1. Kovacs T, Kelemen O, Keri S. {{Decreased fragile X mental retardation protein (FMRP) is associated with lower IQ and earlier illness onset in patients with schizophrenia}}. {Psychiatry Res}. 2013; 210(3): 690-3.
The purpose of this study was to investigate Fragile X Syndrome (FXS)-related mechanisms in schizophrenia, including CGG triplet expansion, FMR1 mRNA, and fragile X mental retardation protein (FMRP) levels in lymphocytes. We investigated 36 patients with schizophrenia and 30 healthy controls using Southern blot analysis, mRNA assay, and enzyme-linked immunosorbent assay (ELISA). General intellectual functions were assessed with the Wechsler Adult Intelligence Scale-III, and the clinical symptoms were evaluated with the Positive and Negative Syndrome Scale. Results revealed that, relative to healthy controls, CGG triplet size and FMR1 mRNA were unaltered in patients with schizophrenia. However, the FMRP level was significantly reduced in patients compared with controls. We found an association between lower FMRP levels, reduced IQ, and earlier illness onset in schizophrenia. Chlorpromazine-equivalent antipsychotic dose did not correlate with FMRP levels. These results raise the possibility of impaired translation of FMR1 mRNA, altered epigenetic regulation, or increased degradation of FMRP in schizophrenia, which may play a role in dysfunctional neurodevelopmental processes and impaired neuroplasticity.
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2. Lionel AC, Tammimies K, Vaags AK, Rosenfeld JA, Ahn JW, Merico D, Noor A, Runke CK, Pillalamarri VK, Carter MT, Gazzellone MJ, Thiruvahindrapuram B, Fagerberg C, Laulund LW, Pellecchia G, Lamoureux S, Deshpande C, Clayton-Smith J, White AC, Leather S, Trounce J, Bedford HM, Hatchwell E, Eis PS, Yuen RK, Walker S, Uddin M, Geraghty MT, Nikkel SM, Tomiak EM, Fernandez BA, Soreni N, Crosbie J, Arnold PD, Schachar RJ, Roberts W, Paterson AD, So J, Szatmari P, Chrysler C, Woodbury-Smith M, Lowry RB, Zwaigenbaum L, Mandyam D, Wei J, Macdonald JR, Howe JL, Nalpathamkalam T, Wang Z, Tolson D, Cobb DS, Wilks TM, Sorensen MJ, Bader PI, An Y, Wu BL, Musumeci SA, Romano C, Postorivo D, Nardone AM, Della Monica M, Scarano G, Zoccante L, Novara F, Zuffardi O, Ciccone R, Antona V, Carella M, Zelante L, Cavalli P, Poggiani C, Cavallari U, Argiropoulos B, Chernos J, Brasch-Andersen C, Speevak M, Fichera M, Ogilvie CM, Shen Y, Hodge JC, Talkowski ME, Stavropoulos DJ, Marshall CR, Scherer SW. {{Disruption of the ASTN2 / TRIM32 locus at 9q33.1 is a risk factor in males for Autism Spectrum Disorders, ADHD and other neurodevelopmental phenotypes}}. {Hum Mol Genet}. 2013.
Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders. The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89,985 individuals across 10 sites, including 64,114 neurodevelopmental disorder subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3′ terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the neurodevelopmental disorder subjects (p=0.002) compared with 44,085 population-based controls. Frequent phenotypes observed in individuals with such deletions included Autism Spectrum Disorders (ASD), Attention Deficit Hyperactivity Disorder (ADHD), speech delay, anxiety and Obsessive Compulsive Disorder (OCD). The 3′-terminal ASTN2 deletions were significantly enriched compared with controls in males with neurodevelopmental disorders, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3′ end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.
