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Updated: Aug 13, 2025
Radiolabeling and Quantification of Cellular Levels of Phosphoinositides by High Performance Liquid Chromatography-coupled Flow Scintillation
Published on: January 6, 2016
Altered phenotypes due to genetic interaction between the mouse phosphoinositide biosynthesis genes Fig4 and Pip4k2c
Xu Cao1, Guy M Lenk1, Miriam H Meisler1
1Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA.
Abstract:
Loss-of-function mutations of FIG4 are responsible for neurological disorders in human and mouse that result from reduced abundance of the signaling lipid PI(3,5)P2. In contrast, loss-of-function mutations of the phosphoinositide kinase PIP4K2C result in elevated abundance of PI(3,5)P2. These opposing effects on PI(3,5)P2 suggested that we might be able to compensate for deficiency of FIG4 by reducing expression of PIP4K2C. To test this hypothesis in a whole animal model, we generated triallelic mice with genotype Fig 4-/-, Pip4k2c+/-; these mice are null for Fig 4 and haploinsufficient for Pip4k2c. The neonatal lethality of Fig 4 null mice in the C57BL/6J strain background was rescued by reduced expression of Pip4k2c. The lysosome enlargement characteristic of Fig 4 null cells was also reduced by heterozygous loss of Pip4k2c. The data demonstrate interaction between these two genes, and suggest that inhibition of the kinase PIPK4C2 could be a target for treatment of FIG4 deficiency disorders such as Charcot-Marie-Tooth Type 4J and Yunis-Varón Syndrome.
Insights
Reducing PIP4K2C expression rescues neonatal lethality in mice with FIG4 deficiency, a genetic cause of neurological disorders. This suggests targeting PIP4K2C kinase may treat FIG4-related diseases.
Area of Science:
- Genetics
- Cell Biology
- Neuroscience
Background:
- Loss-of-function mutations in FIG4 cause neurological disorders due to decreased PI(3,5)P2 levels.
- Conversely, loss-of-function mutations in PIP4K2C lead to increased PI(3,5)P2 abundance.
Purpose of the Study:
- To investigate if reducing PIP4K2C expression can rescue the effects of FIG4 deficiency.
- To explore the therapeutic potential of targeting PIP4K2C for FIG4 deficiency disorders.
Main Methods:
- Generation of triallelic mice (Fig4-/-, Pip4k2c+/-) to model combined FIG4 deficiency and partial PIP4K2C haploinsufficiency.
- Assessment of neonatal lethality and lysosome morphology in the generated mouse models.
Main Results:
- Reduced expression of Pip4k2c rescued the neonatal lethality observed in Fig4 null mice.
- Heterozygous loss of Pip4k2c ameliorated lysosome enlargement in Fig4 null cells.
- Demonstrated a genetic interaction between FIG4 and PIP4K2C.
Conclusions:
- The genetic interaction between FIG4 and PIP4K2C provides a potential therapeutic strategy.
- Inhibition of PIP4K2C kinase may be a viable treatment for FIG4 deficiency disorders, including Charcot-Marie-Tooth Type 4J and Yunis-Varón Syndrome.
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