Gain-of-function mutation in TRPML3 causes the mouse varitint-waddler phenotype

Jin Kim Hyun, Qin Li, Sandra Tjon-Kon-Sang, Insuk So, Kirill Kiselyov, Shmuel Muallem

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Abstract

TRPML3 is a member of the TRPML subfamily of the transient receptor potential cation channel superfamily. The TRPML3(A419P) mutation causes a severe form, whereas the TRPML3(I362T/A419P) mutation results in a mild form of the varitint-waddler phenotype. The channel properties of TRPML3 and how the mutations cause each phenotype are not known. In this study, we report the first channel properties of TRPML3 as a strongly inward rectifying cation channel with a novel regulation by extracytosolic Na+. Preincubating the extracytosolic face of TRPML3 in Na+-free medium is required for channel activation, but then the channel slowly inactivates. The A419P mutation locks the channel in an open unregulated state. Similar gain of function was observed with the A419G mutation, which, like A419P, is expected to destabilize the α-helical fifth transmembrane domain of TRPML3. The I362T mutation results in an inactive channel, but the channel properties of TRPML3(I362T/A419P) are similar to those of TRPML3(A419P). However, the surface expression and current density of TRPML3(I362T/A419P) are lower than those of TRPML3(A419P). The A419P mutation also affects channel glycosylation and causes massive cell death. These findings show that the varitint-waddler phenotype is due to a gain of function of TRPML3(A419P) that is reduced by the TRPML3(I362T/A419P) mutant, resulting in a milder phenotype.

Original languageEnglish
Pages (from-to)36138-36142
Number of pages5
JournalJournal of Biological Chemistry
Volume282
Issue number50
DOIs
StatePublished - 14 Dec 2007

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Transient Receptor Potential Channels
Glycosylation
Phenotype
Mutation
Cell death
Cations
Current density
Chemical activation
Cell Death

Cite this

Hyun, Jin Kim ; Li, Qin ; Tjon-Kon-Sang, Sandra ; So, Insuk ; Kiselyov, Kirill ; Muallem, Shmuel. / Gain-of-function mutation in TRPML3 causes the mouse varitint-waddler phenotype. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 50. pp. 36138-36142.
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abstract = "TRPML3 is a member of the TRPML subfamily of the transient receptor potential cation channel superfamily. The TRPML3(A419P) mutation causes a severe form, whereas the TRPML3(I362T/A419P) mutation results in a mild form of the varitint-waddler phenotype. The channel properties of TRPML3 and how the mutations cause each phenotype are not known. In this study, we report the first channel properties of TRPML3 as a strongly inward rectifying cation channel with a novel regulation by extracytosolic Na+. Preincubating the extracytosolic face of TRPML3 in Na+-free medium is required for channel activation, but then the channel slowly inactivates. The A419P mutation locks the channel in an open unregulated state. Similar gain of function was observed with the A419G mutation, which, like A419P, is expected to destabilize the α-helical fifth transmembrane domain of TRPML3. The I362T mutation results in an inactive channel, but the channel properties of TRPML3(I362T/A419P) are similar to those of TRPML3(A419P). However, the surface expression and current density of TRPML3(I362T/A419P) are lower than those of TRPML3(A419P). The A419P mutation also affects channel glycosylation and causes massive cell death. These findings show that the varitint-waddler phenotype is due to a gain of function of TRPML3(A419P) that is reduced by the TRPML3(I362T/A419P) mutant, resulting in a milder phenotype.",
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Hyun, JK, Li, Q, Tjon-Kon-Sang, S, So, I, Kiselyov, K & Muallem, S 2007, 'Gain-of-function mutation in TRPML3 causes the mouse varitint-waddler phenotype', Journal of Biological Chemistry, vol. 282, no. 50, pp. 36138-36142. https://doi.org/10.1074/jbc.C700190200

Gain-of-function mutation in TRPML3 causes the mouse varitint-waddler phenotype. / Hyun, Jin Kim; Li, Qin; Tjon-Kon-Sang, Sandra; So, Insuk; Kiselyov, Kirill; Muallem, Shmuel.

In: Journal of Biological Chemistry, Vol. 282, No. 50, 14.12.2007, p. 36138-36142.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Hyun, Jin Kim

AU - Li, Qin

AU - Tjon-Kon-Sang, Sandra

AU - So, Insuk

AU - Kiselyov, Kirill

AU - Muallem, Shmuel

PY - 2007/12/14

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