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Lobo-Prada T, Sticht H, Bogantes-Ledezma S, et al. A Homozygous Mutation in GPT2 Associated with Nonsyndromic Intellectual Disability in a Consanguineous Family from Costa Rica. JIMD Rep. 2017;36:59-66doi: 10.1007/8904_2016_40.
Lobo-Prada, T., Sticht, H., Bogantes-Ledezma, S., Ekici, A., Uebe, S., Reis, A., & Leal, A. (2017). A Homozygous Mutation in GPT2 Associated with Nonsyndromic Intellectual Disability in a Consanguineous Family from Costa Rica. JIMD reports, 3659-66. https://doi.org/10.1007/8904_2016_40
Lobo-Prada, Tanya, et al. "A Homozygous Mutation in GPT2 Associated with Nonsyndromic Intellectual Disability in a Consanguineous Family from Costa Rica." JIMD reports vol. 36 (2017): 59-66. doi: https://doi.org/10.1007/8904_2016_40
Lobo-Prada T, Sticht H, Bogantes-Ledezma S, Ekici A, Uebe S, Reis A, Leal A. A Homozygous Mutation in GPT2 Associated with Nonsyndromic Intellectual Disability in a Consanguineous Family from Costa Rica. JIMD Rep. 2017;36:59-66. doi: 10.1007/8904_2016_40. Epub 2017 Jan 28. PMID: 28130718; PMCID: PMC5680285.
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JIMD Rep. 2017;36:59-66. doi: 10.1007/8904_2016_40. Epub 2017 Jan 28.

A Homozygous Mutation in GPT2 Associated with Nonsyndromic Intellectual Disability in a Consanguineous Family from Costa Rica.

JIMD reports

Tanya Lobo-Prada, Heinrich Sticht, Sixto Bogantes-Ledezma, Arif Ekici, Steffen Uebe, André Reis, Alejandro Leal

Affiliations

  1. Section of Genetics and Biotechnology, School of Biology, University of Costa Rica, 11501-2060, San Jose, Costa Rica.
  2. Neuroscience Research Center, University of Costa Rica, San Jose, Costa Rica.
  3. Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
  4. Neurology Department, Hospital San Juan de Dios, San Jose, Costa Rica.
  5. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
  6. Section of Genetics and Biotechnology, School of Biology, University of Costa Rica, 11501-2060, San Jose, Costa Rica. [email protected].
  7. Neuroscience Research Center, University of Costa Rica, San Jose, Costa Rica. [email protected].

PMID: 28130718 PMCID: PMC5680285 DOI: 10.1007/8904_2016_40

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.

SYNOPSIS: 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.

Keywords: Developmental delay; GPT2; Intellectual disability; Missense mutation; Runs of homozygosity; Vineland Social Maturity Scale

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