Homozygous in-frame deletion in CATSPERE in a man producing spermatozoa with loss of CatSper function and compromised fertilizing capacity.
Homozygous in-frame deletion in CATSPERE in a man producing spermatozoa with loss of CatSper function and compromised fertilizing capacity.
复制标题
DOI：
10.1093/humrep/dey278
复制
发表时间：
2018-10-01
期刊：
影响因子：
--
通讯作者：
Martins Da Silva S
中科院分区：
文献类型：
--
作者：
Brown SG;Miller MR;Lishko PV;Lester DH;Publicover SJ;Barratt CLR;Martins Da Silva S
先前描述的精子阳离子通道（CatSper）功能缺陷的男性（患者1）是否存在CatSper-zeta（CATSPERE）和/或CatSper-zeta（CATSPERZ）基因突变？患者1在CATSPERE的外显子18（c.2393_2398delCTATGG，rs761237686）中具有纯合的框内6-bp缺失。CatSper是哺乳动物精子的主要钙通道。来自患者1的精子具有CatSper功能的特异性丧失，并且在IVF时无法受精。CatSper功能的丧失不能归因于七个CatSper亚基编码区的遗传异常。最近发现了另外两个亚基（CatSper-zeta（CATPSERE）和CatSper-zeta（CATSPERZ）），目前认为它们有助于成熟通道复合物的形成。这是一项基础医学研究，分析了来自单个患者（患者1）的CATSPERE和CATSPERZ缺陷的基因组数据。分析患者1的原始外显子组测序数据的CATSPERE和CATSPERZ突变。进行桑格测序以确认罕见变体的存在。患者1对于CATSPERE的外显子18中的框内6-bp缺失（c.2393_2398delCTATGG，rs761237686）是纯合的，其被预测为高度有害的。由rs761237686变体引起的分子缺陷的性质以及它是否专门负责CatSper功能的丧失仍有待阐明。群体遗传学可用于CatSper亚基的大量预测有害变体。纯合子和复合杂合子形式对精子受精能力的影响可能是显著的。选择性靶向CatSper亚基表达可能是开发新型避孕药的可行策略。本研究由MRC（MR/K 013343/1和MR/012492/1）、首席科学家办公室/NHS研究苏格兰的项目赠款。这项工作也得到了NIH R 01 GM 111802，Pew生物医学学者奖00028642和Packer Wentz Endowment Will to P.V.L.的支持。C.L.R.B是《分子人类生殖》杂志的主编，从默克和费林那里获得了演讲费，并且是Ohana生物科学的科学顾问小组成员。C.L.R.B是世界卫生组织男性不育症诊断专家综合小组主席（2012-2016）。
Does a man (patient 1) with a previously described deficiency in principle cation channel of sperm (CatSper) function have a mutation in the CatSper-epsilon (CATSPERE) and/or CatSper-zeta (CATSPERZ) gene? Patient 1 has a homozygous in-frame 6-bp deletion in exon 18 (c.2393_2398delCTATGG, rs761237686) of CATSPERE. CatSper is the principal calcium channel of mammalian spermatozoa. Spermatozoa from patient 1 had a specific loss of CatSper function and were unable to fertilize at IVF. Loss of CatSper function could not be attributed to genetic abnormalities in coding regions of seven CatSper subunits. Two additional subunits (CatSper-epsilon (CATPSERE) and CatSper-zeta (CATSPERZ)) were recently identified, and are now proposed to contribute to the formation of the mature channel complex. This was a basic medical research study analysing genomic data from a single patient (patient 1) for defects in CATSPERE and CATSPERZ. The original exome sequencing data for patient 1 were analysed for mutations in CATSPERE and CATSPERZ. Sanger sequencing was conducted to confirm the presence of a rare variant. Patient 1 is homozygous for an in-frame 6-bp deletion in exon 18 (c.2393_2398delCTATGG, rs761237686) of CATSPERE that is predicted to be highly deleterious. The nature of the molecular deficit caused by the rs761237686 variant and whether it is exclusively responsible for the loss of CatSper function remain to be elucidated. Population genetics are available for a significant number of predicted deleterious variants of CatSper subunits. The consequence of homozygous and compound heterozygous forms on sperm fertilization potential could be significant. Selective targeting of CatSper subunit expression maybe a feasible strategy for the development of novel contraceptives. This study was funded by project grants from the MRC (MR/K013343/1 and MR/012492/1), Chief Scientist Office/NHS research Scotland. This work was also supported by NIH R01GM111802, Pew Biomedical Scholars Award 00028642 and Packer Wentz Endowment Will to P.V.L. C.L.R.B is the editor-in-chief of Molecular Human Reproduction, has received lecturing fees from Merck and Ferring, and is on the Scientific Advisory Panel for Ohana BioSciences. C.L.R.B was chair of the World Health Organization Expert Synthesis Group on Diagnosis of Male infertility (2012–2016).
登录
查看更多内容
DOI：
10.1093/humrep/dev243
发表时间：
2015-12
期刊：
Human reproduction (Oxford, England)
影响因子：
--
作者：
Williams HL;Mansell S;Alasmari W;Brown SG;Wilson SM;Sutton KA;Miller MR;Lishko PV;Barratt CL;Publicover SJ;Martins da Silva S
通讯作者：
Martins da Silva S
DOI：
10.1093/humrep/dey096
发表时间：
2018-06-01
期刊：
Human reproduction (Oxford, England)
影响因子：
--
作者：
Kelly MC;Brown SG;Costello SM;Ramalingam M;Drew E;Publicover SJ;Barratt CLR;Martins Da Silva S
通讯作者：
Martins Da Silva S
DOI：
10.1073/pnas.0610286104
发表时间：
2007-01-23
影响因子：
11.1
作者：
Qi, Huayu;Moran, Magdalene M.;Clapham, David E.
通讯作者：
Clapham, David E.
影响因子：
16.6
作者：
Chung JJ;Navarro B;Krapivinsky G;Krapivinsky L;Clapham DE
通讯作者：
Clapham DE
影响因子：
2.5
作者：
Lishko PV;Mannowetz N
通讯作者：
Mannowetz N