphorylation cascades associated with capacitation. We also provide evidence for IQCH association with calmodulin, a well-established calcium-binding protein that regulates the calmodulin kinase. Notably, we describe IQCH spatial distribution around the sperm axoneme, supporting its function within flagella. Overall, our work highlights the cumulative pathological impact of gene mutations and identifies IQCH as a key protein required for sperm motility and capacitation.
精子受精能力主要依赖于精子在雌性生殖道中的正常推进以及获能过程，这涉及由钙和碳酸氢盐触发的磷酸化信号通路。我们对一名不育的弱精子症患者进行了外显子组测序，在编码一种微管相关蛋白的基因以及编码一种具有酶促和信号特征但功能未知的蛋白的基因中鉴定出截短变异。我们证明了这两种变异对患者精子转录本和蛋白质的有害影响。我们发现，患者的精子无法诱导与获能相关的磷酸化级联反应。我们还提供了IQCH与钙调蛋白相关联的证据，钙调蛋白是一种成熟的钙结合蛋白，可调节钙调蛋白激酶。值得注意的是，我们描述了IQCH在精子轴丝周围的空间分布，支持其在鞭毛中的功能。总体而言，我们的工作突出了基因突变的累积病理影响，并将IQCH鉴定为精子运动和获能所需的关键蛋白。
