Dottorato in BIOLOGIA UMANA E GENETICA MEDICA

Titolo della tesi: D-aspartate oxidase gene duplication is associated with cortical neuroanatomical alterations and intellectual disabilities

D-aspartate oxidase (DDO) gene encodes for the enzyme responsible for the catabolism of D-aspartate (D-Asp), an atypical amino acid that is highly enriched in the embryonic mammalian cortex and stimulates glutamatergic NMDA and mGlu5 receptors. Previous studies in animal models and humans linked D-Asp and DDO alterations to schizophrenia. Moreover, in a recent work it has been demonstrated an alteration of Ddo gene expression in the prefrontal cortex, hippocampus and serum of animal model of idiopathic Autism Spectrum Disorder (ASD). The aim of this thesis is to investigate the still unknown role of DDO on D-aspartate metabolism in both mouse and human brain. In particular, to clarify this enigmatic issue, we generated a knockin mouse model in which the expression of Ddo begins from the zygotic stage and then evaluated the consequences of DDO-mediated embryonic D-Asp removal on a series of neurochemical, neuroanatomical, morphological, functional and behavioral phenotypes at adulthood. Next, we translated our study from mouse to human. We found a clinical case of a patient with a severe intellectual disability and ASD-related symptoms, harbouring a duplication in the 6q21 chromosomal region that includes the entire DDO gene. Further genetic analysis by exome sequencing on the proband and her parents did not highlight additional possible causative mutations. HPLC analysis of the patient’s serum showed that DDO gene duplication reduced the ratio of D-aspartate versus total aspartate as compared to sex- and age-matched controls. In conclusion, the patient’s neuropsychiatric profile combined with the cortical abnormalities observed in the mouse model highlight a key role for DDO and D-Asp metabolism in the regulation of neurodevelopmental processes associated with early glutamatergic transmission.