Alternative titles; symbols
HGNC Approved Gene Symbol: FIG4
SNOMEDCT: 720638000;
Cytogenetic location: 6q21 Genomic coordinates (GRCh38): 6:109,691,296-109,825,426 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q21 | ?Polymicrogyria, bilateral temporooccipital | 612691 | Autosomal recessive | 3 |
| Amyotrophic lateral sclerosis 11 | 612577 | Autosomal dominant | 3 | |
| Charcot-Marie-Tooth disease, type 4J | 611228 | Autosomal recessive | 3 | |
| Yunis-Varon syndrome | 216340 | Autosomal recessive | 3 |
The content of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) in endosomal membranes changes dynamically with fission and fusion events that generate or absorb intracellular transport vesicles. FIG4 is a PtdIns(3,5)P2 5-phosphatase that functions in a trimolecular complex that tightly regulates the level of PtdIns(3,5)P2. Other components of this complex are the PtdIns(3,5)P2-synthesizing enzyme PIKFYVE (609414) and its activator, VAC14 (604632) (Sbrissa et al., 2007).
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1996) cloned full-length FIG4, which they called KIAA0274. The deduced protein contains 907 amino acids. Northern blot analysis detected expression in all tissues examined, with highest expression in testis.
Sbrissa et al. (2007) stated that the full-length 907-amino acid SAC3 protein contains an N-terminal SAC phosphatase domain of about 400 amino acids. SAC3 also has multiple sites for serine/threonine and tyrosine phosphorylation and numerous motifs for interaction with intracellular transport and sorting molecules. Western blot analysis of HEK293 human embryonic kidney cells and other mammalian cell lines detected SAC3 at an apparent molecular mass of 97 kD. The presence of a broad band suggested posttranslational modification of the protein. Fractionation of HEK293 cells showed that SAC3 associated with both cytosol and membranes.
Chow et al. (2007) determined that the human FIG4 gene comprises 23 coding exons.
By radiation hybrid analysis, Nagase et al. (1996) mapped the KIAA0274 gene to chromosome 6. Chow et al. (2007) localized the gene to chromosome 6q21.
Using coimmunoprecipitation analysis, Sbrissa et al. (2007) showed that endogenous SAC3, PIKFYVE, and ARPIKFYVE (VAC14) formed a stable ternary complex in HEK293 cells and other mammalian cell lines. Immunoprecipitated epitope-tagged SAC3 hydrolyzed the D5 phosphate from PtdIns(4,5)P2, PtdIns(3,5)P2, and PtdIns(3,4,5)P3, but it did not use PtdIns(5)P or other PtdIns substrates. Mutation analysis showed that asp488 was required for SAC3 phosphatase activity. Overexpression of SAC3 in HEK293 cells did not produce an obvious morphologic phenotype, but it rendered cells prone to developing dilated intracellular membranes, consistent with perturbation of membrane PtdIns(3,5)P2 levels. In contrast, depletion of SAC3 via small interfering RNA enhanced endosome carrier vesicles/multivesicular body formation.
Lenk and Meisler (2022) used CRISPR editing to generate FIG4 -/- 3D4 cells and treated the cells with chloroquine, a drug that is known to reduce lysosomal acidity. Treatment with chloroquine corrected the abnormal appearance of abnormal lysosomes that were seen in the untreated mutant cells.
Charcot-Marie-Tooth Disease 4J, Autosomal Recessive
In 4 unrelated patients with autosomal recessive Charcot-Marie-Tooth disease type 4J (CMT4J; 611228), Chow et al. (2007) identified compound heterozygous mutations in the FIG4 gene (609390.0001-609390.0005).
In 3 unrelated patients of Australian descent with CMT4J, Nicholson et al. (2011) identified compound heterozygosity for the ancestral I41T FIG4 mutation and 1 of 3 different truncating mutations. Direct screening of the FIG4 gene was performed in these patients based on the early-onset severe phenotype. The mutations segregated with the disorder in all families. Sequencing the FIG4 gene in 4,000 DNA samples submitted for a CMT gene panel identified 8 (0.2%) patients carrying compound heterozygous mutations (see, e.g., 609390.0013 and 609390.0014). Seven of these patients carried the I41T allele in combination with a null allele.
Amyotrophic Lateral Sclerosis 11
In 5 unrelated patients with amyotrophic lateral sclerosis (ALS11; 612577), Chow et al. (2009) identified heterozygosity for a missense, 2 splice site, and 2 truncating mutations in the FIG4 gene (see, e.g., 609390.0006-609390.0008). The mutations were shown to result in complete or significant loss of protein function. Five different missense FIG4 mutations were identified in 5 patients with a diagnosis of ALS or adult-onset primary lateral sclerosis (PLSA1; 611637), but these mutations were not clearly shown to be pathogenic.
Yunis-Varon Syndrome
In 5 patients from 3 unrelated families with Yunis-Varon syndrome (YVS; 216340), Campeau et al. (2013) identified homozygous or compound heterozygous mutations in the FIG4 gene (609390.0009-609390.0012). The phenotype was severe, characterized by cleidocranial dysplasia, digital anomalies, hypotonia, dysmorphic facial features, and severe neurologic involvement, all apparent from birth. Most patients died in infancy. Tissue samples showed enlarged cytoplasmic vacuoles. All the mutations, which were found by exome sequencing, resulted in complete loss of protein function, which Campeau et al. (2013) suggested resulted in a more severe phenotype than that observed in CMT4J; the latter disorder is associated with at least 1 missense hypomorphic mutation in the FIG4 gene. The report demonstrated that absence of FIG4 activity leads to central nervous system dysfunction and extensive skeletal anomalies, which suggested a role for PI(3,5)P2 signaling in skeletal development and maintenance.
Bilateral Temporooccipital Polymicrogyria
In affected members of a consanguineous Moroccan family with bilateral temporooccipital polymicrogyria (BTOP; 612691), Baulac et al. (2014) identified a homozygous missense mutation in the FIG4 gene (D783V; 609390.0016). The mutation was found by whole-exome sequencing.
The phenotype of the 'pale tremor' (plt) mouse, identified by Chow et al. (2007), is characterized by a multi-organ disorder with neuronal degeneration in the central nervous system, peripheral neuronopathy, and diluted pigmentation. Positional cloning identified insertion of ETn2-beta (early transposon 2-beta) into intron 18 of the mouse Fig4 gene, the homolog of a yeast suppressor of actin (SAC) domain phosphatidylinositol(3,5)P(2)5-phosphatase located in the vacuolar membrane. The abnormal concentration of phosphatidylinositol-3,5-bisphosphate in cultured fibroblasts from pale tremor mice demonstrated the conserved biochemical function of mammalian Fig4. The cytoplasm of fibroblasts from pale tremor mice was filled with large vacuoles that were immunoreactive for Lamp2 (309060), consistent with dysfunction of the late endosome-lysosome axis. Neonatal neurodegeneration in sensory and autonomic ganglia was followed by loss of neurons from layers 4 and 5 of the cortex, deep cerebellar nuclei, and other localized brain regions. The sciatic nerve exhibited reduced numbers of large-diameter myelinated axons, slowed nerve conduction velocity, and reduced amplitude of compound muscle action potentials. Zhang et al. (2008) found a profound loss of large motor neurons in the anterior horns of the spinal cord of plt mice. Remaining neurons contained large vacuoles that did not stain for ubiquitin or neurofilaments. There was no evidence of apoptosis of neurons or Schwann cells in plt mice, but there was a loss of large-diameter motor axons as well as evidence of segmental demyelination.
Mutations affecting the conversion of PI3P to the signaling lipid PI(3,5)P2 result in spongiform degeneration of mouse brain and are associated with the human disorders Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis (ALS). Ferguson et al. (2009) reported accumulation of the proteins Lc3II (MAP1LC3A; 601242), p62 (SQSTM1; 601530), and Lamp2 in neurons and astrocytes of mice with mutations in 2 components of the PI(3,5)P2 regulatory complex, Fig4 and Vac14 (604632). Cytoplasmic inclusion bodies containing p62 and ubiquitinated proteins were present in regions of the mutant brain that underwent degeneration. Colocalization of p62 and LAMP2 in affected cells indicated that formation or recycling of the autolysosome may be impaired. The authors proposed a role for PI(3,5)P2 in autophagy in the mammalian central nervous system and demonstrated that mutations affecting PI(3,5)P2 may contribute to inclusion body disease.
In patient fibroblasts, cell culture, and transgenic mice, Lenk et al. (2011) demonstrated that the I41T mutant protein (609390.0001) is unstable, resulting in low levels of FIG4. Low levels of the protein resulted from impaired interaction with VAC14, which stabilizes FIG4. Overexpression of mutant I41T in Fig4-null mice to 10% of wildtype levels rescued the severe neurodegenerative phenotype, whereas lesser overexpression (2-fold) resulted in partial rescue and a CMT-like phenotype. The abundance of the I41T protein in cultured cells could be increased by treatment with a proteasome inhibitor. The findings indicated that I41T is a hypomorphic allele and suggested that increasing expression of the I41T mutant allele in CMT4J patients with the mutation may be therapeutic.
Winters et al. (2011) found that Fig4 -/- mice had a pronounced reduction of myelin in central nerve system (CNS). Examination of Fig4 -/- optic nerve revealed that, in spite of a normal number of axons, loss of Fig4 caused severe dysmyelination due to developmental failure to myelinate small and intermediate size axons. Fig4 -/- optic nerve also had disorganized nodes of Ranvier and paranodes, with an increased number of slow conducting axons. Loss of Fig4 resulted in a decreased number of myelinating oligodendrocytes throughout the CNS due to arrest of oligodendrocyte precursor cell maturation. Neuron-specific expression of wildtype mouse Fig4 rescued the optic nerve dysmyelination phenotype of Fig4 -/- mice, demonstrating that oligodendrocyte precursor cell maturation and myelin development in Fig4 -/- mice were secondary to neuronal defects and that Fig4 had a non-cell-autonomous function in oligodendrocyte development. Global overexpression of the human FIG4 I41T variant, which retains low-level function, rescued Fig4 -/- mice from the myelination defect and early lethality.
In mouse tissue, Campeau et al. (2013) found that Fig4 expression in calvaria, osteoblasts, and bone marrow cells was comparable to its expression in brain. Fig4-null mice showed a smaller skeleton than wildtype mice at day P21, with smaller long bones, clavicles, and pelvic bones. Although the shapes of the bones were similar to wildtype, Fig4-null mouse bones had significantly lower (50%) trabecular and cortical density, bone volume fraction, bone surface, trabecular number, and connectivity density, consistent with abnormal ossification. Cultures of isolated osteoblasts from calvarial tissue showed extensive vacuolization. Fig4-null mice did not exhibit aplasia or hypoplasia of digits on the front or rear limbs.
Baulac et al. (2014) found that the brains of postnatal Fig4-null mice were macroscopically normal, but there was a transient increase in neuronal density associated with apoptosis. There was also delayed maturation of interneurons and dentate granule cells and their processes in various brain regions. The findings indicated postmigration abnormalities in the brains of Fig4-null mice.
Mironova et al. (2018) found that neonatal knockout of Fig4 in mice recapitulated the neurologic defects of constitutive Fig4 -/- mice, including regional spongiform degeneration, CNS hypomyelination, and accumulation of vacuoles in oligodendrocytes. Induced deletion of Fig4 in adult mice recapitulated the lethal disorder of constitutive Fig4 -/- mice with a similar time course. However, adult mice with induced Fig4 deletion displayed normal abundance of CNS myelin proteins, normal structural integrity of myelin sheaths in optic nerve cross sections, and normal electrophysiologic properties. Adult mice with induced Fig4 deletion were defective in axon remyelination and timely repair of damaged white matter. Histologic examination revealed severe Wallerian degeneration of sciatic nerve, but not C-fiber axons in Remak bundles, in mice with induced Fig4 deletion.
Lenk and Meisler (2022) treated Fig4 -/- mice with chloroquine, a drug that is known to reduce lysosomal acidity. The treated Fig4 -/- mice were larger compared to untreated Fig4 -/- mice, and at 30 days of age, the treated mutant mice had improved mobility and other behaviors (running, rearing, grooming) compared to untreated mutant mice. The treated mutant mice survived about 4 weeks longer than the untreated mutant mice. Brain tissue from treated mutant mice had decreased vacuolization compared to untreated mutant mice.
In 4 unrelated patients with severe early-onset autosomal recessive Charcot-Marie-Tooth disease (CMT4J; 611228), Chow et al. (2007) found the same mutation in the FIG4 gene, a T-to-C transition at nucleotide 122 resulting in an ile-to-thr substitution at codon 41 (I41T). The mutation occurred in compound heterozygosity in each patient with 1 of 4 other FIG4 mutations (609390.0002-609390.0005). The 4 patients carried I41T on the same 15-kb haplotype, defined by 3 single-nucleotide polymorphisms (SNPs), consistent with inheritance of a common ancestral mutant allele. The isoleucine at codon 41 is invariant from human to yeast.
In patient fibroblasts, cell culture, and transgenic mice, Lenk et al. (2011) demonstrated that the I41T mutant protein is unstable, resulting in low levels of FIG4. Low levels of the protein resulted from impaired interaction with VAC14 (604362), which stabilizes FIG4. Overexpression of mutant I41T in Fig4-null mice to 10% of wildtype levels rescued the neurodegenerative phenotype. The abundance of the I41T protein in cultured cells could be increased by treatment with a proteasome inhibitor. The findings indicated that I41T is a hypomorphic allele and suggested that increasing expression of the I41T mutant allele in patients with the mutation may be therapeutic.
Nicholson et al. (2011) found that the allele frequency of I41T is 0.001 (13 heterozygotes among 5,769 Northern European controls).
In a patient with Charcot-Marie-Tooth disease type 4J (CMT4J; 611228), Chow et al. (2007) identified a single-basepair deletion, of thymidine, at nucleotide 294 of the FIG4 gene, resulting in frameshift and premature termination of the protein (Phe98fsTer102). The patient was compound heterozygous for the I41T allele (609390.0001).
In a patient and her sib with Charcot-Marie-Tooth disease type 4J (CMT4J; 611228), Chow et al. (2007) found compound heterozygosity for a C-to-T transition at nucleotide 718 of the FIG4 gene, resulting in an arg-to-ter substitution at codon 183 (R183X), and the I41T mutation (609390.0001). Both sibs had severe disease. The proband was a functional quadriplegic, and her sib was wheelchair-bound with normal use of his arms. Both had slow nerve conduction velocities. A sural nerve biopsy from the proband demonstrated profound axonal loss, thinly myelinated nerve fibers, and evidence of de- and remyelination.
In a patient with Charcot-Marie-Tooth disease type 4J (CMT4J; 611228), Chow et al. (2007) found compound heterozygosity for the I41T mutation in FIG4 (609390.0001) and an 8-basepair deletion, of ATCAGGCA, starting at nucleotide position 1043 (Asp348fsTer359).
In a patient with Charcot-Marie-Tooth disease type 4J (CMT4J; 611228), Chow et al. (2007) found a single-basepair deletion of a guanine at position 759 of the FIG4 gene, resulting in a frameshift and early termination (Gly253fsTer261). The patient carried this mutation in compound heterozygosity with the I41T mutation (609390.0001).
In a man with probable amyotrophic lateral sclerosis (ALS11; 612577), Chow et al. (2009) identified a heterozygous 547C-T transition in exon 6 of the FIG4 gene, resulting in an arg183-to-ter (R183X) substitution, predicted to result in loss of phosphatase activity. He had onset at age 62 and presented with bulbar signs. He had prominent cortical spinal tract findings and moderate lower motor neuron findings. EMG showed mild denervation of 3 extremities.
In a woman with amyotrophic lateral sclerosis (ALS11; 612577), Chow et al. (2009) identified a heterozygous G-to-T transversion in intron 11 (1386+5G-T) of the FIG4 gene, predicted to result in the skipping of exon 12 or premature termination. She had onset at age 57 and presented with involvement of the upper extremity. She had both upper and lower motor neuron signs and acute and chronic denervation on EMG.
In a woman with amyotrophic lateral sclerosis (ALS11; 612577), Chow et al. (2009) identified a heterozygous 157G-T transversion in exon 2 of the FIG4 gene, resulting in an asp53-to-tyr (D53Y) substitution. In vitro functional expression studies in yeast showed that the mutant protein had significantly less activity compared to wildtype. The patient presented at age 56 with bulbar signs. She had moderate corticospinal findings, and autopsy showed lower motor neuron loss.
In 2 sibs, born of consanguineous Mexican parents, with Yunis-Varon syndrome (YVS; 216340), who had been reported by Corona-Rivera et al. (2011), Campeau et al. (2013) identified a homozygous 2-bp deletion (c.1260_1261delGT) in exon 11 of the FIG4 gene, resulting in a frameshift and premature termination (Thr422GlnfsTer6) predicted to cause protein truncation upstream of the phosphatase catalytic motif and complete loss of function. Each unaffected parent was heterozygous for the mutation, which was found by exome sequencing.
In 2 sibs, born of unrelated English parents, with Yunis-Varon syndrome (YVS; 216340), who had been reported by Garrett et al. (1990), Campeau et al. (2013) identified compound heterozygous mutations in the FIG4 gene: a c.311G-A transition in exon 4, resulting in a gly104-to-asp (G104D) substitution at a highly conserved residue located at the beginning of beta-sheet 7 in the noncatalytic, protein-binding domain of FIG4, and an 8-bp deletion (c.831_838delTAAATTTG; 609390.0011) in exon 8, resulting in a frameshift and premature termination (Lys278TrpfsTer6). Each unaffected parent carried 1 of the mutations, which were found by exome sequencing. Transfection of the G104D mutation in cultured fibroblasts from the Fig4-null mouse failed to correct cytoplasmic vacuolization, consistent with complete loss of function.
For discussion of the 8-bp deletion in the FIG4 gene (c.831_838delTAAATTTG) that was found in compound heterozygous state in patients with Yunis-Varon syndrome (YVS; 216340) by Campeau et al. (2013), see 609390.0010.
In an Italian girl, born of unrelated parents, with Yunis-Varon syndrome (YVS; 216340), who had been described by Dworzak et al. (1995), Campeau et al. (2013) identified a homozygous c.524T-C transition in exon 6 of the FIG4 gene, resulting in a leu175-to-pro (L175P) substitution at a highly conserved residue in alpha-helix 2 of a noncatalytic, protein-binding domain of FIG4. Each unaffected parent was heterozygous for the mutation, which was found by exome sequencing. Transfection of the mutation in cultured fibroblasts from the Fig4-null mouse failed to correct cytoplasmic vacuolization, consistent with complete loss of function.
In a patient with Charcot-Marie-Tooth disease type 4J (CMT4J; 611228), Nicholson et al. (2011) identified compound heterozygous mutations in the FIG4 gene: leu17-to-pro (L17P) and a null allele (Phe254SerfsTer7). The L17P substitution occurs at a conserved residue and was predicted to alter the conformation of the protein and affect interaction with other proteins, similar to I41T (609390.0001). The patient was ascertained from a large cohort of 4,000 CMT patients who were screened for FIG4 mutations; clinical information on this patient was not available.
In a woman with adult-onset Charcot-Marie-Tooth disease type 4J (CMT4J; 611228), Nicholson et al. (2011) identified compound heterozygous mutations in the FIG4 gene: a glu302-to-lys (E302K) substitution at a highly conserved residue at the interface between the catalytic domain and the N-terminal protein interaction domain, and the common ancestral allele (I41T; 609390.0001). Residue E302 is important for protein stabilization. The E302K mutant was unable to rescue vacuole enlargement in Fig4-null yeast, indicating that it is a functionally null allele.
In a 13-year-old girl, born of unrelated Caucasian parents, with Charcot-Marie-Tooth disease type 4J (CMT4J; 611228), Menezes et al. (2014) identified compound heterozygous mutations in the FIG4 gene: an A-to-T transversion (c.290-2A-T) in a spite site consensus sequence that was predicted to prevent normal splicing of exon 4 (Phe98fsTer38), and the recurrent I41T mutation (609390.0001). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were filtered against the 1000 Genomes Project and Exome Sequencing Project databases and an in-house database of 25,991 reference exomes. Each parent was heterozygous for 1 of the mutations. In addition, the mildly affected mother carried an exonic deletion in the FIG4 gene on the other other allele. The proband, who was severely affected, was found to carry a de novo heterozygous nonsense mutation (R1844X) in the DMD gene (300377), which may have contributed to the phenotype.
In affected members of a consanguineous Moroccan family with bilateral temporooccipital polymicrogyria (BTOP; 612691) previously reported by Ouled Amar Ben Cheikh et al. (2009), Baulac et al. (2014) identified a homozygous c.2348A-T transversion in the FIG4 gene, resulting in an asp784-to-val (D783V) substitution at a highly conserved residue in the C terminus. The mutation, which was found using a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family and was not present in the dbSNP (build 135), 1000 Genomes Project, or Exome Variant Server databases or in 750 in-house controls. The patients had onset of seizures mainly in childhood and most had psychiatric disturbances. Expression of the D783V mutation in Fig4-null cells was unable to rescue the abnormal vacuolization phenotype as well as wildtype FIG4, suggesting that the mutation caused a partial loss of function. Examination of Fig4-null mice showed postmigration abnormalities in several brain regions, consistent with mechanisms underlying polymicrogyria in humans.
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