Linking genetics to epigenetics: The role of folate and folate-related pathways in neurodevelopmental disorders.

There is growing evidence that epigenetic dysregulation plays a role in neurodevelopmental disorders. In humans, folate is one of the main donors of the methyl group required for the synthesis of S-adenosylmethionine, which in turn is needed for DNA and histone methylation as key neurodevelopment processes. Folate deficiency during pregnancy has been correlated with neural tube defects and with a higher incidence of neurocognitive and/or neurobehavioral deficits. A similar outcome may be exerted by gene polymorphisms in folate or folate-related pathways. This has been documented by numerous case/control association studies performed on neurodevelopmental disorders such as autism spectrum disorder and attention deficit hyperactivity disorder. In this regard, the folate cycle represents a "perfect model" of how genetics influences epigenetics. Gene variants in folate and folate-related pathways can be considered risk factors for neurodevelopmental disorders and should therefore be assessed by genetic testing in pregnant women. High-risk women should be considered for folate supplementation during pregnancy. Here, we review all published case/control association studies on gene polymorphisms in folate and folate-related pathways performed on neurodevelopmental disorders, provide an overview of neurodevelopment and DNA methylation changes occurring at this time, and describe the biological basis of neurodevelopmental disorders and recent evidence of their epigenetic dysregulation.

Unraveling molecular pathways shared by Kabuki and Kabuki-like syndromes.

Kabuki syndrome (KS) is a rare genetic syndrome characterized by a typical facial gestalt, variable degrees of intellectual disability, organ malformations, postnatal growth retardation and skeletal abnormalities. So far, KMT2D or KDM6A mutation has been identified as the main cause of KS, accounting for 56%-75% and 3%-8% of cases, respectively. Patients without mutations in 1 of the 2 causative KS genes are often referred to as affected by Kabuki-like syndrome. Overall, they represent approximately 30% of KS cases, pointing toward substantial genetic heterogeneity for this condition. Here, we review all currently available literature describing KS-like phenotypes (or phenocopies) associated with genetic variants located in loci different from KMT2D and KDM6A . We also report on a new KS phenocopy harboring a 5 Mb de novo deletion in chr10p11.22-11.21. An enrichment analysis aimed at identifying functional Gene Ontology classes shared by the 2 known KS causative genes and by new candidate genes currently associated with KS-like phenotypes primarily converges upon abnormal chromatin remodeling and transcriptional dysregulation as pivotal to the pathophysiology of KS phenotypic hallmarks. The identification of mutations in genes belonging to the same functional pathways of KMT2D and KDM6A can help design molecular screenings targeted to KS-like phenotypes.

Autistic phenotypes and genetic testing: state-of-the-art for the clinical geneticist.

Autism spectrum disorders represent a group of developmental disorders with strong genetic underpinnings. Several cytogenetic abnormalities or de novo mutations able to cause autism have recently been uncovered. In this study, the literature was reviewed to highlight genotype-phenotype correlations between causal gene mutations or cytogenetic abnormalities and behavioural or morphological phenotypes. Based on this information, a set of practical guidelines is proposed to help clinical geneticists pursue targeted genetic testing for patients with autism whose clinical phenotype is suggestive of a specific genetic or genomic aetiology.

Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression.

Protein kinase C enzymes play an important role in signal transduction, regulation of gene expression and control of cell division and differentiation. The fsI and betaII isoenzymes result from the alternative splicing of the PKCbeta gene (PRKCB1), previously found to be associated with autism. We performed a family-based association study in 229 simplex and 5 multiplex families, and a postmortem study of PRKCB1 gene expression in temporocortical gray matter (BA41/42) of 11 autistic patients and controls. PRKCB1 gene haplotypes are significantly associated with autism (P<0.05) and have the autistic endophenotype of enhanced oligopeptiduria (P<0.05). Temporocortical PRKCB1 gene expression was reduced on average by 35 and 31% for the PRKCB1-1 and PRKCB1-2 isoforms (P<0.01 and <0.05, respectively) according to qPCR. Protein amounts measured for the PKCbetaII isoform were similarly decreased by 35% (P=0.05). Decreased gene expression characterized patients carrying the 'normal' PRKCB1 alleles, whereas patients homozygous for the autism-associated alleles displayed mRNA levels comparable to those of controls. Whole genome expression analysis unveiled a partial disruption in the coordinated expression of PKCbeta-driven genes, including several cytokines. These results confirm the association between autism and PRKCB1 gene variants, point toward PKCbeta roles in altered epithelial permeability, demonstrate a significant downregulation of brain PRKCB1 gene expression in autism and suggest that it could represent a compensatory adjustment aimed at limiting an ongoing dysreactive immune process. Altogether, these data underscore potential PKCbeta roles in autism pathogenesis and spur interest in the identification and functional characterization of PRKCB1 gene variants conferring autism vulnerability.

Genetic variation of the european eel (Anguilla anguilla)

The genetic population structure of the European eel Anguilla anguilla L. was investigated by sequencing the mitochondrial D-loop region of 55 eels caught at different European locations. In total, 51 haplotypes were identified. Pairwise genetic distances ranged from 0% to 6.33% with an average value +/- SD of 3.01% +/- 1.18%, indicating little DNA differentiation among the European eel population. None of the node bifurcations of the neighbor-joining phylogenetic tree was strongly supported, suggesting that all European eels derive from a common genetic pool. The same result was obtained by a statistical test that confirmed the absence of geographic subdivision in the genotypes of the European eel population. The reported genetic homogeneity of the European eel is discussed in relation to different hypothetical life history scenarios.

1H and 23Na NMR relaxation times study of pectin solutions and gels.

1H and 23Na longitudinal and transverse relaxation times have been measured to examine the concentration dependence of the dynamic behaviour of pectin solutions and gels. T1 and T2 relaxation times were measured in HDE pectin solutions and gels prepared with different cosolutes. A lowering of T1 and T2 values was observed in relation to a better efficiency of the intermolecular forces between polymer molecules and/or the formation of more extended junction zones. The T1/T2 ratio was also exploited indicating that even bulk water experiences anisotropic motions due to the gel formation. A correspondence of NMR results with previous reported data of rheological measurements of pectin gels prepared with the same cosolutes was found.

Effect of cooking on availability and in vitro nitrosation of precursors of volatile N-nitroso compounds in seafood.

Aqueous extracts of uncooked and cooked samples of squid and shrimp, characterized by their high amine content, were exposed to nitrate. The samples were cooked following traditional Italian recipes: stewing, grilling and deep-frying for squid; boiling, grilling and deep-frying for shrimp. Incubation of the aqueous extracts with nitrite in acidic medium yielded appreciable amounts of N-nitrosodimethylamine. Ascorbic acid and alpha-tocopherol were effective in preventing nitrosation of seafood amines only in the presence of molar excesses of these vitamins. An attempt at modulating nitrosation through the use of food ingredients naturally rich in vitamin C was unsuccessful.

Soluble and insoluble dietary fibre in diabetic diets.

The possibility of modulating postprandial metabolic responses in diabetics by an increase in the amount of soluble fibre rather than by the use of the high amounts of total dietary fibre (DF), so far strongly advocated, was investigated. Soluble and insoluble DF components of common foodstuffs were analysed and the data utilized to formulate three different meals with similar quantities of available carbohydrate, protein and fat and differing only in the quantity and quality of DF: low fibre (LF), high soluble fibre (HSF) and high insoluble fibre (HIF). Ten NIDDM patients in good metabolic control received each test meal in randomized order at 2-week intervals. The postprandial blood glucose and serum insulin responses to the LF and HIF test meals were similar. The HSF meal produced significantly lower glucose (P less than 0.001) and insulin (P less than 0.05) responses, compared to either LF or HIF meals. Such results may be of relevance in the formulation of diabetic diets in order to prevent an excess of insoluble fibre, so improving patients' compliance. Fruits and vegetables may be used advantageously to increase quantities of soluble fibre, limiting excesses of legumes or guar additives.

Food fiber choices for diabetic diets.

The use of dietary fiber (DF) in the diet of diabetics, although recommended, is often prevented by a limited tolerance and/or by the high cost and unpalatability of fiber supplements. Knowing that only or mainly the water soluble fraction of DF is effective in modulating postprandial hyperglycemia, the DF content (soluble, insoluble, and total) of a variety of common foodstuffs was determined. Such data were then utilized in the formulation of two complete meals, isocaloric and isoglucidic, characterized by a high-soluble, low-soluble, and total fiber content. The meals were administered to 13 NIDDM patients in good metabolic control. The data confirmed a significant reduction (p less than 0.001) of postprandial hyperglycemia and a moderate less significant reduction of insulinemia after the high fiber meal.

Occurrence and distribution of n-alkanes in sucking-calf tissues.

Samples of subcutaneous and perirenal fat, muscle, heart, liver, kidney, and spleen from eleven 4-month-old sucking calves were analyzed for their hydrocarbon composition. Qualitative and quantitative determinations were carried out by gas chromatography. Ranges of total hydrocarbons and odd-even hydrocarbon distribution for each tissues are reported. In general, a predominance of odd-numbered hydrocarbons in the high carbon number range was observed. As compared to adult bovines, calf tissues, with the exception of adipose tissues, show higher amounts of total hydrocarbons.

Potassium nitrate and nitrosamine formation.

The influence of potassium nitrate on the formation of nitrosamines in salami was studied. Samples of salami were prepared, with and without the addition of potassium nitrate. Under the conditions of the experiment, potassium nitrate did not represent a source of either nitrite or nitrosamines. Independently of the presence of potassium nitrate in the sample formulation, the growth of bacterial flora reached a maximum in the first 20 days of the ripening process.