Haploinsufficiency of the GPD2 gene in a patient with nonsyndromic mental retardation.
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.
Daoud
Hussein
H
Faculté de Médecine, INSERM U930, Université François Rabelais, Tours, France. daoud_h@med.univ-tours.fr
Gruchy
Nicolas
N
Constans
Jean-Marc
JM
Moussaoui
Edgar
E
Saumureau
Simone
S
Bayou
Nadia
N
Amy
Maïté
M
Védrine
Sylviane
S
Vu
Phi Yen
PY
Rötig
Agnès
A
Laumonnier
Frédéric
F
Vourc'h
Patrick
P
Andres
Christian R
CR
Leporrier
Nathalie
N
Briault
Sylvain
S
D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002648:Child; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D053960:DNA Breaks; D017931:DNA Primers / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005993:Glycerolphosphate Dehydrogenase / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008607:Intellectual Disability / Q000201:enzymology* / Q000235:genetics*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014178:Translocation, Genetic
D017931:DNA Primers; D012333:RNA, Messenger; D005993:Glycerolphosphate Dehydrogenase