GPT2 Deficiency

GPT2 (glutamate pyruvate transaminase 2 deficiency) is a neurogenetic disorder and a metabolic disorder that results in intellectual disability and progressive motor disfunction. The deficiency prevents biological brain processing necessary for brain growth from occurring. The brain relies on the creation and augmentation of synapses and the connection between neurons. GPT2 deficiency disrupts the connections between neurons and causes less synapse and weaker brain circuits.This deficiency hinder brain development causing metabolic abnormalities including deficiencies in metabolites that protect the nervous system, individuals with the deficiency become more affected over time. Intellectual disability (ID) affects 3 % of the general population (Daily et al 2000) and is defined as an intelligence quotient (IQ) of less than 70. The etiology of ID is heterogeneous, and includes genetic, teratogenic, and developmental causes (Kaufman et al 2010). The underlying etiology of ID cannot be decided in 75–80 % of mild ID and in 20–50 % of severe ID (Utine et al 2014). The cause of ID is thought to be genetic in 25–50 % of cases, although this percentage increases with ID severity (Kaufman et al 2010). Approximately 15 % of ID is attributable to cytogenetically visible abnormalities (Topper et al 2011) and copy number variants (CNVs) are estimated to account for ~10 % of ID (Kaufman et al 2010). Identification of critical pathogenic CNVs regions has led to the detection of mutations in single genes responsible for syndromic and non-syndromic ID (Ellison et al 2013). Genetic studies have found more than 450 single candidate genes for Mendelian forms of ID (Kaufman et al 2010). Homozygosity mapping in consanguineous families with multiple affected offspring was used in one study of 136 families to find homozygous mutations in 23 genes associated with ID and/or other neurologic disorders, as well as disease-causing variants in 50 novel candidate genes (Najmabadi et al 2011).

What we know:

GPT2 (Glutamic pyruvate transaminase 2), also known as ALT2 (Alanine aminotransferase 2), is involved in amino acid metabolism and neurotransmitter production. It catalyzes a reversible reaction between L-alanine and 2-oxoglutarate to produce glutamate and pyruvate. ALT2 is primarily expressed in the brain and muscle tissues.: ALT2 deficiency can disrupt the glutamate-glutamine/lactate-alanine shuttle pathway crucial for glutamatergic neurotransmission. Mutations in GPT2 can lead to severe developmental encephalopathy, affecting brain function and development. Disruption in neurotransmitter release, particularly glutamate (an excitatory ALT1, another isoform of the enzyme expressed in other tissues, can compensate for ALT2 deficiency outside the brain, thus limiting severe effects to neurological functions. Identified variants like p. Ser153Arg in GPT2 are associated with severe loss of function, contributing to developmental encephalopathy. Functional in vitro studies confirm that mutations in GPT2 result in loss of enzyme function. Attempts to supplement patients with pyridoxine (vitamin B6), a cofactor for ALT2, showed minimal improvement, suggesting limitations in compensating for enzyme deficiency through cofactor supplementation alone. (For more information, please look at our publication )

What we don’t know:

The study mentions only a single family with the identified variant in GPT2. It’s unclear if there are variations in the severity or specific manifestations of the condition across different individuals with similar mutations. Understanding the full phenotypic spectrum of GPT2 deficiency would require studying more cases.

What we’re doing:

We conducted functional studies to characterize the impact of the identified variant. The study confirmed that the p.Ser153Arg variant represents a severe loss-of-function allele of GPT2. This analysis involved measuring ALT (alanine aminotransferase) activities in bacterial lysates and cell lysates transfected with vectors expressing wild-type and mutant forms of ALT2 proteins, as well as performing Western blotting to validate protein expression. We correlated the genetic findings with clinical observations, suggesting that the identified variant likely causes the severe developmental encephalopathy observed in the affected siblings. This conclusion was drawn based on the role of ALT2 in neurotransmitter production and its expression in the brain.