Fig4 deficiency: A newly emerged lysosomal storage disorder?

Abstract

FIG4 (Sac3 in mammals) is a 5’-phosphoinositide phosphatase that coordinates the turnover of phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2), a very low abundance phosphoinositide. Deficiency of FIG4 severely affects the human and mouse nervous systems by causing two distinct forms of abnormal lysosomal storage. The first form occurs in spinal sensory neurons, where vacuolated endolysosomes accumulate in perinuclear regions. A second form occurs in cortical/spinal motor neurons and glia, in which enlarged endolysosomes become filled with electron dense materials in a manner indistinguishable from other lysosomal storage disorders. Humans with a deficiency of FIG4 (known as Charcot-Marie-Tooth disease type 4J or CMT4J) present with clinical and pathophysiological phenotypes indicative of spinal motor neuron degeneration and segmental demyelination. These findings reveal a signaling pathway involving FIG4 that appears to be important for lysosomal function. In this review, we discuss the biology of FIG4 and describe how the deficiency of FIG4 results in lysosomal phenotypes. We also discuss the implications of FIG4/PI(3,5)P2 signaling in understanding other lysosomal storage diseases, neuropathies, and acquired demyelinating diseases.

Myelin abnormality in Charcot–Marie–Tooth type 4J recapitulates features of acquired demyelination

“…I41T mutation has been shown to destabilize FIG4 leading to a rapid degradation of FIG4 by proteasomes in vitro studies 29 . I41T mutation has been hypothesized to produce some functional FIG4 proteins that would moderate the disease 30 . This hypothesis was tested here; the FIG4 level in this case was comparable to other cases in the group with teenage onset.…”

“…First, CNS phenotypes in a subset of patients with CMT4J are suspected to relate to more severe depletion of FIG4 30 . However, patients with early onset and severe CNS abnormalities (#4 and #5) had levels of FIG4 similar to those patients with teenage onset (Figure 2).…”

Novel FIG4 mutations in Yunis–Varon syndrome

“…2 FIG4 encodes FIG4 protein (also known as SAC3) which is a 5 0 -phosphoinositide phosphatase essential for endosome/lysosome function. 3 FIG4 binds with Vac14/ArPIKfyve and Fab1/PIKfyve to form a functional complex on early endosomal membranes known as PIKfyve-ArPIKfyve-Sac3 complex. 3 The PIKfyve-ArPIKfyve-Sac3 complex mediates the conversion of endosomal phosphatidylinositol 3-phosphate (PI3P) to phosphatidylinositol 3,5-biphosphate (PI(3,5)P 2 ), and this conversion is essential for protein sorting, trafficking late endosomes to lysosomal degradation compartment and regulating some other endolysosome/lysosome functions essential for degradation such as ion channel activation and endolysosome fusion/fission.…”

“…Therefore, the accumulation of undegraded materials in these compartments leads to dilatation. 3 FIG4 abnormalities were previously reported to be the causative for autosomal recessive Charcot-Marie-Tooth disease type 4J (CMT4J, MIM#611228) and autosomal dominant amyotrophic lateral sclerosis (ALS, MIM#105400)/primary lateral sclerosis (PLS, MIM#611637). 2,5-7 Vacuolated endolysosomes are found in the perinuclear regions of peripheral neurons of Fig4-null mice and CMT4J patients.…”

“…2,5-7 Vacuolated endolysosomes are found in the perinuclear regions of peripheral neurons of Fig4-null mice and CMT4J patients. 3 In YVS patients, vacuolation was observed in skeletal muscles, fibroblasts and the central nervous system including cerebral cortex, the basal ganglia, cerebellar olives and medullary olives. [8][9][10] The patient was a 2-year-old girl at the time of genetic consultation.…”