The varitint-waddler mouse phenotypes and the TRPML3 ion channel mutation: cause and consequence
The varitint-waddler mouse phenotypes and the TRPML3 ion channel mutation: cause and consequence
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DOI：
10.1007/s00424-008-0523-4
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发表时间：
2008-11-01
影响因子：
4.5
通讯作者：
Samie, Mohammad A.
中科院分区：
文献类型：
--
作者：
Cuajungco, Math P.;Samie, Mohammad A.
瞬时受体电位粘磷脂（trpml）是最近发现的TRP离子通道蛋白亚家族。定位克隆方法确定了TRPML3 （Mcoln3）基因的两个突变导致变异-蹒跚小鼠表型。变异体是变色调（被稀释的毛色）的简称，由Va和Va(J)两种表型组成。与Va表型相关的突变是TRPML3预测的第五跨膜结构域（TM5）内419 （A419P）位置的丙氨酸到脯氨酸的替代。第二种Va(J)小鼠表型自发产生于362 （I362T）位置异亮氨酸到苏氨酸的替换，该位置靠近预测的TM3结构域，此外还有TM5上现有的A419P突变。携带Va和Va(J)突变的小鼠表现出一系列疾病表型，从毛色稀释到听觉和前庭问题，这取决于存在哪些等位基因。这些TRPML3突变的发现已经有5年多了，直到最近，这些突变的性质才被描述出来。在这篇综述中，我们讨论了两种不同的TRPML3突变的分子和细胞生理效应。我们揭示了脯氨酸取代对跨膜结构域结构和通道功能的影响，并讨论了Va突变如何赋予其细胞毒性，而Va(J)突变导致明显的拯救表型。最后，我们简要地讨论了用于中和Va突变的细胞毒性作用和组成通道活性的分子策略。
The transient receptor potential mucolipins (TRPMLs) are the most recently discovered subfamily of TRP ion channel proteins. Positional cloning approach has identified two mutations in the TRPML3 (Mcoln3) gene that cause the varitint-waddler mouse phenotypes. Short for variable tint (diluted coat color), the varitint-waddler consists two phenotypes Va and Va(J). The mutation associated with the Va phenotype is an alanine to proline substitution at position 419 (A419P) within the predicted fifth transmembrane (TM5) domain of TRPML3. The second Va(J) mouse phenotype arose spontaneously from an isoleucine to threonine substitution at position 362 (I362T) that is proximal to the predicted TM3 domain in addition to the existing A419P mutation on TM5. Mice with the Va and Va(J) mutations exhibit a spectrum of disease phenotypes from diluted coat color to auditory and vestibular problems, depending on which alleles are present. It has been over 5 years since the discovery of these TRPML3 mutations, and it was just recently that the nature of these mutations has been characterized. In this review, we discuss the molecular and cell physiological effects of the two distinct TRPML3 mutations. We reveal the effects of proline substitution on transmembrane domain structure and channel function and discuss how the Va mutation confers its cytotoxicity, while the Va(J) mutation results in an apparent rescue phenotype. Finally, we briefly tackle molecular strategies that have been employed to neutralize the cytotoxic effect and constitutive channel activity of the Va mutation.