@article {10419, title = {Genetic profile of patients with early onset inflammatory bowel disease.}, journal = {Gene}, volume = {645}, year = {2018}, month = {2018 Mar 01}, pages = {18-29}, abstract = {

Inflammatory Bowel disease (IBD) is a widespread pathological condition with clinical heterogeneity and with different levels of severity. Although IBD usually occurs in young adults, onset in childhood and infancy are described in patients within the 10th and second year of age. By genome-wide association studies and meta-analysis, several genetic loci have been identified associated with an increased risk of developing IBD in Western populations with variants that may alter the normal mucosal immunity in the gastrointestinal tract. The clinical complexity and the heterogeneity of the IBD phenotype probably reflect the presence of genetic heterogeneity where different genes or combinations of them may be involved, together with environmental factors. We hypothesized that patients with early onset IBD could have either more severe genetic variants in genes associated with IBD or multiple variants in different genes. Under the multifactorial diseases is crucial to consider the small contribution of a single variant in all not only to other small variations in the same gene but also in different genes belonging to the same pathway. We performed direct gene sequencing looking for 94 variations in NOD2, ATG16L1, IL23R, IL10R, IL10 and XIAP genes previously shown as correlated with IBD both in multifactorial and in Mendelian models. All variants identified are known in literature as being associated with IBD except for three variants in the genes NOD2, IL10 and IL10RB that even though present in online databases have never been involved in association studies on IBD patients. Moreover, we coupled genetic variants identification with an accurate "in silico" analysis to verify their predictive impact on the protein structure and function. The in-silico prediction of these variants results as benign therefore even if they exhibit a very low frequency in control population being benign, they cannot be considered pathogenic as monogenic disease but fall within the multifactorial range. The variants identified in our study partially reflect the association data described in the literature but there are no significant differences with the onset of disease (VEO vs EO-IBD).

}, keywords = {Age of Onset, Autophagy-Related Proteins, Child, Child, Preschool, Computer Simulation, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Infant, Inflammatory Bowel Diseases, Interleukin-10, Male, Nod2 Signaling Adaptor Protein, Polymorphism, Single Nucleotide, Receptors, Interleukin, Receptors, Interleukin-10, Sequence Analysis, DNA, X-Linked Inhibitor of Apoptosis Protein}, issn = {1879-0038}, doi = {10.1016/j.gene.2017.12.029}, author = {Girardelli, Martina and Basaldella, Federica and Paolera, Sara Della and Vuch, Josef and Tommasini, Alberto and Martelossi, Stefano and Crovella, Sergio and Bianco, Anna Monica} } @article {8323, title = {Geranylgeraniol and Neurological Impairment: Involvement of Apoptosis and Mitochondrial Morphology.}, journal = {Int J Mol Sci}, volume = {17}, year = {2016}, month = {2016}, pages = {365}, abstract = {

Deregulation of the cholesterol pathway is an anomaly observed in human diseases, many of which have in common neurological involvement and unknown pathogenesis. In this study we have used Mevalonate Kinase Deficiency (MKD) as a disease-model in order to investigate the link between the deregulation of the mevalonate pathway and the consequent neurodegeneration. The blocking of the mevalonate pathway in a neuronal cell line (Daoy), using statins or mevalonate, induced an increase in the expression of the inflammasome gene (NLRP3) and programmed cell death related to mitochondrial dysfunction. The morphology of the mitochondria changed, clearly showing the damage induced by oxidative stress and the decreased membrane potential associated with the alterations of the mitochondrial function. The co-administration of geranylgeraniol (GGOH) reduced the inflammatory marker and the damage of the mitochondria, maintaining its shape and components. Our data allow us to speculate about the mechanism by which isoprenoids are able to rescue the inflammatory marker in neuronal cells, independently from the block of the mevalonate pathway, and about the fact that cell death is mitochondria-related.

}, issn = {1422-0067}, doi = {10.3390/ijms17030365}, author = {Marcuzzi, Annalisa and Piscianz, Elisa and Zweyer, Marina and Bortul, Roberta and Loganes, Claudia and Girardelli, Martina and Baj, Gabriele and Monasta, Lorenzo and Celeghini, Claudio} } @article {8083, title = {Genetics of inflammatory bowel disease from multifactorial to monogenic forms.}, journal = {World J Gastroenterol}, volume = {21}, year = {2015}, month = {2015 Nov 21}, pages = {12296-310}, abstract = {

Inflammatory bowel disease (IBD) is a group of chronic multifactorial disorders. According to a recent study, the number of IBD association loci is increased to 201, of which 37 and 27 loci contribute specifically to the development of Crohn{\textquoteright}s disease and ulcerative colitis respectively. Some IBD associated genes are involved in innate immunity, in the autophagy and in the inflammatory response such as NOD2, ATG16L1 and IL23R, while other are implicated in immune mediated disease (STAT3) and in susceptibility to mycobacterium infection (IL12B). In case of early onset of IBD (VEO-IBD) within the 6(th) year of age, the disease may be caused by mutations in genes responsible for severe monogenic disorders such as the primary immunodeficiency diseases. In this review we discuss how these monogenic disorders through different immune mechanisms can similarly be responsible of VEO-IBD phenotype. Moreover we would highlight how the identification of pathogenic genes by Next Generation Sequencing technologies can allow to obtain a rapid diagnosis and to apply specific therapies.

}, issn = {2219-2840}, doi = {10.3748/wjg.v21.i43.12296}, author = {Bianco, Anna Monica and Girardelli, Martina and Tommasini, Alberto} }