Human genome diversity data reveal that L564P is the predominant TPC2 variant and a prerequisite for the blond hair associated M484L gain-of-function effect.
Human genome diversity data reveal that L564P is the predominant TPC2 variant and a prerequisite for the blond hair associated M484L gain-of-function effect.
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DOI：
10.1371/journal.pgen.1009236
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发表时间：
2021-01
期刊：
影响因子：
4.5
通讯作者：
Grimm C
中科院分区：
文献类型：
--
作者：
Böck J;Krogsaeter E;Passon M;Chao YK;Sharma S;Grallert H;Peters A;Grimm C
内溶酶体双孔通道（TPC 2）是近年来发现的一种具有重要生理和病理生理意义的细胞内阳离子通道。例如，TPC 2-/-小鼠显示胆固醇降解缺陷，导致高胆固醇血症; TPC 2缺乏也导致成熟型肥胖，并且已经提出了在胰高血糖素分泌和糖尿病中的作用。细菌毒素或病毒感染，例如，霍乱毒素或埃博拉病毒导致在不存在TPC 2的情况下或在药理学阻断后感染率降低，并且TPC 2-/-癌细胞失去其有效迁移和转移的能力。最后，黑色素的产生受到hTPC 2活性变化的影响，导致色素沉着缺陷和毛发颜色变化。在这里，我们分析了几个公开的基因组变异数据集，并确定了不同人群中TPC 2蛋白的多种变异。令人惊讶的是，发现一种变异L564 P是全球范围内主要的TPC 2亚型。通过应用内-溶酶体膜片钳电生理学，我们发现L564 P是先前描述的与金发相关的M484 L功能获得效应的先决条件。此外，还发现了具有不同地理和种族分布的其他功能获得性变体，并对其进行了功能表征。进行了全基因组关联研究的荟萃分析，发现多态性与不同和重叠的性状相关。总之，我们提出了第一个系统的分析TPC 2的变化。我们在功能上描述了最常见的变异，并评估了它们与各种疾病特征的关联。随着TPC 2成为治疗各种疾病的新型药物靶标，这项研究为TPC 2多态性的种族和地理分布及其对通道活性的影响提供了有价值的见解。内-溶酶体阳离子通道TPC 2与许多人类疾病有关，从代谢疾病、帕金森病、癌症和色素沉着缺陷到感染性疾病如埃博拉病毒、Covid-19和细菌感染。在这里，我们提出了一个功能分析的几个多态性发生在人类TPC 2蛋白在不同的人群。通过评估几个人类基因组数据库，我们确定了大量的单核苷酸多态性在TPC 2。我们的电生理特点是最常见的多态性，应用内溶酶体膜片钳技术。因此，我们鉴定了几种新的功能获得性变体，并发现TPC 2变体L564 P是先前描述的与金发相关的M484 L功能获得性效应的先决条件。此外，公开可用的全基因组关联研究数据库进行了评估，并询问了所调查的TPC 2多态性的连锁性状。考虑到不同人群携带已鉴定的功能获得性变异的可能性不同，这些发现似乎与进一步评估TPC 2作为药理学药物靶标高度相关。
The endo-lysosomal two-pore channel (TPC2) has been established as an intracellular cation channel of significant physiological and pathophysiological relevance in recent years. For example, TPC2-/- mice show defects in cholesterol degradation, leading to hypercholesterinemia; TPC2 absence also results in mature-onset obesity, and a role in glucagon secretion and diabetes has been proposed. Infections with bacterial toxins or viruses e.g., cholera toxin or Ebola virus result in reduced infectivity rates in the absence of TPC2 or after pharmacological blockage, and TPC2-/- cancer cells lose their ability to migrate and metastasize efficiently. Finally, melanin production is affected by changes in hTPC2 activity, resulting in pigmentation defects and hair color variation. Here, we analyzed several publicly available genome variation data sets and identified multiple variations in the TPC2 protein in distinct human populations. Surprisingly, one variation, L564P, was found to be the predominant TPC2 isoform on a global scale. By applying endo-lysosomal patch-clamp electrophysiology, we found that L564P is a prerequisite for the previously described M484L gain-of-function effect that is associated with blond hair. Additionally, other gain-of-function variants with distinct geographical and ethnic distribution were discovered and functionally characterized. A meta-analysis of genome-wide association studies was performed, finding the polymorphisms to be associated with both distinct and overlapping traits. In sum, we present the first systematic analysis of variations in TPC2. We functionally characterized the most common variations and assessed their association with various disease traits. With TPC2 emerging as a novel drug target for the treatment of various diseases, this study provides valuable insights into ethnic and geographical distribution of TPC2 polymorphisms and their effects on channel activity. The endo-lysosomal cation channel TPC2 is implicated in numerous human diseases ranging from metabolic disease, Parkinson’s disease, cancer and pigmentation defects, to infectious diseases such as Ebola, Covid-19, and bacterial infections. Here, we present a functional analysis of several polymorphisms occurring in the human TPC2 protein in distinct populations. By evaluating several human genome databases, we identified a large number of single nucleotide polymorphisms in TPC2. We electrophysiologically characterized the most common polymorphisms by applying the endo-lysosomal patch-clamp technique. We thereby identified several novel gain-of-function variants and found the TPC2 variation L564P to be a prerequisite for the previously described M484L gain-of-function effect associated with blond hair. In addition, publicly available genome-wide association study databases were assessed, and linked traits of the investigated TPC2 polymorphisms interrogated. Considering that different human populations have a different likelihood of carrying the identified gain-of-function variations, these findings appear highly relevant for further assessment of TPC2 as a pharmacological drug target.
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影响因子：
30.8
作者：
Flannick, Jason;Thorleifsson, Gudmar;Beer, Nicola L.;Jacobs, Suzanne B. R.;Grarup, Niels;Burtt, Noel P.;Mahajan, Anubha;Fuchsberger, Christian;Atzmon, Gil;Benediktsson, Rafn;Blangero, John;Bowden, Don W.;Brandslund, Ivan;Brosnan, Julia;Burslem, Frank;Chambers, John;Cho, Yoon Shin;Christensen, Cramer;Douglas, Desiree A.;Duggirala, Ravindranath;Dymek, Zachary;Farjoun, Yossi;Fennell, Timothy;Fontanillas, Pierre;Forsen, Tom;Gabriel, Stacey;Glaser, Benjamin;Gudbjartsson, Daniel F.;Hanis, Craig;Hansen, Torben;Hreidarsson, Astradur B.;Hveem, Kristian;Ingelsson, Erik;Isomaa, Bo;Johansson, Stefan;Jorgensen, Torben;Jorgensen, Marit Eika;Kathiresan, Sekar;Kong, Augustine;Kooner, Jaspal;Kravic, Jasmina;Laakso, Markku;Lee, Jong-Young;Lind, Lars;Lindgren, Cecilia M.;Linneberg, Allan;Masson, Gisli;Meitinger, Thomas;Mohlke, Karen L.;Molven, Anders;Morris, Andrew P.;Potluri, Shobha;Rauramaa, Rainer;Ribel-Madsen, Rasmus;Richard, Ann-Marie;Rolph, Tim;Salomaa, Veikko;Segre, Ayellet V.;Skaerstrand, Hanna;Steinthorsdottir, Valgerdur;Stringham, Heather M.;Sulem, Patrick;Tai, E. Shyong;Teo, Yik Ying;Teslovich, Tanya;Thorsteinsdottir, Unnur;Trimmer, Jeff K.;Tuomi, Tiinamaija;Tuomilehto, Jaakko;Vaziri-Sani, Fariba;Voight, Benjamin F.;Wilson, James G.;Boehnke, Michael;McCarthy, Mark I.;Njolstad, Pal R.;Pedersen, Oluf;Groop, Leif;Cox, David R.;Stefansson, Kari;Altshuler, David
通讯作者：
Altshuler, David
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen
DOI：
10.1073/pnas.1705739114
发表时间：
2017-10-10
影响因子：
11.1
作者：
Chao, Yu-Kai;Schludi, Verena;Grimm, Christian
通讯作者：
Grimm, Christian
DOI：
10.1073/pnas.1406029111
发表时间：
2014-11-04
影响因子：
11.1
作者：
Favia, Annarita;Desideri, Marianna;Filippini, Antonio
通讯作者：
Filippini, Antonio
影响因子：
64.5
作者：
Ferreira, Ana;Marguti, Ivo;Soares, Miguel P.
通讯作者：
Soares, Miguel P.