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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The varitint-waddler (Va) deafness mutation in TRPML3 generates constitutive, inward rectifying currents and causes cell degeneration
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The varitint-waddler (Va) deafness mutation in TRPML3 generates constitutive, inward rectifying currents and causes cell degeneration

机译：TRPML3中的varitint-waddler（Va）耳聋突变产生本构的，向内的整流电流并引起细胞变性

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摘要

Varitint-waddler (Va and Va~J) mice are deaf and have vestibular impairment, with inner ear defects that include the degeneration and loss of sensory hair cells. The semidominant Va mutation results in an alanine-to-proline substitution at residue 419 (A419P) of the presumed ion channel TRPML3. Another allele, Va~J, has the A419P mutation in addition to an I362T mutation. We found that hair cells, marginal cells of stria vascularis, and other cells lining the cochlear and vestibular endolymphatic compartments express TRPML3. When heterologously expressed in LLC-PK1-CL4 epithelial cells, a culture model for hair cells, TRPML3 accumulated in lyso-somes and in espin-enlarged microvilli that resemble stereocilia. We also demonstrated that wild-type TRPML3 forms channels that are blocked by Gd~(3+), have a conductance of 50-70 pS and, like many other TRP channels, open at very positive potentials and thus rectify outwardly. In addition to this outward current, TRPML3(419P) and (I362T+A419P) generated a constitutive inwardly rectifying current that suggests a sensitivity to hyperpo-larizing negative potentials and that depolarized the cells. Cells expressing TRPML3(A419P) or (I362T+A419P), but not wild-type TRPML3, died and were extruded from the epithelium in a manner reminiscent of degenerating hair cells in Va mice. The increased open probability of TRPML3(A419P) and (I362T+A419P) at physiological potentials likely underlies hair cell degeneration and deafness in Va and Va~J mice.
机译：Varitint-waddler（Va和Va〜J）小鼠是聋的并且有前庭损伤，内耳缺损包括感觉毛细胞的变性和缺失。半显性Va突变导致在假定离子通道TRPML3的残基419（A419P）处丙氨酸取代脯氨酸。另一个等位基因Va〜J除了I362T突变外，还具有A419P突变。我们发现毛细胞，血管纹的边缘细胞，以及衬在耳蜗和前庭内淋巴区室的其他细胞表达TRPML3。当在毛发细胞的培养模型LLC-PK1-CL4上皮细胞中异源表达时，TRPML3会在溶酶体和类似于立体纤毛的，增大的微绒毛中积聚。我们还证明，野生型TRPML3形成被Gd〜（3+）阻断的通道，具有50-70 pS的电导率，并且像许多其他TRP通道一样，以非常高的电势打开，从而向外整流。除了该向外的电流外，TRPML3（419P）和（I362T + A419P）产生本构的向内整流电流，该电流表明对超极化负电势具有敏感性并使细胞去极化。表达TRPML3（A419P）或（I362T + A419P）而非野生型TRPML3的细胞死亡，并从上皮中挤出，其方式类似于Va小鼠中退化的毛细胞。 TRPML3（A419P）和（I362T + A419P）在生理电势下开放可能性增加，可能是Va和Va〜J小鼠毛细胞变性和耳聋的基础。

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