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Haploinsufficiency of the GPD2 gene in a patient with nonsyndromic mental retardation

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We have investigated the chromosome abnormalities in a female patient exhibiting mild nonsyndromic mental retardation. The patient carries a de novo balanced reciprocal translocation 46,XX,t(2;7)(q24.1;q36.1). Physical mapping of the breakpoints by fluorescent in situ hybridization experiments revealed the disruption of the GPD2 gene at the 2q24.1 region. This gene encodes the mitochondrial glycerophosphate dehydrogenase (mGPDH), which is located on the outer surface of the inner mitochondrial membrane, and catalyzes the unidirectional conversion of glycerol-3-phosphate (G3P) to dihydroxyacetone phosphate with concomitant reduction of the enzyme-bound FAD. Molecular and functional studies showed approximately a twofold decrease of GPD2 transcript level as well as decreased activity of the coded mGPDH protein in lymphoblastoid cell lines of the patient compared to controls. Bioinformatics analysis allowed us to confirm the existence of a novel transcript of the GPD2 gene, designated GPD2c, which is directly disrupted by the 2q breakpoint. To validate GPD2 as a new candidate gene for mental retardation, we performed mutation screening of the GPD2 gene in 100 mentally retarded patients; however, no mutations have been identified. Nevertheless, our results propose that a functional defect of the mGPDH protein could be associated with mental retardation, suggesting that GPD2 gene could be involved in mental retardation in some cases.

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We thank the patients and their families for their cooperation. We also thank Brigitte Jauffrion for the establishment of lymphoblastoid cell lines, and Rose-Anne Thepault, Catherine Antar, and Dominique Gourdier for their technical assistance. This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation France Telecom and Fondation pour la Recherche Médicale (HD fellowship), Fondation Jérôme Lejeune, and Fondation de France.

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Correspondence to Sylvain Briault.

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Daoud, H., Gruchy, N., Constans, J. et al. Haploinsufficiency of the GPD2 gene in a patient with nonsyndromic mental retardation. Hum Genet 124, 649–658 (2009). https://doi.org/10.1007/s00439-008-0588-3

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  • Breakpoint Region
  • Derivative Chromosome
  • Denature High Performance Liquid Chromatography
  • GPD2 Gene
  • Balance Reciprocal Translocation