Alternative titles; symbols
HGNC Approved Gene Symbol: FBP1
SNOMEDCT: 28183005; ICD10CM: E74.19;
Cytogenetic location: 9q22.32 Genomic coordinates (GRCh38) : 9:94,603,133-94,640,263 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q22.32 | Fructose-1,6-bisphosphatase deficiency | 229700 | Autosomal recessive | 3 |
Hepatic fructose-1,6-bisphosphatase (FBP1; EC 3.1.3.11) catalyzes the hydrolysis of fructose-1,6 bisphosphate to fructose-6-phosphate and inorganic phosphate. This reaction is an important regulatory site of gluconeogenesis.
See also muscle FBP (FBP2; 603027).
Using subtraction cloning, Solomon et al. (1988) isolated human FBP1 based on its upregulation by 1,25-dihydroxyvitamin D3 during monocytic differentiation of HL-60 human leukemia cells. The deduced protein contains 338 amino acids and shares significant homology with its pig ortholog, including conservation of the putative active site. The authors identified 2 distinct FBP1 mRNAs that were regulated at different stages of HL-60 differentiation.
El-Maghrabi et al. (1995) isolated clones corresponding to the FBP1 gene from human placenta and leukocyte cDNA libraries. The deduced 362-residue protein shares 77% identity to FBP2 (Tillmann and Eschrich, 1998).
Li et al. (2014) used an integrative approach comprising pan-metabolomic profiling and metabolic gene set analysis and determined that FBP1 was uniformly depleted in over 600 clear cell renal cell carcinoma (ccRCC; see 144700) tumors examined. Notably, the human FBP1 locus resides on chromosome 9q22, the loss of which is associated with poor prognosis for ccRCC patients. The data further indicated that FBP1 inhibits ccRCC progression through 2 distinct mechanisms: first, FBP1 antagonizes glycolytic flux in renal tubular epithelial cells, the presumptive ccRCC cells of origin, thereby inhibiting a potential Warburg effect; second, in VHL (608537)-deficient ccRCC cells, FBP1 restrains cell proliferation, glycolysis, and the pentose phosphate pathway in a catalytic activity-independent manner by inhibiting nuclear HIF (see 603348) function via direct interaction with the HIF inhibitory domain. Li et al. (2014) concluded that this unique dual function of the FBP1 protein explains its ubiquitous loss in clear cell renal cell carcinoma, distinguishing FBP1 from previously identified tumor suppressors that are not consistently mutated in all tumors.
El-Maghrabi et al. (1995) determined that the FBP1 gene contains 7 exons and spans more than 31 kb; the 6 introns are in the same positions in the rat gene.
By fluorescence in situ hybridization, El-Maghrabi et al. (1995) localized the FBP1 gene to chromosome 9q22.2-q22.3.
By physical mapping with FISH and by genetic mapping of an associated GA repeat polymorphism, Rothschild et al. (1995) mapped the hepatic FBP gene to 9q22.3. Amplification using FBP exon-specific primers with a YAC contig from this region of chromosome 9 further refined the placement of FBP genomic sequences to an approximately 1.7-cM flanked by D9S289 and D9S287, near the gene for Fanconi anemia group C (227645).
In Japanese patients with FBP1 deficiency (FBP1D; 229700), Kikawa et al. (1997) identified homozygous or compound heterozygous mutations in the FBP1 gene (see, e.g., 611570.0001-611570.0004). The 1-bp insertion (960insG; 611570.0001) was the most common, present in 16 of 22 alleles.
In a Japanese girl with FBP1 deficiency, Matsuura et al. (2002) identified compound heterozygosity for 2 mutations in the FBP1 gene (611570.0005; 611570.0006). Matsuura et al. (2002) stated that 11 different pathogenic FBP1 mutations had been reported.
By linkage analysis with highly informative linked markers, Rothschild et al. (1995) excluded FBP as a candidate gene for maturity-onset diabetes of the young (MODY) and noninsulin-dependent diabetes (NIDDM) in both Caucasian and African American families.
In a 10-year-old Japanese girl with fructose-1,6-bisphosphatase deficiency (FBP1D; 229700), Kikawa et al. (1995) identified a homozygous 1-bp insertion (960insG) in exon 7 of the FBP1 gene. The insertion occurred immediately following codon gly320 in the sequence of 5 Gs at nucleotide region 957-961, and resulted in a truncated protein. The patient's unaffected parents were heterozygous for the mutation. The patient had experienced recurrent attacks of metabolic acidosis and hypoglycemia since birth and had undetectable FBPase activity in leukocytes and a liver sample. Although the mutation was not well conserved, expression studies showed no FBPase activity.
Kikawa et al. (1997) identified the 1-bp insertion in 16 of 22 alleles from Japanese patients with FBP1 deficiency.
In Japanese patients with FBP1 deficiency (FBP1D; 229700), Kikawa et al. (1997) identified a 490G-A transition in exon 4 of the FBP1 gene, resulting in a gly164-to-ser (G164S) substitution. In all patients, the mutation was in compound heterozygosity with another pathogenic FBP1 mutation.
In a Japanese patient with FBP1 deficiency (FBP1D; 229700), Kikawa et al. (1997) identified a 530C-A transversion in exon 4 of the FBP1 gene, resulting in an ala177-to-asp (A177D) substitution. The other allele carried the common 1-bp insertion (611570.0001).
In a Japanese patient with FBP1 deficiency (FBP1D; 229700), Kikawa et al. (1997) identified a homozygous 88G-T transversion in exon 1 of the FBP1 gene, resulting in a glu30-to-ter (E30X) substitution.
In a Japanese girl with FBP1 deficiency (229700), Matsuura et al. (2002) identified compound heterozygosity for 2 mutations in the FBP1 gene: a 581T-C transition in exon 5 resulting in a phe194-to-ser (F194S) substitution, and an 851C-G transversion in exon 7 resulting in a pro284-to-arg (P284R; 611570.0006) substitution. Each unaffected parent was heterozygous for 1 of the mutations.
For discussion of the pro284-to-arg (P284R) mutation in the FBP1 gene that was found in compound heterozygous state in a Japanese patient with FBP1 deficiency (FBP1D; 229700) by Matsuura et al. (2002), see 611570.0005.
El-Maghrabi, M. R., Lange, A. J., Jiang, W., Yamagata, K., Stoffel, M., Takeda, J., Fernald, A. A., Le Beau, M. M., Bell, G. I., Baker, L., Pilkis, S. J. Human fructose-1,6-bisphosphatase gene (FBP1): exon-intron organization, localization to chromosome bands 9q22.2-q22.3, and mutation screening in subjects with fructose-1,6-bisphosphatase deficiency. Genomics 27: 520-525, 1995. [PubMed: 7558035] [Full Text: https://doi.org/10.1006/geno.1995.1085]
Kikawa, Y., Inuzuka, M., Jin, B. Y., Kaji, S., Koga, J., Yamamoto, Y., Fujisawa, K., Hata, I., Nakai, A., Shigematsu, Y., Mizunuma, H., Taketo, A., Mayumi, M., Sudo, M. Identification of genetic mutations in Japanese patients with fructose-1,6-bisphosphatase deficiency. Am. J. Hum. Genet. 61: 852-861, 1997. [PubMed: 9382095] [Full Text: https://doi.org/10.1086/514875]
Kikawa, Y., Inuzuka, M., Jin, B. Y., Kaji, S., Yamamoto, Y., Shigematsu, Y., Nakai, A., Taketo, A., Ohura, T., Mikami, H., Mizunuma, H., Suzuki, Y., Narisawa, K., Sudo, M. Identification of a genetic mutation in a family with fructose-1,6-bisphosphatase deficiency. Biochem. Biophys. Res. Commun. 210: 797-804, 1995. [PubMed: 7763253] [Full Text: https://doi.org/10.1006/bbrc.1995.1729]
Li, B., Qiu, B., Lee, D. S. M., Walton, Z. E., Ochocki, J. D., Mathew, L. K., Mancuso, A., Gade, T. P. F., Keith, B., Nissim, I., Simon, M. C. Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature 513: 251-255, 2014. [PubMed: 25043030] [Full Text: https://doi.org/10.1038/nature13557]
Matsuura, T., Chinen, Y., Arashiro, R., Katsuren, K., Tamura, T., Hyakuna, N., Ohta, T. Two newly identified genomic mutations in a Japanese female patients with fructose-1,6-bisphosphatase (FBPase) deficiency. Molec. Genet. Metab. 76: 207-210, 2002. [PubMed: 12126934] [Full Text: https://doi.org/10.1016/s1096-7192(02)00038-0]
Rothschild, C. B., Freedman, B. I., Hodge, R., Rao, P. N., Pettenati, M. J., Anderson, R. A., Akots, G., Qadri, A., Roh, B., Fajans, S. S., Reis, A., Morris, D. J., Usala, A., Hayward, C., Brock, D., Colle, E., Spray, B. J., Rich, S. S., Bowden, D. W. Fructose-1,6-bisphosphatase: genetic and physical mapping to human chromosome 9q22.3 and evaluation in non-insulin-dependent diabetes mellitus. Genomics 29: 187-194, 1995. [PubMed: 8530070] [Full Text: https://doi.org/10.1006/geno.1995.1230]
Sia, C. L., Traniello, S., Pontremoli, S., Horecker, B. L. Studies on the subunit structure of rabbit liver fructose diphosphatase. Arch. Biochem. Biophys. 132: 325-330, 1969. [PubMed: 4307819] [Full Text: https://doi.org/10.1016/0003-9861(69)90369-5]
Solomon, D. H., Raynal, M.-C., Tejwani, G. A., Cayre, Y. E. Activation of the fructose 1,6-bisphosphatase gene by 1,25-dihydroxyvitamin D3 during monocytic differentiation. Proc. Nat. Acad. Sci. 85: 6904-6908, 1988. [PubMed: 2842796] [Full Text: https://doi.org/10.1073/pnas.85.18.6904]
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]