FIG4 – Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease (CMT) type 4J is an autosomal recessive sensorimotor neuropathy caused by biallelic mutations in the phosphoinositide phosphatase FIG4, a key regulator of PI(3,5)P2 homeostasis and endolysosomal trafficking. The gene–disease relationship is supported by multiple independent pedigrees and concordant functional studies demonstrating loss-of-function mechanisms and downstream cellular pathology.

Genetic evidence for FIG4 involvement in CMT4J includes the original identification of compound heterozygous FIG4(Ile41Thr/null) genotypes in four families, extended by 11 unrelated probands with biallelic FIG4 variants (PMID:21705420) and a consanguineous kindred of three siblings homozygous for p.Ile41Thr presenting with spastic quadriplegia, epilepsy and global developmental delay (PMID:33080143). A single wheelchair-bound patient heterozygous for p.Ile41Thr and an intronic splice-site mutation at IVS17-10 further confirms recessive inheritance (PMID:28859335).

The variant spectrum encompasses missense (e.g., c.122T>C (p.Ile41Thr)), nonsense, frameshift, and splice-site mutations, with the p.Ile41Thr allele occurring at a population frequency of ~0.001 in Northern European controls (PMID:21705420). These variants lead to reduced FIG4 protein stability or complete loss of function in peripheral nerves.

Functional and experimental studies demonstrate pathogenicity via endolysosomal dysfunction: patient fibroblasts show severe FIG4 deficiency, enlarged vesicular vacuoles and TRPV4 accumulation at the plasma membrane, leading to cell death rescued by TRPV4 inhibition (PMID:28859335). Yeast two-hybrid assays reveal impaired FIG4–VAC14 interaction for the I41T allele, and transgenic mice expressing FIG4-I41T on a Fig4 null background show dose-dependent rescue of lethality and neuropathology (PMID:21655088).

Mechanistically, FIG4-I41T is a hypomorphic allele causing protein instability and disruption of PI(3,5)P2 synthesis, resulting in demyelination, axonal loss and variable clinical severity. The combination of genetic segregation in families, robust functional assays and animal models provides definitive evidence for FIG4–CMT4J causality.

Key Take-home: Biallelic FIG4 loss-of-function variants cause a definitive autosomal recessive form of CMT, with clear implications for genetic testing, diagnosis and potential therapeutic targeting of endolysosomal pathways.

References

• Brain • 2011 • Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P₂ phosphatase FIG4 PMID:21705420
• Journal of neuropathology and experimental neurology • 2017 • A New Mutation in FIG4 Causes a Severe Form of CMT4J Involving TRPV4 in the Pathogenic Cascade PMID:28859335
• The International Journal of Neuroscience • 2022 • Charcot-Marie-Tooth disease type 4J with spastic quadriplegia, epilepsy and global developmental delay: a tale of three siblings PMID:33080143
• PLoS genetics • 2011 • Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J PMID:21655088

Evidence Based Scoring (AI generated)