Alternative titles; symbols
HGNC Approved Gene Symbol: FBP2
Cytogenetic location: 9q22.32 Genomic coordinates (GRCh38): 9:94,558,720-94,593,824 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q22.32 | ?Leukodystrophy, childhood-onset, remitting | 619864 | Autosomal dominant | 3 |
Fructose-1,6-bisphosphatase (fru-1,6-P2ase, EC 3.1.3.11) catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate and inorganic phosphate, thus providing a mechanism to permit the reversal of the glycolysis reaction catalyzed by 6-phosphofructo-1-kinase. See the entry for fructose-1,6-bisphosphatase 1 (FBP1; 611570), the human liver FBPase. Tillmann and Eschrich (1998) stated that human liver and muscle fru-1,6-P2ases appear to be distinct enzymes since they differ significantly in their kinetic properties, and no reduction of fru-1,6-P2ase activity was found in muscle in patients with hereditary liver fru-1,6-P2ase deficiency (229700).
By RT-PCR of skeletal muscle RNA with primers based on conserved regions of fru-1,6-P2ases, Tillmann and Eschrich (1998) isolated a partial cDNA encoding a novel fru-1,6-P2ase. Using a PCR strategy, they recovered additional cDNAs which together corresponded to the entire coding region of the gene. The predicted 339-amino acid muscle fru-1,6-P2ase shares 77% protein sequence identity with the liver enzyme. Recombinant enzyme had fru-1,6-P2ase activity in vitro.
Gross (2022) mapped the FBP2 gene to chromosome 9q22.32 based on an alignment of the FBP2 sequence (GenBank BC117477) with the genomic sequence (GRCh38).
In 8 members of a 3-generation family with childhood-onset remitting leukodystrophy (CORLK; 619864), Gizak et al. (2021) identified a heterozygous missense variant in the FBP2 gene (V115M; 603027.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found once in a European male in the gnomAD database (May, 2020) at a frequency of 4.0 x 10(-6). In vitro functional expression studies of the recombinant mutant V115M protein showed that it had reduced activity, thermal stability, and substrate affinity compared to controls. Fibroblasts derived from 1 of the patients showed granular localization of FBP2 only in cell bodies, as compared to nuclear and diffuse cytoplasmic localization in controls. The mutant protein did not colocalize with mitochondria in patient fibroblasts. In addition, patient cells showed disturbances in the mitochondrial membrane network associated with increased production of ROS both in the cytoplasm and mitochondria. Transfection of wildtype cells with V115M led to colocalization of the mutant protein, but not the wildtype protein, to the ER, presumably for degradation through the ER-to-lysosome-associated degradation system (ELRAD). The authors speculated that coexpression of wildtype with mutant FBP2 would form heteromers with reduced enzyme activity and stability, consistent with a dominant-negative effect. The nearly complete neurologic recovery in the patients suggested to the authors that neuronal damage was not occurring, but that the primary affected cells in this disorder may be oligodendrocytes. Gizak et al. (2021) noted that FBP2 has a role in gluconeogenesis in the brain, which may have contributed to the phenotype, although disruption of noncanonical functions of the FBP2 gene could not be excluded.
In 8 members of a 3-generation family with childhood-onset remitting leukodystrophy (CORLK; 619864), Gizak et al. (2021) identified a heterozygous c.343G-A transition (c.343G-A, NM_003837.2) in the FBP2 gene, resulting in a val115-to-met (V115M) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, showing variable expressivity. It was found once in a European male in the gnomAD database (May, 2020) at a frequency of 4.0 x 10(-6). In vitro functional expression studies of the recombinant mutant V115M protein showed that it had reduced activity, thermal stability, and substrate affinity compared to controls. The authors speculated that coexpression of wildtype with mutant FBP2 would form heteromers with reduced enzyme activity and stability, consistent with a dominant-negative effect.
Gizak, A., Diegmann, S., Dreha-Kulaczewski, S., Wisniewski, J., Duda, P., Ohlenbusch, A., Huppke, B., Henneke, M., Hohne, W., Altmuller, J., Thiele, H., Nurnberg, P., Rakus, D., Gartner, J., Huppke, P. A novel remitting leukodystrophy associated with a variant in FBP2. Brain Commun. 3: fcab036, 2021. [PubMed: 33977262] [Full Text: https://doi.org/10.1093/braincomms/fcab036]
Gross, M. B. Personal Communication. Baltimore, Md. 5/11/2022.
Tillmann, H., Eschrich, K. Isolation and characterization of an allelic cDNA for human muscle fructose-1,6-bisphosphatase. Gene 212: 295-304, 1998. [PubMed: 9678974] [Full Text: https://doi.org/10.1016/s0378-1119(98)00181-4]