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.

Julia Böck,Harald Grallert,Annette Peters,Yu-Kai Chao,Einar Krogsaeter,Marcel Passon,Sapna Sharma,Christian Grimm,Elena Oancea

doi:10.1371/journal.pgen.1009236

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.

Highlights

DNA variants are traditionally divided into DNA mutations and single nucleotide polymorphisms (SNPs), based on their occurrence in 1% of the population, respectively
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
By evaluating several human genome databases, we identified a large number of single nucleotide polymorphisms in TPC2

Summary

Introduction

DNA variants are traditionally divided into DNA mutations and single nucleotide polymorphisms (SNPs), based on their occurrence in 1% of the population, respectively. Variations with a proven effect on gene function are termed functional polymorphisms. Such functional polymorphisms may impact development of disease or response to pathogens, chemicals, vaccines or drugs. This is important in the context of personalized medicine, as gene variation can affect, e.g. drug metabolism or side effects. Variations associated with a certain disease in one population may appear harmless or are irrelevant in other populations. One famous example is malaria resistance in people carrying certain variations in hemoglobin, which on the one hand results in sickle-cell anemia, but on the other hand is a selection advantage, at least for heterozygous carriers, in geographic regions where malaria is prevalent [1,2]. As with other genetic variations, functional variations in TPC2 may impact health and survival under certain environmental conditions and in certain geographical areas, while in others they might not

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