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

Area of Science:

• Genetics
• Cell Biology
• Biochemistry

Background:

• Albinism comprises inherited disorders affecting pigmentation of skin, hair, and eyes.
• The TPCN2 gene encodes Two Pore Channel 2 (TPC2), a cation channel crucial for pigment production.
• TPC2 localizes to endolysosomes and melanosomes, regulating pigment synthesis.

Purpose of the Study:

• To identify the genetic cause of an unusual dominant form of albinism.
• To characterize the functional impact of a novel TPCN2 mutation.
• To elucidate the role of TPC2 in pigment regulation and albinism pathogenesis.

Main Methods:

• Genetic sequencing to identify mutations in TPCN2.
• Electrophysiological recordings (inside-out, direct vacuole) of TPC2 channel activity.
• Analysis of mouse models with homologous mutations.
• Biochemical assays on mouse embryonic fibroblasts.

Main Results:

• A de novo point mutation, p.R210C, was identified in the TPCN2 gene of an albinism patient.
• The R210C mutant TPC2 exhibits constitutive channel activation and increased PI(3,5)P2 affinity.
• Mice with the homologous R194C mutation show hypopigmentation and altered melanosomes.
• Fibroblasts with the R194C mutation display enlarged endolysosomes, enhanced Ca2+ release, and hyper-acidification.

Conclusions:

• The p.R210C mutation in TPCN2 is a pathogenic gain-of-function variant.
• This variant underlies a rare dominant form of albinism.
• TPC2 dysfunction significantly impacts pigment production and lysosomal homeostasis.