title: The GLO1 C332 (Ala111) allele confers autism vulnerability: family-based genetic association and functional correlates.
abstract: Glyoxalase I (GLO1) is a homodimeric Zn(2+)-dependent isomerase involved in the detoxification of methylglyoxal and in limiting the formation of advanced glycation end-products (AGE). We previously found the rs4746 A332 (Glu111) allele of the GLO1 gene, which encodes for glyoxalase I, associated with "unaffected sibling" status in families with one or more children affected by Autism Spectrum Disorder (ASD). To identify and characterize this protective allele, we sequenced GLO1 exons and exon-intron junctions, detecting two additional SNPs (rs1049346, rs1130534) in linkage disequilibrium with rs4746. A family-based association study involving 385 simplex and 20 multiplex Italian families yielded a significant association with autism driven only by the rs4746 C332 (Ala111) allele itself (P < 0.05 and P < 0.001 under additive and dominant/recessive models, respectively). Glyoxalase enzymatic activity was significantly reduced both in leukocytes and in post-mortem temporocortical tissue (N = 38 and 13, respectively) of typically developing C332 allele carriers (P < 0.05 and <0.01), with no difference in Glo1 protein levels. Conversely, AGE amounts were significantly higher in the same C332 post-mortem brains (P = 0.001), with a strong negative correlation between glyoxalase activity and AGE levels (τ = -0.588, P < 0.01). Instead, 19 autistic brains show a dysregulation of the glyoxalase-AGE axis (τ = -0.209, P = 0.260), with significant blunting of glyoxalase activity and AGE amounts compared to controls (P < 0.05), and loss of rs4746 genotype effects. In summary, the GLO1 C332 (Ala111) allele confers autism vulnerability by reducing brain glyoxalase activity and enhancing AGE formation, but years after an autism diagnosis the glyoxalase-AGE axis appears profoundly disrupted, with loss of C332 allelic effects.
authors.affiliation: Unit of Child and Adolescent NeuroPsychiatry, Laboratory of Molecular Psychiatry and Neurogenetics, University "Campus Bio-Medico", Rome, Italy; Department of Experimental Neurosciences, I.R.C.C.S. "Fondazione Santa Lucia", Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Gabriele
authors.affiliation: Unit of Child and Adolescent NeuroPsychiatry, Laboratory of Molecular Psychiatry and Neurogenetics, University "Campus Bio-Medico", Rome, Italy; Department of Experimental Neurosciences, I.R.C.C.S. "Fondazione Santa Lucia", Rome, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Lombardi
authors.affiliation: Unit of Child and Adolescent NeuroPsychiatry, Laboratory of Molecular Psychiatry and Neurogenetics, University "Campus Bio-Medico", Rome, Italy; Department of Experimental Neurosciences, I.R.C.C.S. "Fondazione Santa Lucia", Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Sacco
authors.affiliation: Unit of Child and Adolescent NeuroPsychiatry, Laboratory of Molecular Psychiatry and Neurogenetics, University "Campus Bio-Medico", Rome, Italy; Department of Experimental Neurosciences, I.R.C.C.S. "Fondazione Santa Lucia", Rome, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Napolioni
authors.affiliation: Unit of Child and Adolescent NeuroPsychiatry, Laboratory of Molecular Psychiatry and Neurogenetics, University "Campus Bio-Medico", Rome, Italy; Department of Experimental Neurosciences, I.R.C.C.S. "Fondazione Santa Lucia", Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Altieri
authors.affiliation: Hematology Transfusion Medicine, University "Campus Bio-Medico", Rome, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Tirindelli
authors.affiliation: Hematology Transfusion Medicine, University "Campus Bio-Medico", Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Gregorj
authors.affiliation: Department of Translational Medical Science, University "Federico II", Naples, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Bravaccio
authors.affiliation: IntegraGen SA, Genopole, Evry, France.
authors.forename: Francis
authors.initials: F
authors.lastname: Rousseau
authors.affiliation: Unit of Child and Adolescent NeuroPsychiatry, Laboratory of Molecular Psychiatry and Neurogenetics, University "Campus Bio-Medico", Rome, Italy; Department of Experimental Neurosciences, I.R.C.C.S. "Fondazione Santa Lucia", Rome, Italy; Mafalda Luce Center for Pervasive Developmental Disorders, Milan, Italy. Electronic address: a.persico@unicampus.it.
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Persico
mesh_terms: D000293:Adolescent; D000328:Adult; D000409:Alanine / Q000235:genetics; D001921:Brain / Q000473:pathology; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000473:pathology; D002675:Child, Preschool; D005192:Family Health; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D017127:Glycation End Products, Advanced; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000235:genetics* / Q000378:metabolism; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012701:Serotonin / Q000097:blood / Q000652:urine; D013223:Statistics as Topic; D055815:Young Adult
chemical_list: D017127:Glycation End Products, Advanced; D012701:Serotonin; C000597196:GLO1 protein, human; D007791:Lactoylglutathione Lyase; D000409:Alanine
keywords: Advanced glycation end-products; Autism; Autism spectrum disorder; Glyoxalase; Methylglyoxal; Pervasive developmental disorders