FIG4 – Amyotrophic Lateral Sclerosis

Heterozygous variants in FIG4, encoding a phosphoinositide 5-phosphatase, have been implicated in autosomal dominant amyotrophic lateral sclerosis (ALS) (PMID:19118816). FIG4 regulates PI(3,5)P₂ homeostasis in endolysosomal trafficking, a pathway critical for motor neuron integrity. Initial studies reported nonsynonymous FIG4 variants in 9 of 473 ALS/PLS patients (PMID:19118816), expanding the gene’s disease spectrum beyond Charcot–Marie–Tooth type 4J. Subsequent targeted sequencing in a German family demonstrated segregation of a frameshift allele c.759del (p.Phe254fs) in 2 affected relatives and identified FIG4 variants in 6 of 200 sporadic cases, yielding a 3% cohort frequency (PMID:28051077). A single‐patient case report described a novel frameshift c.350dup (p.Asp118GlyfsTer9) in a rapidly progressive ALS presentation (PMID:36090855). More recently, two heterozygous FIG4 patients were identified in a Han Chinese sporadic ALS cohort, including the truncating variant c.2158G>T (p.Glu720Ter) associated with slow disease progression (PMID:35021275).

Segregation of FIG4 variants with disease has been demonstrated in one multigenerational family, supporting autosomal dominant inheritance with incomplete penetrance (PMID:28051077). The variant spectrum in ALS encompasses missense, frameshift, and nonsense changes, with recurrent hypomorphic alleles also implicated in peripheral neuropathy. Functional assays show that loss‐of‐function FIG4 alleles disrupt PI(3,5)P₂-mediated lysosomal fission, leading to vacuolation in patient fibroblasts and neurons (PMID:25926456). Pharmacologic activation of the TRPML1 channel rescues vacuole accumulation, underscoring a pathogenic mechanism of impaired lysosomal Ca²⁺ efflux. In vivo, neuronal expression of catalytically inactive FIG4(Cys486Ser) rescues early lethality in Fig4 null mice but yields late‐onset neurodegeneration, confirming a dose‐sensitive role of FIG4 phosphatase activity (PMID:26604144).

Studies of CMT4J‐associated FIG4‐Ile41Thr reveal impaired interaction with the VAC14 scaffold and reduced protein stability, reinforcing a common haploinsufficiency model across motor neuron and peripheral neuropathies (PMID:21655088). Concordant experimental evidence across cell and animal models validates FIG4 pathogenicity in motor neuron degeneration. Although additional evidence exists for modifier genes and alternative phenotypes, the current data meet ClinGen criteria for a Moderate gene–disease association.

Key Take-home: FIG4 haploinsufficiency contributes to autosomal dominant ALS via disrupted endolysosomal PI(3,5)P₂ metabolism; screening FIG4 variants can inform diagnosis and potential targeting of lysosomal Ca²⁺ pathways.

References

• American Journal of Human Genetics • 2009 • Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS. PMID:19118816
• European Journal of Human Genetics • 2017 • FIG4 variants in central European patients with amyotrophic lateral sclerosis: a whole-exome and targeted sequencing study. PMID:28051077
• Frontiers in Neurology • 2022 • Case report: A variant of the FIG4 gene with rapidly progressive amyotrophic lateral sclerosis. PMID:36090855
• The Journal of Neuroscience • 2015 • Reactivation of Lysosomal Ca2+ Efflux Rescues Abnormal Lysosomal Storage in FIG4-Deficient Cells. PMID:25926456
• PLoS Genetics • 2011 • Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J. PMID:21655088
• Human Molecular Genetics • 2016 • Rescue of neurodegeneration in the Fig4 null mouse by a catalytically inactive FIG4 transgene. PMID:26604144
• Journal of Clinical Neurology • 2022 • Novel Variants in the FIG4 Gene Associated With Chinese Sporadic Amyotrophic Lateral Sclerosis With Slow Progression. PMID:35021275

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