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.

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.

Appendices

Conflict of Interest

T L-P, H S, S B-L, A E, S U, A R, A L declare that we have no conflict of interest. We declare that this article has not been published previously and all the authors approve its publication.

Authors’ Contribution

Tanya Lobo-Prada was involved in the conception design analysis interpretation and drafting of the article. PhD. Alejandro Leal and Prof. André Reis contributed to the conception and design and revised the manuscript critically for important intellectual content. Heinrich Sticht contributed with in silico modeling of the enzyme and contributed critically to the main article draft. Sixto Bogantes did valuable to contributions to the clinical characterization of the patients and revised the manuscript critically. Arif Ekici and Steffen Uebe contributed to analysis and interpretation of the data and revised the article critically.

Guarantor and Corresponding Author

Alejandro Leal accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.

Details of Funding

This research was funded by German Research Foundation (DFG) grant AB393/2-2, University of Costa Rica (project 111-B1-349), German Academic Exchange Program (DAAD) and Graduate Studies System of University of Costa Rica. The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors.

Details of Ethical Approval

The study was performed as per protocol of the University of Costa Rica’s Institutional Review Board.

Patient Consent Statement

All authors declare that informed consent was obtained from all the subjects on this research in accordance with the Code of Ethics of the World Medical Association. The privacy rights of the human subjects were also protected.