FBP1 Gene Mutation: The Genetic Cause of Fructose-1,6-Bisphosphatase Deficiency

FBP1 Gene Mutation: The Genetic Cause of Fructose-1,6-Bisphosphatase Deficiency

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Last Updated: July 26, 2025

Introduction

For most, fructose—the sugar found in fruits and honey—is a harmless source of energy. However, for infants with a rare genetic disorder, it can trigger a life-threatening metabolic crisis. This condition, known as Fructose-1,6-bisphosphatase deficiency (FBPD), is an inborn error of metabolism that impairs the body’s ability to produce its own glucose, a process called gluconeogenesis.

This breakdown can lead to severe hypoglycemia and metabolic acidosis. The root cause lies within a single gene: FBP1. This article explores the molecular basis of this disorder, drawing from the detailed research of Sadaqat Ijaz to understand how an FBP1 gene mutation disrupts a vital metabolic pathway.

Thesis Excerpt & Analysis

What is Fructose-1,6-Bisphosphatase Deficiency?

Fructose-1,6-bisphosphatase deficiency is a rare autosomal recessive metabolic disorder caused by the absence or malfunction of the FBPase enzyme, which is encoded by the FBP1 gene. This enzyme plays a key regulatory role in gluconeogenesis—the synthesis of glucose from non-carbohydrate sources like pyruvate, lactate, and certain amino acids.

When the FBPase enzyme is deficient, the body cannot produce glucose when fasting or during times of illness. This impairment is often fatal in early infancy if not diagnosed promptly and is considered a cause of sudden infant death syndrome. The worldwide prevalence is estimated to be around 1 in 100,000 live births, though it varies between populations.

(Source: Ijaz, S. (2018). MOLECULAR CHARACTERIZATION AND COMPARATIVE GENOMIC STUDIES OF RECESSIVE METABOLIC DISORDERS RELATED GENES FAH, FBP1 AND IDUA. University of Veterinary and Animal Sciences, Lahore, Pakistan. Supervised by Dr. Muhammad Yasir Zahoor. pp. 31, 38.)

The Critical Role of FBPase in Fructose Metabolism and Gluconeogenesis

Fructose metabolism primarily occurs in the liver and kidneys. The FBPase enzyme is a critical gatekeeper in this process, irreversibly converting fructose-1,6-bisphosphate into fructose-6-phosphate. This step is essential for the gluconeogenesis pathway to proceed.

• Function: FBPase helps the body generate glucose when dietary sources are unavailable.
• Location: It is abundantly expressed in the liver and kidney, the primary sites of gluconeogenesis.
• Regulation: Its activity is tightly controlled by hormones and metabolites. For example, insulin decreases its expression, while glucagon stimulates it.

A deficiency in this enzyme means all gluconeogenic precursors are effectively blocked from being converted into glucose, leading to a dangerous metabolic state when the body is stressed or fasting. This is a hallmark of Fructose-1,6-bisphosphatase deficiency.

(Source: Ijaz, S., 2018, pp. 31, 34.)

Clinical Symptoms of Fructose-1,6-Bisphosphatase Deficiency

The clinical presentation of Fructose-1,6-bisphosphatase deficiency is often non-specific, making it difficult to distinguish from other metabolic disorders. Symptoms typically appear within the first few days of life or during the first year, often triggered by an infection or prolonged fasting.

Key clinical features include:

• Severe Hypoglycemia: Dangerously low blood sugar levels that are resistant to glucagon treatment.
• Metabolic Acidosis: An accumulation of acid in the body, often accompanied by hyperventilation and apnea (stopped breathing).
• Hyperlactacidemia: Elevated levels of lactate in the blood.
• Hepatomegaly: Enlarged liver.
• Ketosis: The presence of ketones in the urine and blood.

These episodes can progress rapidly to convulsions, coma, and even brain damage if not treated immediately with an infusion of glucose.

(Source: Ijaz, S., 2018, p. 38.)

The Genetic Link: Understanding the FBP1 Gene Mutation

The genetic basis for Fructose-1,6-bisphosphatase deficiency lies in mutations within the FBP1 gene. This gene is located on chromosome 9q22.2-9q22.3 and contains the instructions for making the FBPase enzyme. The Human Gene Mutation Database has identified over 40 different disease-causing variants, including missense mutations, deletions, and insertions.

An FBP1 gene mutation leads to the production of a non-functional or entirely absent FBPase enzyme. Because the disorder is autosomal recessive, a child must inherit a faulty copy of the FBP1 gene from both parents to be affected. The parents, who each carry one faulty copy, are typically asymptomatic carriers.

(Source: Ijaz, S., 2018, p. 41-42.)

Novel FBP1 Gene Mutations in Fructose-1,6-Bisphosphatase Deficiency: A Case Study

Research conducted by Sadaqat Ijaz on fourteen Pakistani families identified three distinct mutations, including a novel deletion that had not been previously reported.

• Novel Deletion (c.609_612delAAAA): This newly identified FBP1 gene mutation involves the deletion of four ‘A’ base pairs in exon 6. This causes a frameshift, altering the entire downstream amino acid sequence and introducing a premature stop codon.
  • Impact: The resulting protein is truncated (shortened from 339 to 275 amino acids) and non-functional, as it lacks parts of the critical substrate and metal-binding sites.
  • Significance: This finding expands the known spectrum of mutations causing Fructose-1,6-bisphosphatase deficiency and highlights the importance of comprehensive genetic analysis for diagnosis.

Other mutations identified in the study, such as c.841G>A and c.472C>T, were found to be highly prevalent in the Pakistani population, suggesting a founder effect.

(Source: Ijaz, S., 2018, pp. 67, 73, 118.)

Diagnosing Fructose-1,6-Bisphosphatase Deficiency

A definitive diagnosis of Fructose-1,6-bisphosphatase deficiency requires a combination of clinical observation, biochemical tests, and genetic analysis. While biochemical markers like hypoglycemia and metabolic acidosis raise suspicion, they are not specific.

• Enzymatic Assay: The most reliable biological method is to measure FBPase activity in a liver biopsy sample. However, this is an invasive procedure.
• Molecular Genetic Testing: Analyzing the FBP1 gene for mutations is the most reliable and non-invasive approach. It confirms the diagnosis, allows for carrier testing in family members, and enables prenatal diagnosis in future pregnancies.

Once diagnosed, treatment involves avoiding fasting, managing diet to limit fructose and sucrose intake, and prompt infusion of glucose during metabolic crises.

(Source: Ijaz, S., 2018, p. 40-41.)

Conclusion

Fructose-1,6-bisphosphatase deficiency is a severe gluconeogenesis disorder rooted in genetic errors. The discovery of specific variants, including novel ones like the c.609_612delAAAA deletion, underscores that a single FBP1 gene mutation can have catastrophic effects on metabolism. Understanding this genetic link is paramount for accurate diagnosis, effective family counseling, and providing the rapid treatment necessary to save lives and prevent long-term complications.

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Disclaimer: Some sentences have been lightly edited for SEO and readability. For the full, original research, please refer to the complete thesis PDF provided in the initial prompt.

Author Bio: This analysis is based on the doctoral research of Sadaqat Ijaz, a specialist in Molecular Biology and Biotechnology from the University of Veterinary and Animal Sciences, Lahore, Pakistan. Her work provides critical insights into the genetic landscape of rare metabolic disorders.

The diagnosis of rare metabolic disorders remains a major challenge in many parts of the world. What steps can improve awareness and screening? Share this article to help educate others on the importance of genetic research