A gain-of-function TPC2 variant R210C increases affinity to PI(3,5)P2 and causes lysosome acidification and hypopigmentation

Abstract

Albinism is a group of inherited disorders mainly affecting skin, hair and eyes. Here we identify a de novo point mutation, p.R210C, in the TPCN2 gene which encodes Two Pore Channel 2 (TPC2) from a patient with albinism. TPC2 is an endolysosome and melanosome localized non-selective cation channel involved in regulating pigment production. Through inside-out recording of plasma membrane targeted TPC2 and direct recording of enlarged endolysosomal vacuoles, we reveal that the R210C mutant displays constitutive channel activation and markedly increased affinity to PI(3,5)P2. Mice harboring the homologous mutation, R194C, also exhibit hypopigmentation in the fur and skin, as well as less pigment and melanosomes in the retina in a dominant inheritance manner. Moreover, mouse embryonic fibroblasts carrying the R194C mutation show enlarged endolysosomes, enhanced lysosomal Ca2+ release and hyper-acidification. Our data suggest that R210C is a pathogenic gain-of-function TPC2 variant that underlies an unusual dominant type of albinism.

Missing Heritability in Albinism: Deep Characterization of a Hungarian Albinism Cohort Raises the Possibility of the Digenic Genetic Background of the Disease

“…WES of the cases for which the genetic background was not identified (n = 6) revealed one novel rare missense variant (c.2060A>G p.N687S) of the TPCN2 (NM_139075.4) gene. This gene has recently been implicated (2023) in the newly discovered dominant type of albinism [12]. The N687S variant is present in a 15-year-old Hungarian male patient (No.…”

“…Recently, a case with dominant inheritance of albinism was published. The first reported case of dominant albinism is caused by a newly discovered mutation (R210C) of the two-pore channel two (TPCN2) gene, recently identified in a Chinese child by Wang et al [12].…”

“…TPC2 can be activated by phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) or by nicotinic acid adenine dinucleotide phosphate (NAADP) binding [15]. TPC2 regulates melanosome pH and membrane potential and, consequently, pigment production [12][13][14].…”

Deletion of Dictyostelium tpc2 gene forms multi‐tipped structures, regulates autophagy and cell‐type patterning

“…Weak bases increase the pH of intracellular acidic stores and influence early development by decreasing the aggregate number in Dictyostelium (Davies et al., 1993). The gain‐of‐function of the TPC2 causes lysosomal acidification (Wang et al., 2023). Previous studies (Chang et al., 2020) report that tpc2 ̶ cells show sensitivity towards weak bases to inhibit aggregation by raising the pH of acidic vesicles after 4 h of starvation and altered the Ca 2+ signaling by extracellular cAMP.…”

Lysosome pH‐regulated H+/K+ switching channel involved in maintaining lysosomal homeostasis

“…Another driving force may come from reduced K + influx or enhanced Na + /Ca 2+ efflux, which will increase the lysosomal membrane potential to facilitate H + influx [5]. Gain-of-function mutant of TPC2 leads to acidification of lysosomes and melanosomes, the lysosome related organelles where melanin is synthesized, and induces pathologies of albinism [9][10][11]. It is interesting to know the involvement of TMEM175 and the coupling mechanism with TPC2 in regulating organellar acidification and pigment production.…”