title: A Homozygous Mutation in GPT2 Associated with Nonsyndromic Intellectual Disability in a Consanguineous Family from Costa Rica.
abstract: Intellectual disability is a highly heterogeneous disease that affects the central nervous system and impairs patients' ability to function independently. Despite multiples genes involved in the etiology of disease, most of the genetic background is yet to be discovered. We used runs of homozygosity and exome sequencing to study a large Costa Rican family with four individuals affected with severe intellectual disability and found a novel homozygous missense mutation, p. 96G>R, c. 286G>A, in all affected individuals. This gene encodes for a pyridoxal enzyme involved in the production of the neurotransmitter glutamate and is highly expressed in the white matter of brain and cerebellum. Protein modeling of GPT2 predicted that the mutation is located in a loop where the substrate binds to the active site of the enzyme, therefore, suggesting that the catalytic activity is impaired. With our report of a second mutation we fortify the importance of GPT2 as a novel cause of autosomal recessive nonsyndromic intellectual disability and support the premise that GPT2 is highly important for the neurodevelopment of the central nervous system.
  
  
  CONCLUSIONS
  The mutation p. 96G>R c. 286G>A in GPT2, located in a loop where the substrate binds to the active site of the enzyme, fortifies the importance of GPT2 in the pathogenesis of nonsyndromic intellectual disability.
authors.affiliation: Section of Genetics and Biotechnology, School of Biology, University of Costa Rica, 11501-2060, San Jose, Costa Rica.|Neuroscience Research Center, University of Costa Rica, San Jose, Costa Rica.
authors.forename: Tanya
authors.initials: T
authors.lastname: Lobo-Prada
authors.affiliation: Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
authors.affiliation: Neurology Department, Hospital San Juan de Dios, San Jose, Costa Rica.
authors.forename: Sixto
authors.initials: S
authors.lastname: Bogantes-Ledezma
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Arif
authors.initials: A
authors.lastname: Ekici
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Uebe
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.affiliation: Section of Genetics and Biotechnology, School of Biology, University of Costa Rica, 11501-2060, San Jose, Costa Rica. alejandro.leal@ucr.ac.cr.|Neuroscience Research Center, University of Costa Rica, San Jose, Costa Rica. alejandro.leal@ucr.ac.cr.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Leal
keywords: Developmental delay; GPT2; Intellectual disability; Missense mutation; Runs of homozygosity; Vineland Social Maturity Scale