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

Abstract

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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“…Mitochondrial abnormalities have been reported in individuals with schizophrenia, bipolar disorder and major depressive disorder [37,38,39]. Although previous studies have implicated DISC1 in mitochondrial function in neurons [40,41], our findings in astrocytes are new.…”

Mir-132/212 is required for maturation of binocular matching of orientation preference and depth perception

“…63) and Gpd2 (ref. 64). Since many neurodevelopmental disorders including autism are related to alterations of neuronal connectivity and synaptic plasticity, miR-132 dysregulation and subsequent abnormal expression of miR-132 target genes could contribute to some pathological traits present in these diseases.…”

Examination of bioenergetic function in the inner mitochondrial membrane peptidase 2-like (Immp2l) mutant mice

“…http://www.mitomap.org, 2013). GPD2 haploinsufficiency was described in a patient with nonsyndromic mental retardation, but whether GPD2 was the cause is unclear [36]. However, conditional knockout of a gene coding for the Rieske iron–sulfur protein (a complex III subunit) in mice causes oxidative stress in the brain [37], confirming that perturbance of complex III can cause oxidative stress.…”