Molecular Neurobiology

, Volume 56, Issue 12, pp 8656–8667 | Cite as

Severe Consequences of SAC3/FIG4 Phosphatase Deficiency to Phosphoinositides in Patients with Charcot-Marie-Tooth Disease Type-4J

  • Assia ShishevaEmail author
  • Diego Sbrissa
  • Bo Hu
  • Jun Li


Charcot-Marie-Tooth disease type-4J (CMT4J), an autosomal recessively inherited peripheral neuropathy characterized by neuronal degeneration, segmental demyelination, and limb muscle weakness, is caused by compound heterozygous mutations in the SAC3/FIG4 gene, resulting in SAC3/FIG4 protein deficiency. SAC3/FIG4 is a phosphatase that not only turns over PtdIns(3,5)P2 to PtdIns3P but also promotes PtdIns(3,5)P2 synthesis by activating the PIKFYVE kinase that also makes PtdIns5P. Whether CMT4J patients have alterations in PtdIns(3,5)P2, PtdIns5P or in other phosphoinositides (PIs), and if yes, in what direction these changes might be, has never been examined. We performed PI profiling in primary fibroblasts from a cohort of CMT4J patients. Subsequent to myo-[2-3H]inositol cell labeling to equilibrium, steady-state levels of PIs were quantified by HPLC under conditions concurrently detecting PtdIns5P, PtdIns(3,5)P2, and the other PIs. Immunoblotting verified SAC3/FIG4 depletion in CMT4J fibroblasts. Compared to normal human controls (n = 9), both PtdIns(3,5)P2 and PtdIns5P levels were significantly decreased in CMT4J fibroblasts (n = 13) by 36.4 ± 3.6% and 43.1 ± 4.4%, respectively (p < 0.0001). These reductions were independent of patients’ gender or disease onset. Although mean values for PtdIns3P in the CMT4J cohort remained unchanged, there were high variations in PtdIns3P among individual patients. Aberrant endolysosomal vacuoles, typically seen under PtdIns(3,5)P2 reduction, were apparent but not in fibroblasts from all patients. The subset of patients without aberrant vacuoles exhibited especially low PtdIns3P levels. Concomitant decreases in PtdIns5P and PtdIns(3,5)P2 and the link between PtdIns3P levels and cellular vacuolization are novel insights shedding further light into the molecular determinants in CMT4J polyneuropathy.


Charcot-Marie-Tooth type-4J polyneuropathy Demyelination Phosphoinositides PtdIns3P/PtdIns5P/PtdIns(3,5)P2 SAC3/FIG4 PIKFYVE PAS complex HPLC 



Charcot-Marie-Tooth disease type-4J






phosphoinositide kinase for position 5 containing a FYVE domain


associated regulator of PIKFYVE


factor-induced gene, phosphoinositide 5-phosphatase


Sac1 domain-containing phosphoinositide 5-phosphatase 3 (an alternative name of FIG4)

PAS complex



early endosome antigen A1


glycerophosphorylinositol phosphates


high-performance liquid chromatography



We thank Dr. Ognian C. Ikonomov for the helpful discussions. The first author expresses gratitude to the late Violeta Shisheva for her many years of support.

Author Contributions

DS performed the HPLC, phase-contrast microscopy for the vacuolation assays and prepared figures. BH performed the fibroblasts for the assays, phase-contrast microscopy for the vacuolation assays, the statistical analyses and prepared figures. AS and JL conceived and supervised the experiments. AS wrote the first draft of the manuscript. DS, BH, JL, and AS edited the final version. All authors read and approved the final manuscript.


This project was supported by the Department of Defense (W81XWH-17-1-0060), National Institute of Health (DK58058) (to AS), and Department of Veterans Affairs (IBX003385A) and NINDS (R01NS066927) (to JL).

Compliance with Ethical Standards

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Wayne State University Institutional Review Board (IRB) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2019_1693_MOESM1_ESM.pdf (193 kb)
ESM 1 (PDF 192 kb)


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Authors and Affiliations

  1. 1.Department of PhysiologyWayne State University School of MedicineDetroitUSA
  2. 2.Department of NeurologyWayne State University School of MedicineDetroitUSA
  3. 3.John D. Dingell VA Medical CenterDetroitUSA

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