A New Mutation in FIG4 Causes a Severe Form of CMT4J Involving TRPV4 in the Pathogenic Cascade

Area of Science:

• Genetics
• Neuroscience
• Cell Biology

Background:

• Mutations in FIG4, a gene encoding a phosphoinositol(3,5) bisphosphate 5' phosphatase, are linked to recessive forms of Charcot-Marie-Tooth (CMT).
• FIG4 plays a crucial role in vesicular trafficking and fusion, processes vital for cellular function.

Observation:

• A novel intronic mutation in FIG4 was identified in a patient with severe CMT4J, characterized by demyelinating sensorimotor polyneuropathy.
• Patient fibroblasts exhibited diminished FIG4 levels, indicating loss-of-function, and displayed cellular abnormalities including vacuolation and dispersed vesicular organelles.

Findings:

• The patient was heterozygous for two FIG4 mutations: p.I41T and a novel intronic mutation (IVS17-10 T>G) predicted to cause splicing defects.
• FIG4 deficiency resulted in the accumulation of the transient receptor cation channel, TRPV4, at the plasma membrane due to impaired protein turnover.
• Knocking down FIG4 in motor neurons caused vacuolation and cell death, which was partially rescued by inhibiting TRPV4.

Implications:

• This research elucidates a novel pathogenic FIG4 mutation and its severe clinical manifestation in CMT4J.
• A functional interaction between FIG4 and TRPV4 is demonstrated, suggesting TRPV4 as a potential therapeutic target for FIG4-related neuropathies.
• Understanding FIG4's role in vesicular trafficking and protein turnover provides insights into the mechanisms underlying CMT and other neurodegenerative disorders.