Bharadwaj R, Cunningham KM, Zhang K, Lloyd TE. FIG4 regulates lysosome membrane homeostasis independent of phosphatase function. Hum Mol Genet. 2015 Dec 11. pii: ddv505. PMID: 26662798.
From the abstract: "FIG4 is a phosphoinositide phosphatase that is mutated in several
diseases including Charcot-Marie-Tooth Disease 4J (CMT4J) and
Yunis-Varon syndrome (YVS). To investigate the mechanism of disease
pathogenesis, we generated Drosophila models of FIG4-related diseases.
Fig4 null mutant animals are viable but exhibit marked enlargement of
the lysosomal compartment in muscle cells and neurons, accompanied by an
age-related decline in flight ability. Transgenic animals expressing
Drosophila Fig4 missense mutations corresponding to human pathogenic
mutations can partially rescue lysosomal expansion phenotypes,
consistent with these mutations causing decreased FIG4 function.
Interestingly, Fig4 mutations predicted to inactivate FIG4 phosphatase
activity rescue lysosome expansion phenotypes, and mutations in the
phosphoinositide (3) phosphate kinase Fab1 that performs the reverse
enzymatic reaction also causes a lysosome expansion phenotype. ... These data show that FIG4 plays a critical
noncatalytic function in maintaining lysosomal membrane homeostasis, and
that this function is disrupted by mutations that cause CMT4J and YVS."