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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American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders: DSM-IV. American Psychiatric Association, Washington, DC
Brown LJ, Stoffel M, Moran SM et al (1996) Structural organization and mapping of the human mitochondrial glycerol phosphate dehydrogenase-encoding gene and pseudogene. Gene 172(2):309–312
Brown LJ, Koza RA, Everett C et al (2002) Normal thyroid thermogenesis but reduced viability and adiposity in mice lacking the mitochondrial glycerol phosphate dehydrogenase. J Biol Chem 277(36):32892–32898
Bugge M, Bruun-Petersen G, Brondum-Nielsen K et al (2000) Disease associated balanced chromosome rearrangements: a resource for large scale genotype–phenotype delineation in man. J Med Genet 37(11):858–865
Chelly J, Khelfaoui M, Francis F, Cherif B, Bienvenu T (2006) Genetics and pathophysiology of mental retardation. Eur J Hum Genet 14(6):701–713 (Review)
Gong DW, Bi S, Weintraub BD, Reitman M (1998) Rat mitochondrial glycerol-3-phosphate dehydrogenase gene: multiple promoters, high levels in brown adipose tissue, and tissue-specific regulation by thyroid hormone. DNA Cell Biol 17(3):301–309
Gribble SM, Prigmore E, Burford DC et al (2005) The complex nature of constitutional de novo apparently balanced translocations in patients presenting with abnormal phenotypes. J Med Genet 42(1):8–16
Gudayol M, Vidal J, Usac EF et al (2001) Identification and functional analysis of mutations in FAD-binding domain of mitochondrial glycerophosphate dehydrogenase in Caucasian patients with type 2 diabetes mellitus. Endocrine 16(1):39–42
Higgins JJ, Pucilowska J, Lombardi RQ, Rooney JP (2004) A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation. Neurology 63(10):1927–1931
Kriaucionis S, Paterson A, Curtis J, Guy J, Macleod N, Bird A (2006) Gene expression analysis exposes mitochondrial abnormalities in a mouse model of Rett syndrome. Mol Cell Biol 26(13):5033–5042
Larson SA, Lakin KC, Anderson L, Kwak N, Lee JH, Anderson D (2001) Prevalence of mental retardation and developmental disabilities: estimates from the 1994/1995 National Health Interview Survey Disability Supplements. Am J Ment Retard 106(3):231–252
Laumonnier F, Ronce N, Hamel BC et al (2002) Transcription factor SOX3 is involved in X-linked mental retardation with growth hormone deficiency. Am J Hum Genet 71(6):1450–1455
Laumonnier F, Holbert S, Ronce N et al (2005) Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate. J Med Genet 42(10):780–786
Laumonnier F, Roger S, Guerin P et al (2006) Association of a functional deficit of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation. Am J Psychiatry 163:1622–1629
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408
Lord C, Rutter M, Le Couteur A (1994) Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 24:659–685
MacDonald MJ, Brown LJ, Hasan NM, Stoffel M, Dills DG (1997) Single-stranded conformational polymorphism analysis of the mitochondrial glycerol phosphate dehydrogenase gene in NIDDM. Diabetes 46(10):1660–1661
Nguyen NH, Brathe A, Hassel B (2003) Neuronal uptake and metabolism of glycerol and the neuronal expression of mitochondrial glycerol-3-phosphate dehydrogenase. J Neurochem 85(4):831–842
Novials A, Vidal J, Franco C et al (1997) Mutation in the calcium-binding domain of the mitochondrial glycerophosphate dehydrogenase gene in a family of diabetic subjects. Biochem Biophys Res Commun 231(3):570–572
Poling JS, Frye RE, Shoffner J, Zimmerman AW (2006) Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol 21(2):170–172
Rajkovic M, Middendorff R, Wetzel MG et al (2004) Germ cell nuclear factor relieves cAMP-response element modulator tau-mediated activation of the testis-specific promoter of human mitochondrial glycerol-3-phosphate dehydrogenase. J Biol Chem 279(50):52493–52499
Ramoz N, Reichert JG, Smith CJ et al (2004) Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism. Am J Psychiatry 161(4):662–669
Rustin P, Chretien D, Bourgeron T et al (1994) Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta 228(1):35–51 (Review)
Schopler E, Reichler RJ, DeVellis RF, Daly K (1980) Toward objective classification of childhood autism: Childhood Autism Rating Scale (CARS). J Autism Dev Disord 10:91–103
Sladek R, Rocheleau G, Rung J et al (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445(7130):881–885
Sparrow SS, Balla DA, Cicchetti DV (1985) Vineland adaptative behaviour scales: classroom edition. American Guidance Service, Circle Pines
Stork C, Renshaw PF (2005) Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research. Mol Psychiatry 10(10):900–919 (Review)
Tommerup N (1993) Mendelian cytogenetics. Chromosome rearrangements associated with Mendelian disorders. J Med Genet 30(9):713–727 (Review)
Warburton D (1991) De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. Am J Hum Genet 49(5):995–1013
Wells WW, Xu DP, Washburn MP, Cirrito HK, Olson LK (2001) Polyhydroxybenzoates inhibit ascorbic acid activation of mitochondrial glycerol-3-phosphate dehydrogenase: implications for glucose metabolism and insulin secretion. J Biol Chem 276(4):2404–2410
Wirth J, Nothwang HG, van der Maarel S et al (1999) Systematic characterisation of disease associated balanced chromosome rearrangements by FISH: cytogenetically and genetically anchored YACs identify microdeletions and candidate regions for mental retardation genes. J Med Genet 36(4):271–278
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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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
- Breakpoint Region
- Derivative Chromosome
- Denature High Performance Liquid Chromatography
- GPD2 Gene
- Balance Reciprocal Translocation