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

doi:10.1074/jbc.C700190200

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Papers In Press, published online ahead of print October 25, 2007
J. Biol. Chem, 10.1074/jbc.C700190200
Submitted on October 2, 2007
Revised on October 22, 2007
Accepted on October 25, 2007

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 Muallem

Dept. of Physiology, UT Southwestern Medical Center, Dallas, TX 75390-9040

Corresponding Author: shmuel.muallem{at}utsouthwestern.edu

TRPML3 is a member of the TRPML subfamily of the TRP cation channels superfamily. The TRPML3(A419P) mutation causes a severe form while 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. The present study reports the first channel properties of TRPML3 as a strongly inward rectifying cation channel with a novel regulation by extracytosolic Na+. Pre-incubating the extracytosolic face of TRPML3 in Na+-free media is required for channel activation, but then the channel slowly inactivates. The A419P mutation locks the channel in an open state that shows no inactivation. Similar gain-of-function was observed with the A419G mutation that, like A419P, is expected to destabilize the -helical fifth transmembrane domain of TRPML3. The I362T mutation alone results in inactive channel, but, surprisingly, channel properties of TRPML3(I362T/ A419P) are similar to those of TRPML3 (A419P). However 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 to result in a milder phenotype.

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