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Published on: August 15, 2019
The varitint-waddler mouse phenotypes and the TRPML3 ion channel mutation: cause and consequence
Math P Cuajungco1, Mohammad A Samie
1Department of Biological Science, California State University, Fullerton, CA 92831, USA. mcuajungco@fullerton.edu
Abstract:
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.
Insights
Two TRPML3 gene mutations cause distinct varitint-waddler mouse phenotypes. The Va mutation is cytotoxic, while the Va (J) mutation shows a rescue effect, impacting coat color and sensory functions.
Area of Science:
- Ion channel biology
- Genetics and molecular biology
- Mammalian physiology
Background:
- Transient Receptor Potential Mucolipins (TRPMLs) are a recently identified TRP ion channel subfamily.
- Two mutations in the TRPML3 (Mcoln3) gene, Va and Va (J), are linked to varitint-waddler mouse phenotypes, affecting coat color and sensory functions.
Purpose of the Study:
- To review the molecular and cell physiological effects of two distinct TRPML3 mutations.
- To elucidate the impact of proline substitution on transmembrane domain structure and TRPML3 channel function.
- To understand the cytotoxicity of the Va mutation and the rescue phenotype of the Va (J) mutation.
Main Methods:
- Positional cloning to identify TRPML3 gene mutations.
- Analysis of molecular and cell physiological effects of Va and Va (J) mutations.
- Characterization of proline substitution effects on transmembrane domain structure and channel function.
Main Results:
- The Va mutation involves an A419P substitution in the TM5 domain, leading to cytotoxicity.
- The Va (J) mutation combines A419P with an I362T substitution near TM3, resulting in an apparent rescue phenotype.
- Mice with these mutations display a range of phenotypes, including coat color dilution and auditory/vestibular deficits.
Conclusions:
- TRPML3 mutations significantly alter channel function and cellular physiology.
- The Va mutation's cytotoxicity and constitutive activity present therapeutic targets.
- Further research into molecular strategies may neutralize detrimental TRPML3 mutation effects.
