Fructose-1,6-bisphosphatase deficiency with confirmed molecular diagnosis

Salih, Rihab M.; Mohammed, Esraa A.; Alhashem, Amal; Mohamed, Sarar; Al-Aqeel, Aida I.

doi:10.15537/smj.2020.2.24885

Cited by 8 publications

(8 citation statements)

References 12 publications

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“…In addition to deletion and nonsense mutations that block FBP1 expression, human FBP1 deficiency can be caused by missense mutations (Emecen Sanli et al, 2022; Salih et al, 2020). We stably expressed FBP1 missense mutants in Huh7 cells and found most of them to be poorly expressed and devoid of catalytic activity (Figures 7A and S8A).…”

Section: Resultsmentioning

confidence: 99%

“…In addition to deletion and nonsense mutations that block FBP1 expression, human FBP1 deficiency can be caused by missense mutations (Emecen Sanli et al, 2022;Salih et al, 2020).…”

Section: A Complex Disrupting Fbp1-derived Peptide Ameliorates Insuli...mentioning

confidence: 99%

“…While not a direct target for insulin signaling, fructose (F) 1,6 bisphosphatase 1 (FBP1) is rate controlling for GNG, converting F1,6-P 2 to F6-P which is then converted to glucose (G) 6-P by phosphoglucoseisomerase (PGI) (Hunter et al, 2018; Li et al, 2014). FBP1 deficiency is a rare inborn metabolic error (OMIM:229700), that causes severe hypoglycemia, lactic acidosis, seizures, hepatomegaly, hyperlipidemia, hepatosteatosis and liver damage in carbohydrate starved, but not fed, infants (Gorce et al, 2022; Moey et al, 2018; Salih et al, 2020). While hypoglycemia and lactic acidosis are probably caused by low glycogen stores and abrogated GNG, there is no simple biochemical explanation for the hepatomegaly and elevated hepatic lipogenesis, which also affect non-starved older FBP1-deficient individuals (Gorce et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

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FBP1 is a nonenzymatic safety valve that curtails AKT activation to prevent insulin hyperresponsiveness

Zhu

Watari

et al. 2023

Preprint

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SUMMARYInsulin inhibits gluconeogenesis and stimulates glucose conversion to glycogen and lipids. How these activities are coordinated to prevent hypoglycemia and hepatosteatosis is not clear. Fructose-1,6 bisphosphatase (FBP1) is rate controlling for gluconeogenesis. However, inborn human FBP1 deficiency does not cause hypoglycemia unless accompanied by fasting or starvation, which also trigger paradoxical hepatomegaly, hepatosteatosis, and hyperlipidemia in affected individuals. Hepatocyte FBP1-ablated mice exhibit identical fasting-conditional pathologies along with AKT hyperactivation, whose inhibition reversed hepatomegaly, hepatosteatosis and hyperlipidemia but not hypoglycemia. Surprisingly, fasting-mediated AKT hyperactivation is insulin-dependent. FBP1 prevents insulin hyperresponsiveness, independently of its catalytic activity, by interacting with AKT, PP2A-C and Aldolase-B (ALDOB) to specifically accelerate AKT dephosphorylation. Enhanced by fasting and weakened by elevated insulin, FBP1:AKT:PP2A-C:ALDOB complex formation, which is disrupted by human FBP1 deficiency mutations or a C-terminal FBP1 truncation, prevents insulin-triggered liver pathologies and maintains lipid and glucose homeostasis. Conversely, a complex disrupting peptide reverses diet-induced insulin resistance.

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Section: Resultsmentioning

confidence: 99%

“…In addition to deletion and nonsense mutations that block FBP1 expression, human FBP1 deficiency can be caused by missense mutations (Emecen Sanli et al, 2022;Salih et al, 2020).…”

Section: A Complex Disrupting Fbp1-derived Peptide Ameliorates Insuli...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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FBP1 is a nonenzymatic safety valve that curtails AKT activation to prevent insulin hyperresponsiveness

Zhu

Watari

et al. 2023

Preprint

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“…After literature review, we found different population had its own hotspots. For example, two missense mutations c.841G > A and c.472C > T are reported as the most common alleles in the India and Pakistan population [1,2], c.958G > A and c.986T > C are the most frequent variants in the Southern Brazilian [10], while c.114_119dup is prevalent in Saudi Arabia [13], c.960_961insG and c.490G > A are common in Japan [8,14]. The situation for the Turkish patients is signi cantly different, as the exon 1 deletion (NM_000507.4) is the most common variant and considered as the founder mutation in Turkish FBP1D patients.…”

Section: Introductionmentioning

confidence: 99%

Fructose-1,6-bisphosphatase deficiency: estimation of prevalence in the Chinese population and analysis of genotype-phenotype association

Tang

Chen

et al. 2023

Preprint

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Background Fructose-1,6-bisphosphatase deficiency (FBP1D) is a rare inborn error due to mutations in the FBP1 gene. The genetic spectrum of FBP1D in China is unknown, also nonspecific manifestations confuse disease diagnosis. Materials & Methods We collected 101 FBP1 variants from our cohort and public resources, and manually curated pathogenicity of these variants. Ninety-seven pathogenic or likely pathogenic variants were used in our cohort to estimate Chinese FBP1D prevalence by three methods: 1) carrier frequency, 2) permutation and combination, 3) Bayesian framework. Allele frequencies (AFs) of these variants in our cohort, China Metabolic Analytics Project (ChinaMAP) and gnomAD were compared to reveal the different hotspots in Chinese and other populations. Clinical and genetic information of 122 FBP1D patients from our cohort and published literature were collected to analyze the genotype-phenotypes association. Phenotypes of 68 hereditary fructose intolerance (HFI) patients from our previous study were used to compare the phenotypic differences between these two fructose metabolism diseases. Result The estimated Chinese FBP1D prevalence was 1/1,310,034. In the Chinese population, c.490G > A and c.355G > A had significantly higher AFs than in the non-Finland European population, and c.841G > A had significantly lower AF value than in the South Asian population (all P values < 0.05). The genotype-phenotype association analyses showed that patients carrying homozygous c.841G > A were more likely to present increased urinary glycerol, carrying two CNVs (especially homozygous exon1 deletion) were often with hepatic steatosis, carrying two missense variants were not likely to present fever, carrying compound heterozygous variants were usually with lethargy, and carrying homozygous variants were usually with ketosis and hepatic steatosis (all P values < 0.05). By comparing to phenotypes of HFI patients, FBP1D patients were more likely to present hypoglycemia, metabolic acidosis, and seizures (all P value < 0.05). Conclusion The prevalence of FBP1D in the Chinese population is extremely low. Genetic sequencing could effectively help to diagnose FBP1D.

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“…1,2 Clinical manifestations are characterized by life-threatening episodes of acidosis, hypoglycemia, hyperventilation, convulsion and coma. 2,3 In about half of the cases, the deficiency presents in the 1 st week of life. 4 In infants and young children, episodes are triggered by febrile infections and gastroenteritis if oral food intake decreases.…”

Section: Introductionmentioning

confidence: 99%

An Iranian Patient with Fructose 1,6 Bisphosphatase Deficiency: A Case Report

Mirhosseini¹,

Mirhosseini²,

Saeida-Ardekani³

2022

WJPN

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Background: Deficiency of hepatic fructose 1,6 bisphosphatase (FBPase), a key enzyme in gluconeogenesis, impairs the formation of glucose from all gluconeogenic precursors including dietary fructose. Patients present with life threatening metabolic acidosis, fasting hypoglycemia, hepatomegaly, hyperketosis, elevated lactate and uric acid level. Glycerol and glycerol-3 phosphate have been found in the urine. The diagnosis of FBPase deficiency is confirmed via DNA molecular analysis from peripheral leukocytes. The acute life threatening episodes are treated with IV glucose at high rate and bicarbonate to control hypoglycemia and acidosis. Case Report: Here we report a girl referred with anorexia, lethargy, recurrent vomiting, progressive respiratory distress, and hepatomegaly following respiratory viral infection. She also had a history of twice similar attacks but milder than previous episodes. The test results showed hypoglycemia and severe metabolic acidosis. Despite proper treatment, the patient died of pulmonary edema following a respiratory viral infection. Conclusion: Once FBPase deficiency has been diagnosed and adequate management introduced, its course is usually benign. Growth both psychomotor and intellectual development are unimpaired and tolerance to fasting improves with age.

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Fructose-1,6-bisphosphatase deficiency with confirmed molecular diagnosis

Abstract: Fructose-1,6-bisphosphatase deficiency with confirmed molecular diagnosis. An important cause of hypoglycemia in children

Cited by 8 publications

References 12 publications

FBP1 is a nonenzymatic safety valve that curtails AKT activation to prevent insulin hyperresponsiveness

FBP1 is a nonenzymatic safety valve that curtails AKT activation to prevent insulin hyperresponsiveness

Fructose-1,6-bisphosphatase deficiency: estimation of prevalence in the Chinese population and analysis of genotype-phenotype association

An Iranian Patient with Fructose 1,6 Bisphosphatase Deficiency: A Case Report

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