[7] The founding protein, containing this evolutionarily-conserved domain, has been the first gene product isolated in a screen for Suppressors of yeast ACtin mutations and therefore named Sac1.
[16][17] This unique physical association of two enzymes with opposing functions leads to activation of the phosphoinositide kinase PIKfyve and increases of PIKfyve-catalized PtdIns(3,5)P2 and PtdIns5P production.
Small interfering RNA-mediated knockdown of endogenous Sac3 by ~60%, resulting in a slight but significant elevation of PtdIns(3,5)P2 in 3T3L1 adipocytes, increases GLUT4 translocation and glucose uptake in response to insulin.
[20] Most CMT4J patients (15 out of the reported 16) are compound heterozygotes, i.e., the one FIG4 allele is null whereas the other encodes a mutant protein with threonine for isoleucine substitution at position 41.
[24][25] Clinically, the onset and severity of CMT4J symptoms vary markedly, suggesting an important role of genetic background in the individual course of disease.
[25] In two siblings, with severe peripheral motor deficits and moderate sensory symptoms, the disease had relatively little impact on the central nervous system.
[26] Phosphoinositide profiling in fibroblasts derived from the largest CMT4J cohort reported in USA thus far reveals decreased steady-state levels of both PtdIns(3,5)P2 and PtdIns5P.
This unexpected direction of the changes is a result of impaired activation of the PIKFYVE kinase under the condition of Sac3 protein deficiency and a failure of the PAS complex assembly.
[27] FIG4 mutations are also found (without proven causation) in patients with amyotrophic lateral sclerosis (ALS)[28] as well as in other spectrum of phenotypes such as Yunis-Varon syndrome, cortical malformation with seizures and psychiatric co-morbidities, and cerebral hypomyelination.