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J. Biol. Chem., Vol. 282, Issue 50, 36138-36142, December 14, 2007

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Accelerated Publication

Gain-of-function Mutation in TRPML3 Causes the Mouse Varitint-Waddler Phenotype^*

Hyun Jin Kim, Qin Li, Sandra Tjon-Kon-Sang, Insuk So, Kirill Kiselyov^¶, and Shmuel Muallem¹

From the Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, the Department of Physiology and Biophysics, Seoul National University College of Medicine, Seoul 110-799, Korea, and the ^¶Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260

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 -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.

Received for publication, October 2, 2007 , and in revised form, October 22, 2007.

FOOTNOTES

^* This work was supported by National Institutes of Health Grants DE12309 and DK38938 and by the Ruth S. Harrell Professorship in Medical Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. E-mail: Shmuel.Muallem{at}UTSouthwestern.edu.

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