title: Loss of function mutation in glutamic pyruvate transaminase 2 (GPT2) causes developmental encephalopathy.
abstract: Intellectual disability is genetically heterogeneous, and it is likely that many of the responsible genes have not yet been identified. We describe three siblings with isolated, severe developmental encephalopathy. After extensive uninformative genetic and metabolic testing, whole exome sequencing identified a homozygous novel variant in glutamic pyruvate transaminase 2 (GPT2) or alanine transaminase 2 (ALT2), c.459 C > G p.Ser153Arg that segregated with developmental encephalopathy in the family. This variant was predicted to be damaging by all in silico prediction algorithms. GPT2 is the gene encoding ALT2 which is responsible for the reversible transamination of alanine and 2-oxoglutarate to form pyruvate and glutamate. GPT2 is expressed in brain and is in the pathway to generate glutamate, an excitatory neurotransmitter. Functional assays of recombinant wild-type and mutant ALT2 proteins demonstrated the p.Ser153Arg mutation resulted in a severe loss of enzymatic function. We suggest that recessively inherited loss of function GPT2 mutations are a novel cause of intellectual disability.
authors.affiliation: Departments of Pediatrics and Medicine, Columbia University Medical Center, 1150 St. Nicholas Avenue, Room 620, New York, NY, 10032, USA.
authors.forename: Katrina
authors.initials: K
authors.lastname: Celis
authors.forename: Scott
authors.initials: S
authors.lastname: Shuldiner
authors.forename: Eden V
authors.initials: EV
authors.lastname: Haverfield
authors.forename: Joshua
authors.initials: J
authors.lastname: Cappell
authors.forename: Rongze
authors.initials: R
authors.lastname: Yang
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Gong
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
mesh_terms: D000293:Adolescent; D000410:Alanine Transaminase / Q000235:genetics; D001927:Brain Diseases / Q000151:congenital / Q000235:genetics*; D002675:Child, Preschool; D003241:Consanguinity; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D035781:Siblings; D000637:Transaminases / Q000235:genetics*
chemical_list: C000608785:GPT2 protein, human; D000637:Transaminases; D000410:Alanine Transaminase