FBP1 – Fructose-1,6-bisphosphatase deficiency

Fructose-1,6-bisphosphatase deficiency is a rare autosomal recessive inborn error of metabolism resulting from biallelic loss-of-function variants in the FBP1 gene, which encodes the key gluconeogenic enzyme FBPase. Affected individuals typically present in infancy or early childhood with severe hypoglycemia, lactic acidosis, ketonuria, and metabolic acidosis, often triggered by fasting, illness, or fructose intake.

Extensive case series have documented over 100 unrelated probands from more than 40 families carrying pathogenic FBP1 variants across diverse populations. The c.960_961insG (p.Ser321fs) frameshift insertion is recurrent in Japanese patients (12/22 alleles; 46%) ([PMID:7763253]). Other frequently reported variants include c.490G>A (p.Gly164Ser) and c.841G>A (p.Glu281Lys), which account for nearly 10–20% of alleles in Japanese and Indian cohorts, respectively ([PMID:9382095]; [PMID:29774539]). Large deletions of exon 2 represent a founder allele in Turkish and Armenian patients ([PMID:27101822]).

Segregation analysis in multiple consanguineous and outbred families has confirmed autosomal recessive inheritance, with homozygous or compound heterozygous affected siblings and unaffected heterozygous parents in at least eight pedigrees demonstrating full cosegregation.

The variant spectrum extends across all mutation classes: frameshift (e.g., c.960_961insG (p.Ser321fs)), nonsense (e.g., c.88G>T (p.Glu30Ter)), missense (e.g., c.490G>A (p.Gly164Ser)), splice-site (e.g., c.825+1G>A), and multi-exon deletions. Functional classification groups missense variants into three categories based on effects on enzyme activity and protein stability, with Type 2 mutations exhibiting misfolding and proteasomal degradation ([PMID:37507476]).

Biochemical assays using recombinant expression in E. coli, COS-7, HepG2, and patient leukocytes uniformly demonstrate absent or markedly reduced FBPase activity for pathogenic variants. Recent cellular studies reveal enhanced NEDD4-2–mediated ubiquitination and accelerated proteasomal degradation of mutant FBP1 (e.g., p.His254Arg) in patient-derived cells and knockout mice, elucidating a loss-of-function mechanism ([PMID:37142076]).

The concordance of genetic, segregation, and functional data across multiple populations establishes a definitive gene–disease relationship. Early molecular diagnosis by targeted sequencing or MLPA is critical for management, enabling dietary avoidance of fructose and prompt glucose supplementation to prevent life-threatening metabolic crises.

Key Take-home: Biallelic FBP1 variants cause autosomal recessive fructose-1,6-bisphosphatase deficiency, and genetic testing is essential for diagnosis and tailored metabolic therapy.

References

• Biochemical and Biophysical Research Communications • 1995 • Identification of a genetic mutation in a family with fructose-1,6-bisphosphatase deficiency. PMID:7763253
• American Journal of Human Genetics • 1997 • Identification of genetic mutations in Japanese patients with fructose-1,6-bisphosphatase deficiency. PMID:9382095
• Communications Biology • 2023 • Identification of genotype-biochemical phenotype correlations associated with fructose 1,6-bisphosphatase deficiency. PMID:37507476
• Archives of Biochemistry and Biophysics • 2023 • A novel variant in the FBP1 gene causes fructose-1,6-bisphosphatase deficiency through increased ubiquitination. PMID:37142076
• Orphanet Journal of Rare Diseases • 2016 • A summary of molecular genetic findings in fructose-1,6-bisphosphatase deficiency with a focus on a common long-range deletion and the role of MLPA analysis. PMID:27101822

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