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Böck, J.* ; Krogsaeter, E.* ; Passon, M.* ; Chao, Y.K.* ; Sharma, S. ; Grallert, H. ; Peters, A. ; Grimm, C.*

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.

PLoS Genet. 17:e1009236 (2021)
Verlagsversion Forschungsdaten DOI
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Mucolipidosis Type-iv; 2-pore Channels; Ion Channels; Naadp; Pigmentation; Population; Mutations; Sequence; Dynamics; Farmers
ISSN (print) / ISBN 1553-7390
e-ISSN 1553-7404
Zeitschrift PLoS Genetics
Quellenangaben Band: 17, Heft: 1, Seiten: , Artikelnummer: e1009236 Supplement: ,
Verlag Public Library of Science (PLoS)
Verlagsort 1160 Battery Street, Ste 100, San Francisco, Ca 94111 Usa
Begutachtungsstatus Peer reviewed
Förderungen NCL (Neuronal Ceroid Lipofuscinosis) Foundation, Hamburg, Germany
German Research Foundation DFG