TPCN2 – Albinism

Albinism comprises a spectrum of inherited disorders characterized by hypopigmentation of skin, hair and eyes due to disrupted melanin synthesis. Two-Pore Channel 2 (TPC2), encoded by TPCN2, is a nonselective endolysosomal and melanosomal cation channel involved in intracellular Ca²⁺ signaling and pigment production.

A de novo missense variant, c.628C>T (p.Arg210Cys), was identified in a patient with oculocutaneous albinism, establishing autosomal dominant inheritance of this gain-of-function allele ([PMID:36641477]).

A separate report describes an independent gain-of-function TPC2 mutation that also leads to constitutive channel activation and hypopigmentation in a dominant fashion, reinforcing the pathogenic mechanism ([PMID:36841139]).

In contrast, a rare TPCN2 p.Asn687Ser variant did not segregate with albinism in a Hungarian cohort and required an additional OCA2 p.Arg305Trp allele to manifest pigment loss, suggesting potential digenic interactions or allele-specific effects ([PMID:38279271]).

Electrophysiological studies of R210C channels demonstrate constitutive activation, markedly increased PI(3,5)P2 affinity, enhanced lysosomal Ca²⁺ release and hyper-acidification—changes that impair melanosome maturation and melanin synthesis ([PMID:36641477]).

Knock-in mice harbouring the homologous R194C mutation exhibit dominant hypopigmentation of fur and retina, recapitulating the human phenotype through a gain-of-function mechanism ([PMID:36641477]).

Together, these findings support TPCN2 as an autosomal dominant albinism gene with a gain-of-function mechanism. TPCN2 gain-of-function mutations should be included in genetic testing panels for autosomal dominant albinism to inform clinical decision-making and therapeutic development.

References

• Nature communications • 2023 • A gain-of-function TPC2 variant R210C increases affinity to PI(3,5)P2 and causes lysosome acidification and hypopigmentation. PMID:36641477
• Cell calcium • 2023 • A novel gain of function mutation in TPC2 reiterates pH-pigmentation interplay: Emerging role of ionic homeostasis as a master pigmentation regulator. PMID:36841139
• International journal of molecular sciences • 2024 • Missing Heritability in Albinism: Deep Characterization of a Hungarian Albinism Cohort Raises the Possibility of the Digenic Genetic Background of the Disease. PMID:38279271

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