GTP-cyclohydrolase I (GTP-CH1, EC 3.5.4.16) is encoded by the GCH1 gene. Mutations in the GCH1 gene cause both dopa-responsive dystonia (McKusick 128230) and recessive GTP-CH1 deficiency (McKusick 600225). The exact molecular mechanism resulting in decreased GTP-CH1 activity in the patients is still obscure. We report the clinical features and molecular and functional study of the GCH1 gene in eight Italian patients affected by dominant and recessive GTP-CH1 deficiency. All the studied patients had mutations in the GCH1 gene. Three missense mutations (V205G, K224R, P199A), a frameshift mutation (Delta G693), and a splice-site mutation (ivs5 + 1g > c) were found. Except for K224R these are all novel mutations. To analyse the defect caused by the novel mutations, an in vivo functional assay in a Saccharomyces cerevisiae strain lacking the endogenous gene encoding GTP-CH1 ( FOL2 ) was performed. Complementation analysis showed that the Delta G693 and V205G mutations abolish the enzymatic function, while the P199A mutation causes a conditional defect. In conclusion, the clinical phenotypes displayed by our patients confirm the wide clinical spectrum of the disease and further support the lack of correlation between a given mutation and a clinical phenotype. Complementation analysis in yeast is a useful tool for confirming the pathogenetic effect of GCH1 mutations.

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The yeast SDA1 gene was reported to play a critical role in G 1 events and to be involved in 60S ribosome biogenesis. Although the basic cellular mechanisms appear conserved from yeast to man, the human genes may have more diversified functions. In this view we obtained the first experimental evidences about the human ortholog of the yeast SDA1, i.e., hSDA. The gene is localized at the chromosomal region 4q21 and encodes for a 627a.a. long protein highly homologous to the yeast Sda1. Subcellular localization experiments indicate that the human protein behaves similarly to nucleolar proteins involved in rRNA processing machinery but not in RNA PolI transcriptional events. hSda appears localized in the granular component of the nucleolus and in the nucleoplasm, which is consistent with a role in early-intermediate steps of ribosome biogenesis. hSDA appears preferentially expressed in fetal tissues, pinpointing its role during development. Different expression levels in different tumor cell lines might suggest that the gene is involved also in tumorigenesis. However our preliminary results indicate that hSDA does not behave like a proapoptotic gene and its involvement in tumorigenesis is still to be clarified.

Sda1 is an essential protein required for cell cycle progression in Saccharomyces cerevisiae. Here, we show that the sda1-1 mutation causes a defect in the formation and nuclear export of 60S ribosomal subunits. Moreover, the sda1-1, but also other mutants defective in ribosome biogenesis (e.g., rix1-1 and tif6∆), exhibit a G 1 arrest, which could be the consequence of impaired ribosome biogenesis. Interestingly, additional deletion of the non-essential Swe1 kinase, the homolog of S. pombe Wee1, causes a pronounced delay in entering a new cell cycle in sda1-1, rix1-1 and tif6∆ cells, when shifted back from restrictive to permissive conditions. However, such a prolonged delay is independent of the Tyr19 phosphorylation in Cdc28. Moreover, the lack of Swe1 causes delay in budding and DNA replication in cells released from the G 1 arrest due to the block of protein synthesis. Our data suggest that Swe1 is required for timely entry into cell cycle after a G 1 arrest caused by impairment in pre-60S biogenesis and in protein synthesis. Therefore we propose that Swe1, which is required for coordination of cell growth and cell division in G 2 /M, also has a role in the beginning of the cell cycle.

Embodied cognition theories suggest that observation of facial expression induces the same pattern of muscle activation, and that this contributes to emotion recognition. Consequently, the inability to form facial expressions would affect emotional understanding. Patients with schizophrenia show a reduced ability to express and perceive facial emotions. We assumed that a physical training specifically developed to mobilize facial muscles could improve the ability to perform facial movements, and, consequently, spontaneous mimicry and facial expression recognition. Twenty-four inpatient participants with schizophrenia were randomly assigned to the experimental and control group. At the beginning and at the end of the study, both groups were submitted to a facial expression categorization test and their data compared. The experimental group underwent a training period during which the lip muscles, and the muscles around the eyes were mobilized through the execution of transitive actions. Participants were trained three times a week for five weeks. Results showed a positive impact of the physical training in the recognition of others’ facial emotions, specifically for the responses of “fear”, the emotion for which the recognition deficit in the test is most severe. This evidence suggests that a specific deficit of the sensorimotor system may result in a specific cognitive deficit.