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

Böck, Julia; Krogsaeter, Einar; Passon, Marcel; Chao, Yu-Kai; Sharma, Sapna; Grallert, Harald; Peters, Annette und Grimm, Christian (2021): 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.
In: PLOS Genetics 17(1), e1009236

Abstract

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. Author summary 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1553-7404
• Sprache: Englisch